FDA label 8d230242-c927-49c7-9798-4f73576449c8

BOX WARNING HEPATOTOXICITY HEPATIC FAILURE RESULTING IN FATALITIES HAS OCCURRED IN PATIENTS RECEIVING VALPROIC ACID AND ITS DERIVATIVES. 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. WHEN VALPROIC ACID INJECTION, USP 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. 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. TERATOGENICITY VALPROATE CAN PRODUCE TERATOGENIC EFFECTS SUCH AS NEURAL TUBE DEFECTS (E.G., SPINA BIFIDA). ACCORDINGLY, THE USE OF VALPROATE PRODUCTS IN WOMEN OF CHILDBEARING POTENTIAL REQUIRES THAT THE BENEFITS OF ITS USE BE WEIGHED AGAINST THE RISK OF INJURY TO THE FETUS. THIS IS ESPECIALLY IMPORTANT WHEN THE TREATMENT OF A SPONTANEOUSLY REVERSIBLE CONDITION NOT ORDINARILY ASSOCIATED WITH PERMANENT INJURY OR RISK OF DEATH (E.G., MIGRAINE) IS CONTEMPLATED. SEE WARNINGS , INFORMATION FOR PATIENTS . PANCREATITIS CASES OF LIFE-THREATENING PANCREATITIS HAVE BEEN REPORTED IN BOTH CHILDREN AND ADULTS RECEIVING VALPROATE. SOME OF THE CASES HAVE BEEN DESCRIBED AS HEMORRHAGIC WITH A RAPID PROGRESSION FROM INITIAL SYMPTOMS TO DEATH. CASES HAVE BEEN REPORTED SHORTLY AFTER INITIAL USE AS WELL AS AFTER SEVERAL YEARS OF USE. 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 WARNINGS and PRECAUTIONS .)

WARNINGS 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 of valproate therapy. 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 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 with the aforementioned conditions. When valproate sodium injection 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. Use of valproate sodium injection has not been studied in children below the age of 2 years. Above this age group, experience with valproate products 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 BOXED WARNING ). Urea Cycle Disorders (UCD) Valproate 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 CONTRAINDICATIONS and PRECAUTIONS ). 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 DOSAGE AND ADMINISTRATION ). Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia [see PRECAUTIONS ]) may be dose-related. In a clinical trial of divalproex sodium as monotherapy in patients with epilepsy, 34/126 patients (27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x 10 9 /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. Post-traumatic Seizures A study was conducted to evaluate the effect of IV valproate in the prevention of post-traumatic seizures in patients with acute head injuries. Patients were randomly assigned to receive either IV valproate given for one week (followed by oral valproate products for either one or six months per random treatment assignment) or IV phenytoin given for one week (followed by placebo). In this study, the incidence of death was found to be higher in the two groups assigned to valproate treatment compared to the rate in those assigned to the IV phenytoin treatment group (13% vs 8.5%, respectively). Many of these patients were critically ill with multiple and/or severe injuries, and evaluation of the causes of death did not suggest any specific drug-related causation. Further, in the absence of a concurrent placebo control during the initial week of intravenous therapy, it is impossible to determine if the mortality rate in the patients treated with valproate was greater or less than that expected in a similar group not treated with valproate, or whether the rate seen in the IV phenytoin treated patients was lower than would be expected. Nonetheless, until further information is available, it seems prudent not to use valproate sodium injection in patients with acute head trauma for the prophylaxis of post-traumatic seizures. 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 Congenital Malformations 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%-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 2.0% 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 4.0; 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. Neural Tube Defects THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS IS INCREASED IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE CENTERS FOR DISEASE CONTROL (CDC) HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED WOMEN HAVING CHILDREN WITH SPINA BIFIDA TO BE APPROXIMATELY 1 TO 2%. THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG) ESTIMATES THE GENERAL POPULATION RISK FOR CONGENITAL NEURAL TUBE DEFECTS AS 0.14% TO 0.2%. Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving valproate. Evidence suggests that pregnant women who receive folic acid supplementation may be at decreased risk for congenital neural tube defects in their offspring compared to pregnant women not receiving folic acid. Whether the risk of neural tube defects in the offspring of women receiving valproate specifically is reduced by folic acid supplementation is unknown. DIETARY FOLIC ACID SUPPLEMENTATION BOTH PRIOR TO AND DURING PREGNANCY SHOULD BE ROUTINELY RECOMMENDED TO PATIENTS CONTEMPLATING PREGNANCY. Other Adverse Pregnancy Effects PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES (SEE PRECAUTIONS - GENERAL AND WARNINGS ). 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 VALPROATE IS USED IN PREGNANCY, THE CLOTTING PARAMETERS SHOULD BE MONITORED CAREFULLY. PATIENTS TAKING VALPROATE MAY DEVELOP HEPATIC FAILURE (SEE WARNINGS - HEPATOTOXICITY AND BOX WARNING ). FATAL HEPATIC FAILURES, IN A NEWBORN AND IN AN INFANT, HAVE BEEN REPORTED FOLLOWING THE MATERNAL USE OF VALPROATE DURING PREGNANCY. 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 2 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 2 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 2 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).

