Epival: Indications, Dosage, Precautions, Adverse Effects
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Epival - Product Information

Manufacture: Abbott Laboratories
Country: Canada
Condition: Epilepsy
Class: Anticonvulsants
Form: Tablets
Ingredients: sodium alginate, microcrystalline cellulose, povidone, magnesium stearate, hypromellose, macrogol 400, macrogol 6000, talc, titanium dioxide (171), iron oxide red, glycol butylene glycol montanate

Summary Product Information

Route of
Administration
Dosage
Form/Strength
Non-medicinal Ingredients
oral enteric-coated tablets /
125 mg
diacetylated monoglycerides, FD&C Red No. 40, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide, and vanillin.
250 mg diacetylated monoglycerides, FD&C Yellow No. 6, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide and vanillin.
500 mg diacetylated monoglycerides, FD&C Blue No. 2, FD&C Red No. 30, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide and vanillin.

Indications and Clinical Use

EPIVAL (divalproex sodium) enteric-coated tablets is indicated for:

Epilepsy

  • use as sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal, and is useful in primary generalized seizures with tonic-clonic manifestations.
  • use adjunctively in patients with multiple seizure types which include either absence or tonic clonic seizures.

In accordance with the International Classification of Seizures, simple absence is defined as a very brief clouding of the sensorium or loss of consciousness (lasting usually 2 to 15 seconds), accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

Acute Mania

  • the treatment of the manic episodes associated with bipolar disorder (DSM-III-R).

The safety and effectiveness of EPIVAL for long-term use in mania, that is for more than 3 weeks, has not been evaluated in controlled trials.

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

See CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity for statement regarding serious or fatal hepatic dysfunction.

Geriatrics (≥65 Years of Age)

The safety and efficacy of EPIVAL in elderly patients with epilepsy or 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 EPIVAL in this population. For a brief discussion, see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (65 years of age), DOSAGE AND ADMINISTRATION, Dosing in Elderly Patients and< ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics.

Pediatrics (< 18 Years of Age)

When EPIVAL is used in children under the age of 2 years, it should be used with extreme caution and as a sole agent. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. For a brief discussion, see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (< 18 years of age). The safety and effectiveness of EPIVAL for the treatment of acute mania has not been studied in individuals below the age of 18 years.

Contraindications

EPIVAL (divalproex sodium) enteric-coated tablets is contraindicated:

  • in patients with hepatic disease or significant hepatic dysfunction. See WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions, Hepatotoxicity and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity.
  • in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic.
  • in patients with known hypersensitivity to the drug, any ingredient in the formulation or component of the container. For a complete listing of ingredients, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
  • in patients with known urea cycle disorders. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Urea Cycle Disorders
  • in patients with known porphyria.

Warnings and Precautions

Serious Warnings and Precautions

  • Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving EPIVAL (divalproex sodium). These incidences usually occurred during the first 6 months of treatment with EPIVAL. Caution should be observed when administering EPIVAL 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 2 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 Hepatotoxicity.
  • Teratogenicity: EPIVAL can produce teratogenic effects such as neural tube defects (e.g., spina bifida) in a dose-dependent manner. 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. This is especially important when EPIVAL use is considered for a condition not usually associated with permanent injury or death. Women of childbearing potential should use an effective method of contraception during EPIVAL therapy. EPIVAL should only be used to treat pregnant women if other medications have failed to control their symptoms or are otherwise unacceptable. See WARNINGS AND PRECAUTIONS, Special Populations, Women of Childbearing Potential and WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.
  • Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). EPIVAL is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder. See CONTRAINDICATIONS. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, EPIVAL should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with EPIVAL for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Patients with Mitochondrial Disease.
  • Pancreatitis: Cases of life-threatening pancreatitis have been reported in both children and adults receiving EPIVAL. Patients and guardians should be warned that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that require prompt medical attention. If pancreatitis is diagnosed, EPIVAL should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated. 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 PRECAUTIONS, Hepatic/Biliary/Pancreatic, Pancreatitis.

General

Interaction With Carbapenem Antibiotics

Carbapenem antibiotics (ertapenem, imipenem, meropenem, doripenem) can reduce serum valproic acid concentrations to sub- therapeutic levels. This can result in loss of seizure control in epileptic patients or loss of efficacy in non-epileptics. In some cases of co-administration in epileptic patients, breakthrough seizures have occurred. Increasing valproic acid dose may not be sufficient to overcome this interaction. If co-administration is essential, serum valproic acid concentrations should be monitored daily after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.

Effects of Valproate on HIV and CMV Viruses Replication

There are in vitro studies that suggest valproate stimulates the replication of the Human Immunodeficiency Virus and Cytomegalovirus (HIV and CMV) viruses under certain experimental conditions. The clinical relevance of these in vitro data is unknown. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

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

EPIVAL (divalproex sodium) enteric-coated tablet is contraindicated in patients with known urea cycle disorders. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of EPIVAL in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. Prior to initiation of EPIVAL, evaluation for urea cycle disorders (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 blood urea nitrogen (BUN), protein avoidance;
  • those with a family history of UCD or a family history of unexplained infant deaths (particularly males);
  • those with other signs or symptoms of UCD. Patients receiving EPIVAL who develop symptoms of unexplained hyperammonemic encephalopathy should receive prompt treatment (including discontinuation of EPIVAL) 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 EPIVAL 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. Hyperammonemia should also be considered in patients who present with hypothermia. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypothermia. If serum ammonia is increased, EPIVAL 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 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 EPIVAL should be considered.

