Epival

Interactions with herbal products have not been established.

Refer to Warnings and Precautions, Neurologic, Driving and Hazardous Occupations for details.

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

Summary of Drug-Drug Interaction Studies Including Important Interactions, Non-clinically Important Interactions and No Observed Interactions

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

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

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

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

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

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

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy and whenever enzyme-inducing drugs are introduced or withdrawn.

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

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

In patients previously receiving DEPAKENE (valproic acid) 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 valproate or concomitant medications should be accompanied by increased monitoring of plasma concentrations of valproate and other medications, as well as the patient’s clinical status.

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 1000 mg/day to 2500 mg/day. The maximum recommended dosage is 60 mg/kg/day.

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

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 µg/mL (350 to 700 micromole/L).Some patients may be controlled with lower or higher serum concentrations (see Warnings and Precautions).

EPIVAL may be taken with or without food.

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

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.

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 µg/mL (females) or ≥135 µg/mL (males) (see Warnings and Precautions). Therefore, the benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse effects.

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

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

Antiepileptic drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

Any changes in dosage and administration, or the addition or discontinuance of concomitant drugs, should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.

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

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, urinary tract infection, and other adverse events. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence. The ultimate therapeutic dose should be achieved on the basis of clinical response (see Warnings and Precautions).

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

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

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage (see 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.

anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.

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

alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.

There have been reports of irregular menses, secondary amenorrhea, breast enlargement, galactorrhea and parotid gland swelling in patients receiving valproic acid.

Abnormal thyroid function tests have been reported (see Drug Interactions, Drug-Laboratory Test Interactions).

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

chest pain, chills, chills and fever, cyst, fever, infection, neck pain, neck rigidity.

The most commonly reported adverse reactions are nausea, vomiting and indigestion. Since divalproex sodium 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 divalproex sodium alone or to the combination of drugs.

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

Hyperammonemia (see Warnings and Precautions), hyponatremia and inappropriate ADH secretion. There have been rare reports of Fanconi syndrome 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 preexisting non-ketotic hyperglycinemia.

hypertension, hypotension, palpitations, postural hypotension, tachycardia, vascular anomaly, vasodilation.

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.

Enuresis and urinary tract infection.

Sedative effects have been noted in patients receiving valproic acid alone but occur most often in patients on combination therapy. Sedation usually disappears upon reduction of other antiepileptic medication.

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

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

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

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 and constipation have also been reported. Anorexia with some weight loss and increased appetite with some weight gain have also been reported. The administration of delayed-release divalproex sodium 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 divalproex sodium extended-release tablets in the stool.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

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

edema, peripheral edema.

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

arthralgia, arthrosis, leg cramps, twitching.

There have been reports of acute pancreatitis, including rare fatal cases, occurring in patients receiving valproate therapy (see Warnings and Precautions).

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

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

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

Weakness has been reported.

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

dysmenorrhea, dysuria, urinary incontinence.

A 24 week cross-over study compared the safety and efficacy of EPIVAL ER (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% vs 6.8% respectively) and treatment-emergent mild thrombocytopenia (16.2% vs 6.8%, respectively).

dyspnea, rhinitis.

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

Transient increases in hair loss 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 six month old infant taking valproate and several other concomitant medications. An additional case of toxic epidermal necrosis 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 valproate (see Drug Interactions).

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

ecchymosis.

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

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 for statement regarding serious or fatal hepatic dysfunction.

use as sole or adjunctive therapy in the treatment of simple or complex absence seizures, including petit mal, and are useful in primary generalized seizures with tonic-clonic manifestations. Divalproex sodium may also be used 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.

The safety and efficacy of valproate in elderly patients with epilepsy and mania has not been evaluated in clinical trials. Caution should thus be exercised in dose selection for an elderly patient, recognizing the more frequent hepatic and renal dysfunctions, and limited experience with valproate in this population. For a brief discussion, see Warnings and Precautions, Special Populations, Geriatrics (≥65 years of age); Dosage and Administration and Action and Clinical Pharmacology, Special Populations and Conditions, Geriatrics.

Each enteric-coated, peach-colored tablet contains: divalproex sodium equivalent to valproic acid 250 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated monoglycerides, FD&C Yellow No. 6, povidone, pregelatinized starch (contains cornstarch), silicon dioxide, talc, titanium dioxide and vanillin. Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Bottles of 100 and 500.

Each enteric-coated, pink-colored tablet contains: divalproex sodium equivalent to valproic acid 500 mg. Nonmedicinal ingredients: cellulosic polymers, D&C Red No. 30, diacetylated monoglycerides, FD&C Blue No. 2, povidone, pregelatinized starch (contains cornstarch), silicon dioxide, talc, titanium dioxide and vanillin. Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Bottles of 100 and 500.

Each enteric-coated, salmon-pink tablet contains: divalproex sodium equivalent to valproic acid 125 mg. Nonmedicinal ingredients: cellulosic polymers, diacetylated monoglycerides, FD&C Red No. 40, povidone, pregelatinized starch (contains cornstarch), silicon dioxide, talc, titanium dioxide and vanillin. Alcohol-, gluten-, lactose-, paraben-, sucrose-, sulfite- and tartrazine-free. Bottles of 100.

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related. In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤75×10⁹/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 µg/mL (females) or ≥135 µg/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 extended-release tablets, in 44 epilepsy patients, indicate that the frequency of treatment-emergent mild thrombocytopenia (platelet count between 100-150×10⁹/L) was significantly higher after 12 weeks of treatment with EPIVAL ER than after 12 weeks of treatment with EPIVAL (7 vs 3 low counts, respectively).

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. These incidences usually occurred during the first six months of treatment with valproic acid. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.

Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. The risk in this age group decreased considerably in patients receiving valproate as monotherapy. Similarly, patients aged 3 to 10 years were at somewhat greater risk if they received multiple anticonvulsants than those who received only valproate. Above the age of two years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patients. No deaths have been reported in patients over 10 years of age who received valproate alone.

If valproate products are to be used for the control of seizures in children two years old or younger, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks (see Warnings and Precautions, Special Populations, Pediatrics (<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 valproate products.

Liver function tests should be performed prior to therapy and at frequent intervals thereafter especially during the first 6 months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

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

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

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.

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

Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered as a possible cause and serum ammonia level should be measured. If serum ammonia is increased, valproate therapy should be discontinued. Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should undergo investigation for underlying urea cycle disorders (see Contraindications and Warnings and Precautions, Endocrine and Metabolism, Urea Cycle Disorders (UCD) and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use).

Asymptomatic elevations of serum ammonia are more common and, when present, require close monitoring of serum ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered.

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

A study of elderly patients revealed valproate-related somnolence and discontinuation of valproate therapy 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).

According to published and unpublished reports in the medical literature, valproic acid may produce teratogenic effects, such as neural tube defects (e.g., spina bifida) in the offspring of human females receiving the drug during pregnancy. There are data that suggest an increased incidence of congenital malformations associated with the use of valproic acid during pregnancy when compared with some other antiepileptic drugs. Therefore, valproic acid should be considered for women of childbearing potential only after the risks have been thoroughly discussed with the patient and weighed against the potential benefits of treatment.

Multiple reports in the clinical literature indicate an association between the use of antiepileptic drugs and an elevated incidence of birth defects in children born to epileptic women taking such medication during pregnancy. The incidence of congenital malformations in the general population is regarded to be approximately 2%; in children of treated epileptic women, this incidence may be increased 2- to 3-fold. The increase is largely due to specific defects 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.

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.

Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days; range 1 to 40). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here may occur. If this reaction is suspected, valproate should be discontinued and an alternative treatment started. Although the existence of cross sensitivity with other drugs that produce this syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility.

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

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction.

It is not known if topiramate monotherapy is associated with hyperammonemia.

Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons (see Contraindications and Warnings and Precautions, Endocrine and Metabolism, Urea Cycle Disorders (UCD) and Hyperammonemia).

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

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

   
   

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

   
   

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

   
   

4. Those with other signs or symptoms of UCD. Patients receiving valproate therapy who develop symptoms of unexplained hyperammonemic encephalopathy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see Contraindications and Warnings and Precautions, Endocrine and Metabolism, Hyperammonemia and Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use).

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

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

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

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy and whenever enzyme-inducing drugs are introduced or withdrawn (see Drug Interactions).

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Some cases have occurred shortly after initial use as well as after several years of use. The rate based upon the reported cases exceeds that expected in the general population and there have been cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were 2 cases of pancreatitis without alternative etiology in 2416 patients, representing 1044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated.

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

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

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

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

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

The data described below were gained almost exclusively from women who received valproate to treat epilepsy. The incidence of neural tube defects in the fetus is increased in mothers receiving valproic acid during the first trimester of pregnancy. Based upon a single report, it was estimated that the risk of valproic acid-exposed women having children with spina bifida is approximately 1 to 2%.

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

The higher incidence of congenital anomalies in antiepileptic drug-treated women with seizure disorders cannot be regarded as a cause and effect relationship. There are intrinsic methodologic problems in obtaining adequate data on drug teratogenicity in humans; genetic factors or the epileptic condition itself, may be more important than the drug therapy in contributing to congenital anomalies.

There have been reports of developmental delay in the offspring of women who have received valproic acid during pregnancy.

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

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

Antiepileptic drugs should not be abruptly discontinued in patients to whom the drug is administered to prevent major seizures, because of the strong possibility of precipitating status epilepticus with attendant hypoxia and risks to both the mother and the unborn child. With regard to drugs given for minor seizures, the risks of discontinuing medication prior to or during pregnancy should be weighed against the risk of congenital defects in the particular case and with the particular family history. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

In summary, current best practice guidelines should be considered in order to provide the optimal counsel to patients regarding the teratogenic risks associated with valproic acid.

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

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

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

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

Animal studies have demonstrated valproic acid induced teratogenicity, 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 µg/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 µg/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 µg/mL (2.8 times the upper limit of the human therapeutic range for epilepsy).

Because of reports of thrombocytopenia, inhibition of the second phase of platelet aggregation, and abnormal coagulation parameters (e.g., low fibrinogen), platelet counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving divalproex sodium be monitored for platelet count and coagulation parameters prior to planned surgery. Clinical evidence of hemorrhage, bruising or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy (see also Warnings And Precautions, Hematologic, Dose-related Adverse Reactions: Thrombocytopenia).

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

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; Endocrine and Metabolism, Hyperammonemia, Hematologic, Thrombocytopenia, and Drug Interactions, Drug-Drug Interactions.

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.

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.

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m² and 11 L/1.73 m², respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m² and 92 L/1.73 m², respectively. These estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproic acid clearance, monitoring of valproate and concomitant drug concentrations should be intensified whenever enzyme-inducing drugs are introduced or withdrawn.

Elimination of valproic acid and its metabolites occurs principally in the urine, with minor amounts in the feces and expired air. Very little unmetabolized parent drug is excreted in the urine.

The serum half-life (t_½) 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.

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).

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

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

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

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 µg/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 µg/mL and 125 µg/mL. Protein binding of valproate is saturable ranging from 90% at 50 µg/mL to 82% at 125 µg/mL.

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.

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

See Contraindications, and Warnings and Precautions for statements regarding hepatic dysfunction and associated fatalities.

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

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

See Warnings and Precautions, Renal, Renal Impairment.

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 µg/mL to 18.5% at 130 µg/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).

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