ADVERSE REACTIONS The adverse events that can result from valproate sodium injection use include all of those associated with oral forms of valproate. The following describes experience specifically with valproate sodium injection. Valproate sodium injection has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6000 mg (total daily dose). A total of 2% of patients discontinued treatment with valproate sodium injection due to adverse events. The most common adverse events leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse events leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min. Adverse events reported by at least 0.5% of all subjects/patients in clinical trials of valproate sodium injection are summarized in Table 1. Table 1. Adverse Events Reported During Studies of valproate sodium injection Body System/Event N = 463 Body as a Whole Chest Pain 1.7% Headache 4.3% Injection Site Inflammation 0.6% Injection Site Pain 2.6% Injection Site Reaction 2.4% Pain (unspecified) 1.3% Cardiovascular Vasodilation 0.9% Dermatologic Sweating 0.9% Digestive System Abdominal Pain 1.1% Diarrhea 0.9% Nausea 3.2% Vomiting 1.3% Nervous System Dizziness 5.2% Euphoria 0.9% Hypesthesia 0.6% Nervousness 0.9% Paresthesia 0.9% Somnolence 1.7% Tremor 0.6% Respiratory Pharyngitis 0.6% Special Senses Taste Perversion 1.9% In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate sodium injection (up to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse events (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse events was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse events in the 2 cohorts cannot be made because of differences in patient populations and study designs. Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV valproate sodium injection cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium injection. 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. Table 2 lists treatment-emergent adverse events which were reported by ≥ 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse events can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs. Table 2. 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 Divalproex sodium (%) (n = 77) Placebo (%) (n = 70) 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 Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse events can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs. Table 3. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures 1 Body System/Event High Dose (%) (n = 131) Low Dose (%) (n = 134) 1 Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or greater incidence in the low dose group. 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 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: Body as a Whole Back pain, chest pain, malaise. Cardiovascular System Tachycardia, hypertension, palpitation. Digestive System Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess. Hemic and Lymphatic System Petechia. Metabolic and Nutritional Disorders SGOT increased, SGPT increased. Musculoskeletal System Myalgia, twitching, arthralgia, leg cramps, myasthenia. Nervous System Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder. Respiratory System Sinusitis, cough increased, pneumonia, epistaxis. Skin and Appendages Rash, pruritus, dry skin. Special Senses Taste perversion, abnormal vision, deafness, otitis media. Urogenital System 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. Gastrointestinal 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 using oral therapy. CNS Effects 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 WARNINGS – Urea Cycle Disorders and PRECAUTIONS ). Several reports have noted reversible cerebral atrophy and dementia in association with valproate therapy. Dermatologic 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 PRECAUTIONS - Drug Interactions ). Psychiatric Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral deterioration. Musculoskeletal Weakness. Hematologic Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage (see PRECAUTIONS - General and Drug Interactions ). 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. Hepatic 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 WARNINGS ). Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see PRECAUTIONS ). There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established. Pancreatic Acute pancreatitis including fatalities (see WARNINGS ). Metabolic Hyperammonemia (see PRECAUTIONS ), 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. Genitourinary Enuresis and urinary tract infection. Special Senses Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported. Other Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia. Mania Although valproate sodium injection has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets. Body as a Whole Chills, neck pain, neck rigidity. Cardiovascular System Hypotension, postural hypotension, vasodilation. Digestive System Fecal incontinence, gastroenteritis, glossitis. Musculoskeletal System Arthrosis. Nervous System Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo. Skin and Appendages Furunculosis, maculopapular rash, seborrhea. Special Senses Conjunctivitis, dry eyes, eye pain. Urogenital Dysuria. Migraine Although valproate sodium injection has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of divalproex sodium tablets. Body as a Whole Face edema. Digestive System Dry mouth, stomatitis. Urogenital System Cystitis, metrorrhagia, and vaginal hemorrhage.

<table> <caption>Table 1. Adverse Events Reported During Studies of valproate sodium injection</caption> <col/> <col/> <thead> <tr> <td> <content styleCode="bold">Body System/Event</content> </td> <td align="center"> <content styleCode="bold">N = 463</content> </td> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole</content> </td> <td align="center"> </td> </tr> <tr> <td> Chest Pain</td> <td align="center"> 1.7%</td> </tr> <tr> <td> Headache</td> <td align="center"> 4.3%</td> </tr> <tr> <td> Injection Site Inflammation</td> <td align="center"> 0.6%</td> </tr> <tr> <td> Injection Site Pain</td> <td align="center"> 2.6%</td> </tr> <tr> <td> Injection Site Reaction</td> <td align="center"> 2.4%</td> </tr> <tr> <td> Pain (unspecified)</td> <td align="center"> 1.3%</td> </tr> <tr> <td> <content styleCode="bold">Cardiovascular</content> </td> <td align="center"> </td> </tr> <tr> <td> Vasodilation</td> <td align="center"> 0.9%</td> </tr> <tr> <td> <content styleCode="bold">Dermatologic</content> </td> <td align="center"> </td> </tr> <tr> <td> Sweating</td> <td align="center"> 0.9%</td> </tr> <tr> <td> <content styleCode="bold">Digestive System</content> </td> <td align="center"> </td> </tr> <tr> <td> Abdominal Pain</td> <td align="center"> 1.1%</td> </tr> <tr> <td> Diarrhea</td> <td align="center"> 0.9%</td> </tr> <tr> <td> Nausea</td> <td align="center"> 3.2%</td> </tr> <tr> <td> Vomiting</td> <td align="center"> 1.3%</td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td align="center"> </td> </tr> <tr> <td> Dizziness</td> <td align="center"> 5.2%</td> </tr> <tr> <td> Euphoria</td> <td align="center"> 0.9%</td> </tr> <tr> <td> Hypesthesia</td> <td align="center"> 0.6%</td> </tr> <tr> <td> Nervousness</td> <td align="center"> 0.9%</td> </tr> <tr> <td> Paresthesia</td> <td align="center"> 0.9%</td> </tr> <tr> <td> Somnolence</td> <td align="center"> 1.7%</td> </tr> <tr> <td> Tremor</td> <td align="center"> 0.6%</td> </tr> <tr> <td> <content styleCode="bold">Respiratory</content> </td> <td align="center"> </td> </tr> <tr> <td> Pharyngitis</td> <td align="center"> 0.6%</td> </tr> <tr> <td> <content styleCode="bold">Special Senses</content> </td> <td align="center"> </td> </tr> <tr> <td> Taste Perversion</td> <td align="center"> 1.9%</td> </tr> </tbody> </table>

<table> <caption>Table 2. Adverse Events Reported by &#x2265; 5% of Patients Treated with divalproex sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures</caption> <col/> <col/> <col/> <thead> <tr> <td valign="bottom"> <content styleCode="bold">Body System/Event</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Divalproex sodium (%) (n = 77)</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Placebo (%) (n = 70)</content> </td> </tr> </thead> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Headache</td> <td align="center"> 31</td> <td align="center"> 21</td> </tr> <tr> <td> Asthenia</td> <td align="center"> 27</td> <td align="center"> 7</td> </tr> <tr> <td> Fever</td> <td align="center"> 6</td> <td align="center"> 4</td> </tr> <tr> <td> <content styleCode="bold">Gastrointestinal System </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Nausea</td> <td align="center"> 48</td> <td align="center"> 14</td> </tr> <tr> <td> Vomiting</td> <td align="center"> 27</td> <td align="center"> 7</td> </tr> <tr> <td> Abdominal Pain</td> <td align="center"> 23</td> <td align="center"> 6</td> </tr> <tr> <td> Diarrhea</td> <td align="center"> 13</td> <td align="center"> 6</td> </tr> <tr> <td> Anorexia</td> <td align="center"> 12</td> <td align="center"> 0</td> </tr> <tr> <td> Dyspepsia</td> <td align="center"> 8</td> <td align="center"> 4</td> </tr> <tr> <td> Constipation</td> <td align="center"> 5</td> <td align="center"> 1</td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Somnolence</td> <td align="center"> 27</td> <td align="center"> 11</td> </tr> <tr> <td> Tremor</td> <td align="center"> 25</td> <td align="center"> 6</td> </tr> <tr> <td> Dizziness</td> <td align="center"> 25</td> <td align="center"> 13</td> </tr> <tr> <td> Diplopia</td> <td align="center"> 16</td> <td align="center"> 9</td> </tr> <tr> <td> Amblyopia/Blurred Vision</td> <td align="center"> 12</td> <td align="center"> 9</td> </tr> <tr> <td> Ataxia</td> <td align="center"> 8</td> <td align="center"> 1</td> </tr> <tr> <td> Nystagmus</td> <td align="center"> 8</td> <td align="center"> 1</td> </tr> <tr> <td> Emotional Lability</td> <td align="center"> 6</td> <td align="center"> 4</td> </tr> <tr> <td> Thinking Abnormal</td> <td align="center"> 6</td> <td align="center"> 0</td> </tr> <tr> <td> Amnesia</td> <td align="center"> 5</td> <td align="center"> 1</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Flu Syndrome</td> <td align="center"> 12</td> <td align="center"> 9</td> </tr> <tr> <td> Infection</td> <td align="center"> 12</td> <td align="center"> 6</td> </tr> <tr> <td> Bronchitis</td> <td align="center"> 5</td> <td align="center"> 1</td> </tr> <tr> <td> Rhinitis</td> <td align="center"> 5</td> <td align="center"> 4</td> </tr> <tr> <td> <content styleCode="bold">Other</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Alopecia</td> <td align="center"> 6</td> <td align="center"> 1</td> </tr> <tr> <td> Weight Loss</td> <td align="center"> 6</td> <td align="center"> 0</td> </tr> </tbody> </table>

<table> <caption>Table 3. Adverse Events Reported by &#x2265; 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures¹ </caption> <col/> <col/> <col/> <thead> <tr> <td valign="bottom"> <content styleCode="bold">Body System/Event</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">High Dose (%) (n = 131)</content> </td> <td align="center" valign="bottom"> <content styleCode="bold">Low Dose (%) (n = 134)</content> </td> </tr> </thead> <tfoot> <tr> <td> <paragraph> <content styleCode="italics">1 Headache was the only adverse event that occurred in &#x2265; 5% of patients in the high dose group and at an equal or greater incidence in the low dose group.</content> </paragraph> </td> </tr> </tfoot> <tbody> <tr> <td> <content styleCode="bold">Body as a Whole</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Asthenia</td> <td align="center"> 21</td> <td align="center"> 10</td> </tr> <tr> <td> <content styleCode="bold">Digestive System</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Nausea</td> <td align="center"> 34</td> <td align="center"> 26</td> </tr> <tr> <td> Diarrhea</td> <td align="center"> 23</td> <td align="center"> 19</td> </tr> <tr> <td> Vomiting</td> <td align="center"> 23</td> <td align="center"> 15</td> </tr> <tr> <td> Abdominal Pain</td> <td align="center"> 12</td> <td align="center"> 9</td> </tr> <tr> <td> Anorexia</td> <td align="center"> 11</td> <td align="center"> 4</td> </tr> <tr> <td> Dyspepsia</td> <td align="center"> 11</td> <td align="center"> 10</td> </tr> <tr> <td> <content styleCode="bold">Hemic/Lymphatic System </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Thrombocytopenia</td> <td align="center"> 24</td> <td align="center"> 1</td> </tr> <tr> <td> Ecchymosis</td> <td align="center"> 5</td> <td align="center"> 4</td> </tr> <tr> <td> <content styleCode="bold">Metabolic/Nutritional </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Weight Gain</td> <td align="center"> 9</td> <td align="center"> 4</td> </tr> <tr> <td> Peripheral Edema</td> <td align="center"> 8</td> <td align="center"> 3</td> </tr> <tr> <td> <content styleCode="bold">Nervous System</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Tremor</td> <td align="center"> 57</td> <td align="center"> 19</td> </tr> <tr> <td> Somnolence</td> <td align="center"> 30</td> <td align="center"> 18</td> </tr> <tr> <td> Dizziness</td> <td align="center"> 18</td> <td align="center"> 13</td> </tr> <tr> <td> Insomnia</td> <td align="center"> 15</td> <td align="center"> 9</td> </tr> <tr> <td> Nervousness</td> <td align="center"> 11</td> <td align="center"> 7</td> </tr> <tr> <td> Amnesia</td> <td align="center"> 7</td> <td align="center"> 4</td> </tr> <tr> <td> Nystagmus</td> <td align="center"> 7</td> <td align="center"> 1</td> </tr> <tr> <td> Depression</td> <td align="center"> 5</td> <td align="center"> 4</td> </tr> <tr> <td> <content styleCode="bold">Respiratory System </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Infection</td> <td align="center"> 20</td> <td align="center"> 13</td> </tr> <tr> <td> Pharyngitis</td> <td align="center"> 8</td> <td align="center"> 2</td> </tr> <tr> <td> Dyspnea</td> <td align="center"> 5</td> <td align="center"> 1</td> </tr> <tr> <td> <content styleCode="bold">Skin and Appendages </content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Alopecia</td> <td align="center"> 24</td> <td align="center"> 13</td> </tr> <tr> <td> <content styleCode="bold">Special Senses</content> </td> <td align="center"> </td> <td align="center"> </td> </tr> <tr> <td> Amblyopia/Blurred Vision</td> <td align="center"> 8</td> <td align="center"> 4</td> </tr> <tr> <td> Tinnitus</td> <td align="center"> 7</td> <td align="center"> 1</td> </tr> </tbody> </table>