Hyperammonemia and Encephalopathy Associated With Concomitant Topiramate Use

Concomitant administration of topiramate and EPIVAL 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. Hypothermia can also be a manifestation of hyperammonemia. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypothermia. 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 EPIVAL may exacerbate existing defects or unmask deficiencies in susceptible persons. See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Urea Cycle Disorders and Hyperammonemia.

Hypothermia

Hypothermia, defined as an unintentional drop in core body temperature to < 35°C (95°F), has been reported in association with EPIVAL therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with EPIVAL after starting topiramate treatment or after increasing the daily dose of topiramate. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperammonemia, Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use and DRUG INTERACTIONS, Drug-Drug Interactions, Table2.

Hypothermia may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. Consideration should be given to stopping EPIVAL in patients who develop hypothermia. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperammonemia and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use.

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 EPIVAL 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 EPIVAL 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 ER (divalproex sodium extended-release tablets), in 44 epilepsy patients, indicate that the frequency of treatment-emergent mild thrombocytopenia (platelet count between 100 to150 x 109/L) was significantly higher after 12 weeks of treatment with EPIVAL ER than after 12 weeks of treatment with EPIVAL (7 versus 3 low counts, respectively).

Hepatic/Biliary/Pancreatic

Serious or Fatal Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving EPIVAL and its derivatives. These incidences usually occurred during the first 6 months of treatment with EPIVAL. Caution should be observed when administering EPIVAL 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 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. The risk in this age group decreased considerably in patients receiving EPIVAL as monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they received multiple anticonvulsants than those who received only EPIVAL. Above the age of 2 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 EPIVAL alone.

If EPIVAL is to be used for the control of seizures in children 2 years old or younger, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. See WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics (< 18 years of age).

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 EPIVAL.

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, EPIVAL 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.

Patients with Mitochondrial Disease

Valproate induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. See CONTRAINDICATIONS.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura. POLG mutation testing should be performed in accordance with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, EPIVAL should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with EPIVAL for the development of acute liver injury with regular clinical assessments and liver function test monitoring.

In the presence of significant hepatic dysfunction, suspected or apparent, EPIVAL should be discontinued and alternative therapy initiated. In some cases, hepatic dysfunction has progressed in spite of discontinuation of the drug. See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS.

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving EPIVAL. 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 EPIVAL. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2, 416 patients, representing 1, 044 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, EPIVAL should ordinarily be discontinued.

Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

Muscle Effects/Rhabdomyolysis

Rare cases of rhabdomyolysis, independent of neuroleptic malignant syndrome, have been reported to occur in patients treated with EPIVAL. Cases have included renal failure and fatalities.

Patients should be carefully monitored for muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever or tea-coloured urine. Blood creatine phosphokinase (CPK) levels should be assessed in patients experiencing these symptoms and EPIVAL therapy should be discontinued if markedly elevated CPK levels are measured or if the patient develops signs and symptoms indicative of rhabdomyolysis.

Caution should be exercised in prescribing EPIVAL to patients with predisposing/risk factors, including: prior history of muscular disorders such as CPT II deficiency (carnitine palmitoyltransferase type II); uncontrolled hypothyroidism; hepatic or renal impairment; concomitant medications that are known to be associated with rhabdomyolysis (eg statins, antipsychotics, diuretics, some antidepressants)

Neurologic

Brain Atrophy

There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy with neurological symptoms, in children, adults, and the elderly, receiving valproate therapy. A temporal relationship between valproate therapy and the development of cerebral atrophy and associated signs and symptoms was also demonstrated. In some cases, symptoms disappeared after valproate discontinuation but patients recovered with permanent sequelae. See ADVERSE REACTIONS. The motor and cognitive functions of patients on valproate should be routinely monitored and drug should be discontinued in the presence of suspected or apparent signs of brain atrophy.

Neurological Problems in Children After In-utero Exposure to Valproate

Reports of cerebral atrophy with various forms of neurological problems including developmental delays psychomotor impairment and decreased IQ scores have been reported in children who were exposed in-utero to valproate products. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.

Driving and Hazardous Occupations

EPIVAL may produce central nervous system (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 Behaviour and Ideation

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.

All patients treated with antiepileptic drugs (AEDs), irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

An FDA meta-analysis of randomized placebo controlled trials, in which AEDs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known.

There were 43, 892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indication the treatment (AED or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (AED or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more AED). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on AEDs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (AED or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking AEDs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct AED treatment in both arms.

Behavioural Disorders

There have been postmarketing reports of behavioural disorders, including aggression, agitation, abnormal behaviour, disturbance in attention, and learning disorders. Although patients of all ages were affected, including the elderly and those exposed to valproate products in-utero, a large number of cases were reported in children. There was no clear trend with respect to valproate dose. In some cases, patients improved or recovered following valproate discontinuation.

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 EPIVAL 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, EPIVAL 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 EPIVAL on testicular development and on sperm production and fertility in humans is unknown. See TOXICOLOGY, Reproduction and Teratology, Fertility for results in animal studies.

Skin

Serious Skin Reactions

The dose of lamotrigine should be reduced when co-administered with EPIVAL. Serious skin reactions (such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis) have been reported with concomitant lamotrigine and EPIVAL administration (see Lamotrigine Product Monograph for details on lamotrigine dosing with concomitant EPIVAL administration).

Special Populations

Women of Childbearing Potential

Because of the risk to the fetus of major congenital malformations (including neural tube defects) EPIVAL 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. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.

This is especially important when EPIVAL use is considered for a condition not usually associated with permanent injury or death.

Women of childbearing potential must use an effective method of contraception while using EPIVAL.

Pregnant Women

EPIVAL can cause fetal harm when administered to pregnant women. In comparison with some other antiepileptics drugs (AEDs), EPIVAL use during pregnancy is associated with an increased risk of severe birth defects such as neural tube defects (e.g., spina bifida), craniofacial defects, cleft palate, cardiovascular malformations, hypospadias, etc. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Birth Defects.

Since some of the congenital malformations occur in the first trimester of pregnancy before many women know that they are pregnant, all women of childbearing potential should be informed of the potential hazard to the fetus from exposure to EPIVAL.

If the decision is made to use EPIVAL, women who are not planning a pregnancy should be advised to use an effective method of contraception. If the woman is planning a pregnancy or becomes pregnant, risks of using EPIVAL should be thoroughly discussed with the patient, weighed against the potential benefits of treatment, and alternative therapeutic options should be considered for these patients.

Women who are pregnant or who plan to become pregnant should not be treated with EPIVAL unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with EPIVAL during pregnancy should be carefully weighed against the risk of malformation and other fetal abnormalities.

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 each 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/or during pregnancy, and alternative therapy considered, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Women of childbearing age should be encouraged to seek the counsel of their physician and should report a positive pregnancy test promptly. Where the necessity for continued use of antiepileptic medication is in doubt, appropriate consultation is indicated. Current best practice guidelines should be considered in order to provide the optimal counsel to patients regarding the teratogenic risks associated with EPIVAL

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

Pregnancy Registry

Pregnant patients taking EPIVAL should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://www.aedpregnancyregistry.org/.

Birth Defects

There are multiple reports in the clinical literature that indicate the use of antiepileptic drugs during pregnancy results in an increased incidence of birth defects in the offspring. 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 antiepileptic medications deliver normal infants.

The data described below were gained almost exclusively from women who received valproate to treat epilepsy. Data from Pregnancy Registries indicate an increased risk of congenital anomalies in infants exposed to EPIVAL monotherapy during the first trimester of pregnancy as compared to other antiepileptic drugs. Based on Pregnancy Registry data and the United States Centers for Disease Control (CDC), the estimated risk of valproate-exposed women having children with spina bifida, oral clefts, neural tube defects, and hypospadias is approximately 1 to 2% as compared to the risk of spina bifida in the general population which is about 0.06 to 0.07%.

In a study using NAAED Pregnancy Registry data, 16 cases of major malformations following prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included craniofacial defects, cardiovascular malformations and malformations of varying severity involving other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7% in the offspring of women exposed to valproate monotherapy during pregnancy (average daily dose: 1000 mg; range: 500 – 2000 mg/day) as compared to major malformation rate of 2.9% among 1, 048 epileptic women who received any other antiepileptic drug monotherapy during pregnancy. These data show a four-fold increased risk for any major malformation following valproate exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug monotherapy.

Data from a meta-analysis (including registries and cohort studies) has shown an increased incidence of congenital malformations in children born to epileptic women exposed to valproate monotherapy during pregnancy. Available data indicate dose-dependency of this effect.

Risk of Neurological Problems from In-Utero Exposure
Cerebral Atrophy

Exposure in-utero to valproate products has been associated with cerebral atrophy with varying degrees/manifestations of neurological compromise, including developmental delays and psychomotor impairment. See ADVERSE REACTIONS and WARNINGS AND PRECAUTIONS, Neurologic, Brain Atrophy.

Developmental Delay, Decreased IQ, Autism and/or Autism Spectrum Disorders

There have been post-marketing reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to EPIVALduring pregnancy.

Valproate can cause decreased IQ scores following in utero exposure in a dose-dependent fashion. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that in utero exposure to EPIVAL can cause decreased IQ in children.

Withdrawal Syndrome in the Neonate

Withdrawal syndrome (such as, in particular, agitation, irritability, hyperexcitability, jitteriness, hyperkinesia, tonicity disorders, tremor, convulsions and feeding disorders) may occur, in the days following birth, in neonates whose mothers have taken valproate during the last trimester of pregnancy.

Coagulation Abnormalities

There have been reported postmarketing cases of coagulation abnormalities in patients of all ages receiving valproate therapy. These include thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which can lead to bleeding and other complications, especially in the cases of decrease in factors VII, VIII and XIII. These abnormalities may not necessarily be dose-dependent. Some of the hemorrhage manifestations may include mucosal bleeding (e.g., menorrhagia, epistaxis, hematuria, melena), easy-bruising, soft-tissue hematoma, hemarthrosis, and intracranial hemorrhage. Caution should be taken in patients taking valproate and anticoagulants and in cases of injury or surgery to avoid life-threatening or fatal bleeding. See WARNINGS AND PRECAUTIONS, Hematologic, Thrombocytopenia.

Pregnant women taking EPIVAL may also develop coagulation abnormalities, which may result in hemorrhagic complications in the neonate including death. See WARNINGS AND PRECAUTIONS, Hematologic, Thrombocytopenia. If EPIVAL is used in pregnancy, the coagulation parameters should be monitored carefully.

Hepatic Failure

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

Hypoglycemia

Serious postmarketing reports of hypoglycaemia have been received for neonates whose mothers received EPIVAL treatment during pregnancy. In most cases, EPIVAL was the only reported antiepileptic drug (AED). Most of these neonates also displayed other congenital anomalies including hypospadias, complex facial dysmorphism, limb anomalies, severe cardiac anomalies, etc. Therefore, if a decision has been made to use EPIVAL 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.

Thyroid Gland Abnormalities

Cases of hypothyroidism have been reported in neonates whose mothers have taken valproate during pregnancy. There have also been reported cases of increased serum thyroid stimulating hormone or decreased serum thyroxine levels in children receiving valproate therapy. In addition, there have been reported cases of hypothyroidism and hyperthyroidism in adults and children receiving valproate monotherapy.

Teratogenicity in Animals

Animal studies have demonstrated valproic acid induced teratogenicity, see TOXICOLOGY, Reproduction and Teratology, 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

EPIVAL 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 EPIVAL. Based on literature and clinical experience, hematological disorders in the newborn may occur.

Pediatrics (< 18 years of age)

Experience has indicated that children under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity. 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. See Contraindications.

Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, EPIVAL should only be used after other anticonvulsants have failed. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Patients with Mitochondrial Disease.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. The variability in free fraction limits the clinical usefulness of monitoring total serum valproate concentrations. Interpretation of valproate concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

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

Geriatrics (≥ 65 years of age)

Alterations in the kinetics of unbound valproate in the elderly indicate that the initial dosage should be reduced in this population. See DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics.

The safety and efficacy of EPIVAL 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 EPIVAL in this population.

A study of elderly patients revealed valproate-related somnolence and discontinuation of EPIVAL for this adverse event. See WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics, 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.

Somnolence in the Elderly

In a group of elderly patients (mean age 83 years old, n = 172), EPIVAL 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 EPIVAL 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 EPIVAL 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

Protein binding of valproate is reduced in the elderly, in patients with renal impairment, and in the presence of other drugs (e.g., 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 WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperammonemia, WARNINGS AND PRECAUTIONS, Hematologic, Thrombocytopenia and DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.

Medication Residue

There have been rare reports of medication residue in the stool, some of which have occurred in the context of transient diarrhea or those with anatomic or functional gastrointestinal disorders with shortened transit time (e.g., ileostomy, colostomy, etc). It is recommended that patients with shortened gastrointestinal transit time be only given the immediate release formulation of valproate. Plasma valproate levels should be checked if a patient is experiencing uncontrolled and/or unexpected seizures. If clinically indicated, valproate should be gradually discontinued and alternative treatment considered.

Adverse Reactions

Adverse Drug Reaction Overview

Epilepsy

The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since EPIVAL (divalproex sodium) enteric- coated tablets has usually been used with other antiepileptics, it is not possible in most cases to determine whether the adverse reactions mentioned in this section are due to EPIVAL alone or to the combination of drugs.

Adverse events that have been reported with EPIVAL from epilepsy trials, spontaneous reports, and other sources are listed below by system organ class.

Blood and Lymphatic
System Disorders:
Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and hemorrhage. See WARNINGS AND PRECAUTIONS, Hematologic, Thrombocytopenia. 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.
Cardiac Disorders: Bradycardia
Ear and Labyrinth Disorders: Nausea, vomiting and indigestion are the most commonly reported side effects at the initiation of therapy. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea, abdominal cramps, constipation , gingival disorder (mainly gingival hyperplasia) and parotid gland swelling have also been reported. The administration of delayed-release EPIVAL may result in reduction of gastrointestinal side effects in some patients. In some patients, many of whom have functional or anatomic (including ileostomy or colostomy) gastrointestinal disorders with shortened gastrointestinal transit times, there have been postmarketing reports of EPIVAL ER extended-release tablets in the stool.

There have been reports of acute pancreatitis, including rare fatal cases, occurring in patients receiving EPIVAL. See WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Pancreatitis.
General Disorders and
Administration Site
Conditions:
Edema of extremities, fever and hypothermia
Hepatobiliary Disorders: Minor elevations of transaminases [e.g., serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT)] and lactate dehydrogenase (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 AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity.
Immune System Disorders: Allergic reaction, anaphylaxis
Infections and Infestations: Pneumonia and otitis media
Investigations: Abnormal thyroid function tests (including both hyperthyroidism and hypothyroidism). See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Thyroid Gland Abnormalities and DRUG INTERACTIONS, Drug-Laboratory Interactions.
Metabolism and Nutrition
Disorders:
Hyperammonemia, see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hyperammonemia, hyponatremia, biotin deficiency/biotinidase deficiency and inappropriate antidiuretic hormone (ADH) secretion. There have been rare reports of Fanconi syndrome (proximal renal tubular dysfunction) occurring primarily in children. Decreased carnitine concentrations have been reported although the clinical relevance is undetermined. Hyperglycinemia (elevated plasma glycine concentration) has been reported and associated with a fatal outcome in a patient with pre-existing non-ketotic hyperglycinemia.

Anorexia with some weight loss and increased appetite with some weight gain have also been reported.
Musculoskeletal and
Connective Tissue Disorders:
Weakness, rhabdomyolysis, and bone pain have been reported. (see WARNINGS AND PRECAUTIONS, Muscle Effects /Rhabdomyolysis).

Reports have been received of decreased bone mass, potentially leading to osteoporosis and osteopenia, during long-term therapy with some anticonvulsant medications, including EPIVAL. Some studies have indicated that supplemental calcium and vitamin D may be of benefit to patients who are on chronic EPIVAL therapy.

A lupus erythematosus-like syndrome has been reported rarely.
Neoplasms Benign,
Malignant and Unspecified
(including cysts and polyps):
Myelodysplastic syndrome in both adults and children (all children were on valproate monotherapy). In some cases in adults and/or children, myelodysplastic syndrome was reversible upon valproate discontinuation.
Nervous System Disorders: Sedative effects have been noted in patients receiving EPIVAL alone but occur most often in patients on combination therapy. Sedation usually disappears upon reduction of other antiepileptic medication.

Hallucination, ataxia, headache, nystagmus, diplopia, asterixis, "spots before the eyes", tremor (may be dose-related), confusion, dysarthria, dizziness, hypesthesia, vertigo, incoordination, memory impairment, cognitive disorder, and parkinsonism have been noted. Rare cases of coma have been reported in patients receiving EPIVAL alone or in conjunction with phenobarbital.

Encephalopathy, with or without fever or hyperammonemia, has been reported without evidence of hepatic dysfunction or inappropriate valproate plasma levels. Most patients recovered, with noted improvement of symptoms, upon discontinuation of the drug.

There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases the patients recovered with permanent sequelae. See WARNINGS AND PRECAUTIONS, Neurologic, Brain Atrophy. Cerebral atrophy seen in children exposed to valproate in utero led to various forms of neurological events, including developmental delays and psychomotor impairment. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women.
Psychiatric Disorders: Emotional upset, depression, psychosis, aggression, psychomotor hyperactivity, hostility, agitation, disturbance in attention, abnormal behaviour, learning disorder and behavioural deterioration.

See WARNINGS AND PRECAUTIONS, Psychiatric.
Renal and Urinary Disorders: Enuresis, acute renal failure, tubulointerstitial nephritis and urinary tract infection.
Reproductive System and
Breast Disorders:
There have been reports of irregular menses, secondary amenorrhea, breast enlargement and galactorrhea in patients receiving EPIVAL. Hyperandrogenism (hirsutism, virilism, acnea, male pattern alopecia, and/or androgen increased).

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
Respiratory, Thoracic and
Mediastinal Disorders:
Increased cough, pleural effusion.
Skin and Subcutaneous
Tissue Disorders:
Transient and/or dose related alopecia (hair loss) and hair disorders (such as hair texture abnormal, hair colour changes, hair growth abnormal), have been observed. Skin rash, photosensitivity, generalized pruritus, erythema multiforme, Stevens-Johnson syndrome (SJS), and petechiae have rarely been noted.

Rare cases of Toxic Epidermal Necrolysis (TEN) have been reported including a fatal case of a 6 month old infant taking EPIVAL and several other concomitant medications. An additional case of Toxic Epidermal Necrolysis resulting in death was reported in a 35 year old patient with AIDS taking several concomitant medications and with a history of multiple cutaneous drug reactions.

Serious skin reactions have been reported with concomitant administration of lamotrigine and EPIVAL. See DRUG INTERACTIONS, Drug-Drug Interactions, Table 2.

Cutaneous vasculitis has also been reported.

EPIVAL versus EPIVAL ER

A 24 week cross-over study compared the safety and efficacy of EPIVAL ER (divalproex sodium extended-release tablets) administered once daily to that of equal doses of EPIVAL (administered twice daily or three times daily) in the treatment of adolescent and adult epileptic patients with generalized seizures (n=44). Two adverse events occurred in significantly more patients on EPIVAL ER than on EPIVAL: asthenia (15.9% versus 6.8% respectively) and treatment-emergent mild thrombocytopenia (16.2% versus 6.8%, respectively).

Bipolar Disorder

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

Most Commonly Observed

During the short-term placebo-controlled trials, the six most commonly reported adverse events in patients (n = 89) exposed to EPIVAL were nausea (22%), headache (21%), somnolence (19%), pain (15%), vomiting (12%), and dizziness (12%).

In the long-term retrospective trials (634 patients exposed to EPIVAL), 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 EPIVAL 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 EPIVAL 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 EPIVAL. A notable exception was alopecia, which was first experienced after 3 to 6 months of exposure by 8 of the 15 patients who discontinued EPIVAL 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 EPIVAL group was at least 5%. (Maximum treatment duration was 21 days; maximum dose in 83% of patients was between 1, 000 to 2, 500 mg per day).

Table 1. Treatment-Emergent Adverse Event Incidence (≥5%) in Short-Term Placebo-Controlled
Trials (Oral Administration)
System Organ Class/Event EPIVAL
N = 89
(%)
placebo
N = 97
(%)
Gastrointestinal Disorders
Nausea
Vomiting
Diarrhea
Abdominal Pain
Dyspepsia
Constipation

22.5
12.4*
10.1
9
9
7.9

15.5
3.1
13.4
8.2
8.2
8.2
General Disorders and
Administration Site Conditions

Pain
Asthenia

14.6
10.1

15.5
7.2
Injury, Poisoning and Procedural
Complications

Accidental Injury

11.2

5.2
Musculoskeletal and Connective
Tissue Disorders

Back Pain

5.6

6.2
Nervous System Disorders
Headache
Somnolence
Dizziness
Tremor

21.3
19.1
12.4
5.6

30.9
12.4
4.1
6.2
Respiratory, Thoracic and
Mediastinal Disorders

Pharyngitis

6.7

9.3
Skin and Subcutaneous Tissue
Disorders

Rash

5.6

3.1

*Statistically significant at P < 0.05 level.

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 EPIVAL® tablets.

Cardiac Disorders: Palpitations, tachycardia.
Congenital, Familial and
Genetic Disorders:
Vascular anomaly.
Ear and Labyrinth Disorders: Deafness, ear disorder, ear pain, tinnitus, vertigo.
Eye Disorders: Abnormal vision, amblyopia, conjunctivitis, diplopia, dry eyes, eye pain.
Gastrointestinal Disorders: Fecal incontinence, flatulence, gastroenteritis, glossitis.
General Disorders and
Administration Site
Conditions:
Abnormal gait, chest pain, chills, chills and fever, cyst, edema, fever,
furunculosis, periodontal abscess, peripheral edema.
Infections and Infestations: Infection, rhinitis.
Metabolism and Nutrition
Disorders:
Anorexia.
Musculoskeletal and
Connective Tissue Disorders:
Arthralgia, arthrosis, leg cramps, neck pain, neck rigidity twitching.
Nervous System Disorders: Ataxia, dysarthria, hypertonia, hypokinesia, paresthesia, reflexes increased, tardive dyskinesia.
Psychiatric Disorders: Abnormal dreams, agitation, catatonic reaction, confusion, depression, hallucinations, insomnia, thinking abnormalities.
Renal and Urinary Disorders: Dysurea, urinary incontinence.
Reproductive System and
Breast Disorders:
Dysmenorrhea.
Respiratory, Thoracic and
Mediastinal Disorders:
Dyspnea.
Skin and Subcutaneous
Tissue Disorders:
Alopecia, discoid lupus erythematosus, dry skin, maculopapular rash, seborrhea.
Vascular Disorders: Ecchymosis, hypertension, hypotension, postural hypotension, vasodilation.

Adverse Events in Elderly Patients

In elderly patients (above 65 years of age), there were more frequent reports of accidental injury, infection, pain, and to a lesser degree, somnolence and tremor, when compared to patients18 to 65 years of age. Somnolence and tremor tended to be associated with the discontinuation of EPIVAL.

Drug Interactions

Serious Drug Interactions

  • Rare cases of coma have been reported in patients receiving EPIVAL alone or in conjunction with phenobarbital. See Drug-Drug Interactions, Table 2.
  • Serious skin reactions (such as Stevens-Johnson syndrome and Toxic Epidermal Necrolysis) have been reported with concomitant lamotrigine and EPIVAL administration. See Drug-Drug Interactions, Table 2.
  • Overview

    EPIVAL 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 (such as ritonavir; see Table 2 below), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on EPIVAL 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 EPIVAL clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation.

    The concomitant administration of EPIVAL 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 EPIVAL 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.

    Table 2. Summary of Drug-Drug Interaction Studies Including Important Interaction, Non-clinically Important Interactions and No Observed Interactions
    Concomitant Drug Ref Effect Clinical comment
    Acetaminophen CT ↔acetaminophen EPIVAL had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.
    Acetylsalicylic Acid CT ↑valproate A study involving the co-administration of acetylsalicylic acid at antipyretic doses (11 to 16 mg/kg) with EPIVAL 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 acetylsalicylic acid compared to EPIVAL alone. The beta-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on EPIVAL alone to 8.3% in the presence of acetylsalicylic acid. Caution should be observed when EPIVAL is administered with drugs affecting coagulation, (e.g., acetylsalicylic acid and warfarin). See ADVERSE REACTIONS.
    Alcohol T No
    pharmacokinetic
    (PK) interaction
    EPIVAL may potentiate the CNS depressant action of alcohol.
    Amitriptyline /
    Nortriptyline
    CT In general:
    ↓ amitriptyline
    ↓nortriptyline
    Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received EPIVAL (500 mg twice daily) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline.
    Rarely:
    ↑ amitriptyline
    ↑ nortriptyline
    Rare post-marketing reports of concurrent use of EPIVAL and amitriptyline resulting in an increased amitriptyline and nortriptyline levels have been received. Concurrent use of EPIVAL and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking EPIVAL concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of EPIVAL.
    Antacids CT ↔ valproate A study involving the co-administration of EPIVAL 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 milliequivalent doses) did not reveal any effect on the extent of absorption of valproate.
    Other -
    Antipsychotics,
    Monoamine
    Oxidase Inhibitors
    (MAOIs) and
    Tricyclic
    Antidepressants
    In addition to enhancing CNS depression when used concurrently with EPIVAL, antipsychotics, tricyclic antidepressants and MAOIs may lower the seizure threshold. Dosage adjustments may be necessary to control seizures.
    Benzodiazepines EPIVAL may decrease oxidative liver metabolism of some benzodiazepines, resulting in increased serum concentrations. See Table 1. Diazepam and Lorazepam.
    Carbamazepine /
    carbamazepine-
    10, 11-epoxide
    CT ↓ CBZ
    ↑ CBZ-E

    ↓ valproate
    Concomitant use of carbamazepine (CBZ) with EPIVAL 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. Changes in the serum concentration of the 10, 11-epoxide (CBZ-E) metabolite of carbamazepine, however, will not be detected by routine serum carbamazepine assay.

    Serum levels of carbamazepine decreased 17% while that of carbamazepine-10, 11-epoxide increased by 45% upon coadministration of EPIVAL and CBZ to epileptic patients.
    Carbapenem
    Antibiotics
    ↓ valproate Carbapenem antibiotics (ertapenem, imipenem, meropenem, doripenem) can reduce serum valproic acid concentrations to sub-therapeutic levels. This can result in loss of seizure control in epileptic paitents or loss of efficacy in nonepileptics. In some cases of co-administration in epileptic patients breakthrough seizures have occurred. Increasing valproic acid dose may not be sufficient to overcome this interaction. If co-administration is essential, serum valproic acid concentrations should be monitored daily. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates. See WARNINGS AND PRECAUTIONS, General, Interaction with Carbapenem Antibiotics.
    Chlorpromazine CT ↑ valproate A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving EPIVAL (200 mg twice daily) revealed a 15% increase in trough plasma levels of valproate. This increase is not considered clinically important.
    Cimetidine T ↑ valproate Cimetidine may decrease the clearance and increase the half-life of EPIVAL by altering its metabolism. In patients receiving EPIVAL, serum valproic acid levels should be monitored when treatment with cimetidine is instituted, increased, decreased, or discontinued. The EPIVAL dose should be adjusted accordingly.
    Clonazepam T No PK interaction The concomitant use of EPIVAL and clonazepam may induce absence status in patients with a history of absence type seizures.
    Clozapine CT No interaction In psychotic patients (n = 11), no interaction was observed when EPIVAL was co-administered with clozapine.
    Diazepam CT ↑ diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of EPIVAL (1, 500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate
    Ethosuximide CT ↑ ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with EPIVAL (800 to 1, 600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving EPIVAL and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.
    Felbamate CT ↑ valproate A study involving the co-administration of 1, 200 mg/day of felbamate with EPIVAL to patients with epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to EPIVAL alone. Increasing the felbamate dose to 2, 400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in EPIVAL dosage may be necessary when felbamate therapy is initiated. Lower doses of EPIVAL may be necessary when used concomitantly with felbamate.
    Haloperidol CT ↔ valproate A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving EPIVAL (200 mg twice daily) revealed no significant changes in valproate trough plasma levels.
    Lamotrigine CT ↑lamotrigine
    ↓valproate
    The effects of EPIVAL on lamotrigine were investigated in 6 healthy male subjects. Each subject received a single oral dose of lamotrigine alone and with EPIVAL 200 mg every 8 hours for 6 doses starting 1 hour before the lamotrigine dose was given. EPIVAL 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 EPIVAL co-administration (a 165% increase).

