FDA label 970a776f-2cac-4d2e-be54-e10a3af85ec4

BOXED WARNING BOXED WARNING WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. Children under the age of 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When divalproex sodium extended-release tablets are 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. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. These incidents usually have occurred during the first 6 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 6 months [see Warnings and Precautions (5.1) ] . Fetal Risk: Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4) ]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2 , 5.3 , 5.4) ]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17) ]. 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 (5.5) ] . WARNING: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning • Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of 2 years are at considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter ( 5.1 ) • Teratogenicity, including neural tube defects ( 5.2 ) • Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) • Pancreatitis, including fatal hemorrhagic cases ( 5.3 )

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity; monitor liver function tests ( 5.1 ) • Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential ( 5.2 , 5.3 , 5.4 ) • Pancreatitis; divalproex sodium extended-release tablets should ordinarily be discontinued ( 5.5 ) • Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium extended-release tablets, increase the risk of suicidal thoughts or behavior ( 5.7 ) • