DIVALPROEX SODIUM DELAYED-RELEASE

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Overview

What is DIVALPROEX SODIUM DELAYED-RELEASE?

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:

Divalproex sodium occurs as a white powder with a characteristic odor.

Divalproex sodium delayed-release tablets are for oral administration. Divalproex sodium delayed-release tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.

Inactive Ingredients

Divalproex sodium delayed-release tablets: pregelatinized starch, povidone, microcrystalline cellulose, silicon dioxide, opadry clear, methacrylic acid co-polymer, sodium hydroxide, simethicone emulsion, triethyl citrate, talc, vanilla flavor and opacode black.

In addition, individual tablets contain:

250 mg tablets: Ferric oxide.

500 mg tablets: FD&C Blue No. 1.

The components of opadry clear are hypromellose and polyethylene glycol 6000 and the components of opacode black are shellac glaze, iron oxide black, n-butyl alcohol, industrial methylated spirit, lecithin (soya), antifoam DC 1510 (food grade).

What does DIVALPROEX SODIUM DELAYED-RELEASE look like?

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What interacts with DIVALPROEX SODIUM DELAYED-RELEASE?

DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.

Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.

Divalproex sodium is contraindicated in patients with known urea cycle disorders (See ).

What are the warnings of DIVALPROEX SODIUM DELAYED-RELEASE?

Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months. However, physicians should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination.

Caution should be observed when administering divalproex sodium products to patients with a prior history of hepatic disease. Patients 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 with the aforementioned conditions. When divalproex sodium 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 this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

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.

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with 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 (see ).

Urea Cycle Disorders (UCD)

Divalproex sodium 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 the 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 a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or 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 who develop symptoms of unexplained hyperammonemic encephalopathy while receiving valproate therapy should receive prompt treatment (including discontinuation of valproate therapy) and be evaluated for underlying urea cycle disorders (see and ).

Somnolence in the Elderly

In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, 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 ).

Thrombocytopenia

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see ]) may be dose-related. In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 10/L. Approximately half of these patients had treatment discontinued, with return of platelet counts to normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the higher doses should therefore be weighed against the possibility of a greater incidence of adverse effects.

Usage In Pregnancy

VALPROATE CAN PRODUCE TERATOGENIC EFFECTS. DATA SUGGEST THAT THERE IS AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS ASSOCIATED WITH THE USE OF VALPROATE BY WOMEN WITH SEIZURE DISORDERS DURING PREGNANCY WHEN COMPARED TO THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO DO NOT USE ANTIEPILEPTIC DRUGS DURING PREGNANCY, THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO USE OTHER ANTIEPILEPTIC DRUGS, AND THE BACKGROUND INCIDENCE FOR THE GENERAL POPULATION. THEREFORE, VALPROATE 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.

THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE THAT INDICATE THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS IN OFFSPRING. ANTIEPILEPTIC DRUGS, INCLUDING VALPROATE, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR MEDICAL CONDITION.

Antiepileptic drugs should not be discontinued abruptly 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. 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.

HUMAN DATA

The North American Antiepileptic Drug Pregnancy Registry reported 16 cases of congenital malformations among the offspring of 149 women with epilepsy who were exposed to valproic acid monotherapy during the first trimester of pregnancy at doses of approximately 1,000 mg per day, for a prevalence rate of 10.7% (95% CI 6.3% to 16.9%). Three of the 149 offspring (2%) had neural tube defects and 6 of the 149 (4%) had less severe malformations. Among epileptic women who were exposed to other antiepileptic drug monotherapies during pregnancy (1,048 patients) the malformation rate was 2.9% (95% CI 2% to 4.1%). There was a 4 fold increase in congenital malformations among infants with valproic acid-exposed mothers compared with those treated with other antiepileptic monotherapies as a group (Odds Ratio 4; 95% CI 2.1 to 7.4). This increased risk does not reflect a comparison versus any specific antiepileptic drug, but the risk versus the heterogeneous group of all other antiepileptic drug monotherapies combined. The increased teratogenic risk from valproic acid in women with epilepsy is expected to be reflected in an increased risk in other indications (e.g., migraine or bipolar disorder).

THE STRONGEST ASSOCIATION OF MATERNAL VALPROATE USAGE WITH CONGENITAL MALFORMATIONS IS WITH NEURAL TUBE DEFECTS (AS DISCUSSED UNDER THE NEXT SUBHEADING). HOWEVER, 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 IS NOT AVAILABLE.

ANIMAL DATA

Animal studies have demonstrated valproate-induced teratogenicity. 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) 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/m 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 or greater). Behavioral 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/m 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/m 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).

What are the precautions of DIVALPROEX SODIUM DELAYED-RELEASE?

Hepatic Dysfunction

See , and .

Pancreatitis

See and .

Hyperammonemia

Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. If 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 and – and - ).

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be considered. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. (see and - U and - ).

Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

Concomitant administration of topiramate and valproic acid has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. In most cases, symptoms and signs abated with discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia with or without encephalopathy. Although not studied, an interaction of topiramate and valproic acid may exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured. (see and - and - )

General

Because of reports of thrombocytopenia (see ), inhibition of the secondary 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. In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 10/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). Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

Since divalproex sodium 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. (See .)

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

There have been reports of altered thyroid function tests associated with valproate. The clinical significance of these is unknown.

Suicidal ideation may be a manifestation of certain psychiatric disorders, and may persist until significant remission of symptoms occurs. Close supervision of high risk patients should accompany initial drug therapy.

There are studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these 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.

Multi-organ Hypersensitivity Reaction

Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to 40 days). Although there have been a limited number of reports, many of these cases resulted in hospitalization and at least one death has been reported. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. Other associated manifestations may include lymphadenopathy, hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia, thrombocytopenia, neutropenia), pruritis, nephritis, oliguria, hepatorenal 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.

Information for Patients

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly.

Patients should be informed of the signs and symptoms associated with hyperammonemic encephalopathy (see ) and be told to inform the prescriber if any of these symptoms occur.

Since divalproex sodium products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), patients should be advised not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Since divalproex sodium has been associated with certain types of birth defects, female patients of child-bearing age considering the use of divalproex sodium should be advised of the risk and of alternative therapeutic options and to read the , which appears as the last section of the labeling. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is considered.

Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately (see ).

Drug Interactions

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

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

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported.

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

The following list provides information about the potential for an influence of valproate coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Valproic acid was administered orally to Sprague Dawley rats and ICR (HA/ICR) mice at doses of 80 and 170 mg/kg/day (approximately 10 to 50% of the maximum human daily dose on a mg/m basis) for two years. A variety of neoplasms were observed in both species. The chief findings were a statistically significant increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproic acid and a statistically significant dose-related trend for benign pulmonary adenomas in male mice receiving valproic acid. The significance of these findings for humans is unknown.

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

Chronic toxicity studies in juvenile and adult rats and dogs demonstrated reduced spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately equivalent to or greater than the maximum human daily dose on a mg/m basis) and 150 mg/kg/day or greater in dogs (approximately 1.4 times the maximum human daily dose or greater on a mg/m basis). Segment I fertility studies in rats have shown doses up to 350 mg/kg/day (approximately equal to the maximum human daily dose on a mg/m basis) for 60 days to have no effect on fertility. THE EFFECT OF VALPROATE ON TESTICULAR DEVELOPMENT AND ON SPERM PRODUCTION AND FERTILITY IN HUMANS IS UNKNOWN.

Pregnancy

Teratogenic Effects: Pregnancy Category D: See .

Nursing Mothers

Valproate is excreted in breast milk. Concentrations in breast milk have been reported to be 1 to 10% of serum concentrations. It is not known what effect this would have on a nursing infant. Consideration should be given to discontinuing nursing when divalproex sodium is administered to a nursing woman.

Pediatric Use

Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions (see ). When divalproex sodium 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 acid 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 safety and effectiveness of divalproex sodium for the prophylaxis of migraines has not been studied in individuals below the age of 16 years.

The basic toxicology and pathologic manifestations of valproate sodium in neonatal (4 day old) and juvenile (14 day old) rats are similar to those seen in young adult rats. However, additional findings, including renal alterations in juvenile rats and renal alterations and retinal dysplasia in neonatal rats, have been reported. These findings occurred at 240 mg/kg/day, a dosage approximately equivalent to the human maximum recommended daily dose on a mg/m basis. They were not seen at 90 mg/kg, or 40% of the maximum human daily dose on a mg/m basis.

Geriatric Use

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence (see ). The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence (see ).

There is insufficient information available to discern the safety and effectiveness of divalproex sodium for the prophylaxis of migraines in patients over 65.

What are the side effects of DIVALPROEX SODIUM DELAYED-RELEASE?

Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively.

Array

The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials:

**Table 1. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Placebo- Controlled Trials of Acute Mania**
	Adverse Event
Nausea		22%	15%
Somnolence		19%	12%
Dizziness		12%	4%
Vomiting		12%	3%
Asthenia		10%	7%
Abdominal pain		9%	8%
Dyspepsia		9%	8%
Rash		6%	3%

Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.

Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.

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

Ecchymosis.

Edema, peripheral edema.

Arthralgia, arthrosis, leg cramps, twitching.

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

Dyspnea, rhinitis.

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

Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.

Dysmenorrhea, dysuria, urinary incontinence.

Migraine

Based on two placebo-controlled clinical trials and their long term extension, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ≥ 1% of 248 divalproex sodium-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Array

The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled clinical trials:

**Table 2. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo**
	Body System Event
	Gastrointestinal System
Nausea		31%	10%
Dyspepsia		13%	9%
Diarrhea		12%	7%
Vomiting		11%	1%
Abdominal pain		9%	4%
Increased appetite		6%	4%
	Nervous System
Asthenia		20%	9%
Somnolence		17%	5%
Dizziness		12%	6%
Tremor		9%	0%
	Other
Weight gain		8%	2%
Back pain		8%	6%
Alopecia		7%	1%

Chest pain, chills, face edema, fever and malaise.

Vasodilatation.

Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.

Ecchymosis.

Peripheral edema, SGOT increase, and SGPT increase.

Leg cramps and myalgia.

Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.

Cough increased, dyspnea, rhinitis, and sinusitis.

Pruritus and rash.

Conjunctivitis, ear disorder, taste perversion, and tinnitus.

Cystitis, metrorrhagia, and vaginal hemorrhage.

Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.

Array

Array

The following additional adverse events were reported by greater than 1% but less than 5% of the 358 patients treated with divalproex sodium in the controlled trials of complex partial seizures:

**Table 3. Adverse Events Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures**
	Body System/Event
	Body as a Whole
Headache		31	21
Asthenia		27	7
Fever		6	4
	Gastrointestinal System
Nausea		48	14
Vomiting		27	7
Abdominal Pain		23	6
Diarrhea		13	6
Anorexia		12	0
Dyspepsia		8	4
Constipation		5	1
	Nervous System
Somnolence		27	11
Tremor		25	6
Dizziness		25	13
Diplopia		16	9
Amblyopia/Blurred Vision		12	9
Ataxia		8	1
Nystagmus		8	1
Emotional Lability		6	4
Thinking Abnormal		6	0
Amnesia		5	1
	Respiratory System
Flu Syndrome		12	9
Infection		12	6
Bronchitis		5	1
Rhinitis		5	4
	Other
Alopecia		6	1
Weight Loss		6	0
	Body System/Event
	Body as a Whole
Asthenia		21	10
	Digestive System
Nausea		34	26
Diarrhea		23	19
Vomiting		23	15
Abdominal Pain		12	9
Anorexia		11	4
Dyspepsia		11	10
	Hemic/Lymphatic System
Thrombocytopenia		24	1
Ecchymosis		5	4
	Metabolic/Nutritional
Weight Gain		9	4
Peripheral Edema		8	3
	Nervous System
Tremor		57	19
Somnolence		30	18
Dizziness		18	13
Insomnia		15	9
Nervousness		11	7
Amnesia		7	4
Nystagmus		7	1
Depression		5	4
	Respiratory System
Infection		20	13
Pharyngitis		8	2
Dyspnea		5	1
	Skin and Appendages
Alopecia		24	13
	Special Senses
Amblyopia/Blurred Vision		8	4
Tinnitus		7	1

Back pain, chest pain, malaise.

Tachycardia, hypertension, palpitation.

Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Petechia.

SGOT increased, SGPT increased.

Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Sinusitis, cough increased, pneumonia, epistaxis.

Rash, pruritus, dry skin.

Taste perversion, abnormal vision, deafness, otitis media.

Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

Other Patient Populations

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

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

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders (see and ).

Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy.

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-Johnson syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case in a 6 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 ).

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration.

Weakness.

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 and ). Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

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

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see ).

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

Acute pancreatitis including fatalities (see ).

Hyperammonemia (see ), hyponatremia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.

Enuresis and urinary tract infection.

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

Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.

What should I look out for while using DIVALPROEX SODIUM DELAYED-RELEASE?

DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.

Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.

Divalproex sodium is contraindicated in patients with known urea cycle disorders (See ).

What might happen if I take too much DIVALPROEX SODIUM DELAYED-RELEASE?

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL.

In 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 maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

How should I store and handle DIVALPROEX SODIUM DELAYED-RELEASE?

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature].Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75Divalproex sodium delayed-release tablets,USP are supplied as:125 mg tablets: White to off white colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2142-11Unit dose packages of 100 (10x10) NDC 0228-2142-75250 mg tablets: Pale brown colored with mottled appearance modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2144-11Bottles of 500 NDC 0228-2144-50Unit dose packages of 100 (10x10) NDC 0228-2144-75500 mg tablets: Blue colored modified oval biconvex enteric film coated tablet imprinted with on one side in black ink and plain on the other side.Bottles of 100 NDC 0228-2145-11Bottles of 500 NDC 0228-2145-50Unit dose packages of 100 (10x10) NDC 0228-2145-75

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

Non-Clinical Toxicology

DIVALPROEX SODIUM SHOULD NOT BE ADMINISTERED TO PATIENTS WITH HEPATIC DISEASE OR SIGNIFICANT HEPATIC DYSFUNCTION.

Divalproex sodium is contraindicated in patients with known hypersensitivity to the drug.

Divalproex sodium is contraindicated in patients with known urea cycle disorders (See ).

See , and .

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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