    In a study involving 16 epileptic patients, EPIVAL doubled the elimination half-life of lamotrigine. In an open-labelled study, patients receiving enzyme inducing AEDs (e.g., carbamazepine, phenytoin, phenobarbital, or primidone) demonstrated a mean lamotrigine plasma elimination half-life of 14 hours while the elimination halflife was 30 hours in patients taking EPIVAL 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 EPIVAL 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 EPIVAL administration.
    Lithium CT ↔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 valproate. 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.

    Co-administration of EPIVAL (500 mg twice daily) and lithium carbonate (300 mg three times daily) to normal male volunteers (n = 16) had no effect on the steady-state kinetics of lithium.
    Lorazepam CT ↑lorazepam Concomitant administration of EPIVAL (500 mg twice daily) and lorazepam (1 mg twice daily) in normal male volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam. This decrease is not considered clinically important.
    Olanzapine CT ↓olanzapine Administration of a single 5 mg dose of olanzapine to 10 healthy, non-epileptic volunteers with Depakote ER (divalproex sodium extended-release tablets) 1000 mg QD did not affect olanzapine Cmax and elimination half-life. However, olanzapine AUC was 35% lower in the presence of Depakote ER (divalproex sodium extended-release tablets). The clinical significance of these observations is unknown.
    Oral contraceptive
    Steroids
    CT No PK interaction Evidence suggests that there is an association between the use of certain AEDs 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. EPIVAL is not a significant enzyme inducer and would not be expected to decrease concentrations of steroid hormones. However, clinical data about the interaction of EPIVAL with oral contraceptives are minimal.

    Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on EPIVAL (200 mg twice daily) therapy for 2 months did not reveal any pharmacokinetic interaction.
    Phenobarbital CT ↑phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of EPIVAL (250 mg twice daily 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 CT ↑phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of PIVAL (400 mg three times daily) 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 EPIVAL and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation.
    Primidone T ↑phenobarbital Primidone is metabolized into a barbiturate (phenobarbital), and therefore, may also be involved in a similar or identical interaction with EPIVAL as phenobarbital.
    Quetiapine Co-administration of valproate and quetiapine may increase the risk of neutropenia/leucopenia.
    Rifampin CT ↓valproate A study involving the administration of a single dose of EPIVAL (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. EPIVAL dosage adjustment may be necessary when it is co-administered with rifampin.
    Ritonavir C ↓valproate Reduction of therapeutic effect of valproate was observed in a patient with bipolar disorder with the initiation of HIV treatment with lopinavir/ritonavir, zidovudine, and lamivudine.
    Selective Serotonin
    Re-Uptake
    Inhibitors (SSRIs)
    C ↑valproate Some evidence suggests that SSRIs inhibit the metabolism of EPIVAL, resulting in higher than expected levels of valproate.
    Tolbutamide T ↑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 EPIVAL. The clinical relevance of this displacement is unknown.
    Topiramate CT Effect unknown Hyperammonemia

    Concomitant administration of EPIVAL and topiramate has been associated with hyperammonemia with and without encephalopathy. See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Urea Cycle Disorders, Hyperammonemia and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use.

    Hypothermia

    Concomitant administration of topiramate with EPIVAL has also been associated with hypothermia in patients who have tolerated either drug alone. Blood ammonia levels should be measured in patients with reported onset of hypothermia. See WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Hypothermia.
    Warfarin T Effect unknown 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 EPIVAL is instituted in patients taking anticoagulants.

    Caution is recommended when EPIVAL is administered with drugs affecting coagulation. See ADVERSE REACTIONS.
    Zidovudine CT ↑zidovudine In 6 patients who were seropositive for HIV, the clearance of zidovudine (100 mg every 8 hours) was decreased by 38% after administration of EPIVAL (250 or 500 mg every 8 hours); the half-life of zidovudine was unaffected.
    Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

    Drug-Herb Interactions

    Interactions with herbal products have not been established.

    Drug-Laboratory Interactions

    EPIVAL 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 EPIVAL; the clinical significance of these is unknown. See WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women, Thyroid Gland Abnormalities.

    Drug-Lifestyle Interactions

    Refer to WARNINGS AND PRECAUTIONS, Neurologic, Driving and Hazardous Occupations 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 EPIVAL (divalproex sodium) is titrated upward, blood concentrations of phenobarbital, carbamazepine and/or phenytoin may be affected. See DRUG INTERACTIONS.

    AEDs 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 EPIVAL 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, Special Populations, Geriatrics (≥years of age).

    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, Hematologic, Dose-related Adverse Reactions: Thrombocytopenia. 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 (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 (Table 3).

    Table 3. Initial Doses by Weight (based on 15 mg/kg/day)
    Weight Total Daily
    Dose (mg)
    Dosage (mg) equivalent to valproic acid
    kg lb Dose 1 Dose 2 Dose 3
    10 to 24.9 22 to 54.9 250 125 0 125
    25 to 39.9 55 to 87.9 500 250 0 250
    40 to 59.9 88 to 131.9 750 250 250 250
    60 to 74.9 132 to 164.9 1, 000 250 250 500
    75 to 89.9 165 to 197.9 1, 250 500 250 500
    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 to EPIVAL

    EPIVAL enteric -coated tablets dissociate to the valproate ion in the gastrointestinal tract. EPIVAL tablets are uniformly and reliably absorbed, however, because of the enteric coating, absorption is delayed by an hour when compared to DEPAKENE (valproic acid).

    The bioavailability of both types of divalproex sodium tablets (EPIVAL and EPIVAL ER) is equivalent to that of DEPAKENE capsules.

    In patients previously receiving DEPAKENE therapy, EPIVAL should be initiated at the same daily dosing schedule. After the patient is stabilized on EPIVAL, a dosing schedule of two or three times a day may be elected in selected patients. Changes in dosage administration of EPIVAL 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 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 1, 000 to 2, 500 mg/day. The maximum recommended dosage is 60 mg/kg/day.

    The relationship of plasma concentration to clinical response has not been established for EPIVAL. In controlled clinical studies, 79% of patients achieved and tolerated serum valproate concentrations between 50 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 may be taken with or without food.

    Patients who experience gastrointestinal irritation may benefit from administration of the drug with food or by a progressive increase of the dose from the initial low level. The tablets should be swallowed without chewing. Co-administration of EPIVAL with food should cause no clinical problems in the management of patients with epilepsy.

    Overdosage

    For management of a suspected drug overdose, contact your regional Poison Control Centre.

    Overdosage with EPIVAL (divalproex sodium) may result in somnolence, muscular hypotonia, hyporeflexia, miosis, impaired respiratory function, hypotension, metabolic acidosis, heart block, deep coma and circulatory collapse/shock. Cases of intracranial hypertension related to cerebral oedema have been reported. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2, 120 mcg/mL.

    The presence of sodium content in the valproate formulations may lead to hypernatremia when taken in overdose.

    In a reported case of overdosage with EPIVAL after ingesting 36 g in combination with phenobarbital and phenytoin, the patient presented in deep coma. An electroencephalogram (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 EPIVAL overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of EPIVAL, it should be used with caution in patients with epilepsy.

    Action and Clinical Pharmacology

    Pharmacotherapeutic group: Anticonvulsant and mood-stabilizing drug; ATC-Code: N03AG01.

    Mechanism of Action

    EPIVAL (divalproex sodium) has anticonvulsant properties, and is chemically related to valproic acid. EPIVAL 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 and 125 mcg/mL. Protein binding of valproate is saturable ranging from 90% at 50 mcg/mL to 82% at 125 mcg/mL.

    Pharmacokinetics

    Table 4. Summary of the Pharmacokinetic Parameters of EPIVAL in Healthy, Fasting Subjects
    Mean (SD) Pharmacokinetic Parameters
    Single Dose Dosage N Cmax
    (mg/L)
    Tmax
    (h)
    t%
    (h)
    AUC4
    (mg h/L)
    CL
    (l/h)
    Vd
    (L)
    EPIVAL 2 x 500 mg
    once daily
    28 93.9
    (11.7)
    4.0
    (1.2)
    15.2
    (15.3)
    1818
    (345)
    -- --

    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 to 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 to 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 AEDs (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 (t½) 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 2 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

    The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. See DOSAGE AND ADMINISTRATION.

    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

    See CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Serious or Fatal Hepatotoxicity for statements regarding hepatic dysfunction and associated fatalities.

    Renal Insufficiency

    See WARNINGS AND PRECAUTIONS, Renal, Renal Impairment.

    Genetic Polymorphism

    No data available on genetic polymorphism.

    Storage and Stability

    Store EPIVAL (divalproex sodium) enteric-coated tablets between 15 and 25°C. Tablets should be protected from light.

    Dosage Forms, Composition and Packaging

    EPIVAL enteric-coated tablets are formulated for oral administration containing divalproex sodium in three strengths: 125 mg, 250 mg and 500 mg.

    EPIVAL 125 mg enteric-coated tablets are supplied as salmon-pink, ovaloid, film-coated tablets, with the Abbott logo printed on one side, and are available in bottles of 100 tablets.

    EPIVAL 250 mg enteric- coated tablets are supplied as peach, ovaloid, film-coated tablets, with the Abbott logo printed on one side, and are available in bottles of 100 and 500 tablets.

    EPIVAL 500 mg enteric- coated tablets are supplied as pink, ovaloid, film-coated tablets, with the Abbott logo printed on one side, and are available in bottles of 100 and 500 tablets.

    Listing of Non-Medicinal Ingredients

    Each EPIVAL 125 mg enteric-coated tablet contains 125 mg of divalproex sodium with the following non-medicinal ingredients: diacetylated monoglycerides, FD&C Red No. 40, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide, and vanillin.

    Each EPIVAL 250 mg enteric-coated tablet contains 250 mg of divalproex sodium with the following non-medicinal ingredients: diacetylated monoglycerides, FD&C Yellow No. 6, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide, and vanillin.

    Each EPIVAL 500 mg enteric-coated tablet contains 500 mg of divalproex sodium with the following non-medicinal ingredients: diacetylated monoglycerides, D&C Red No. 30, FD&C Blue No. 2, hydroxypropylmethyl cellulose phthalate, povidone, pregelatinized starch (contains corn starch), silicon dioxide, talc, titanium dioxide, and vanillin.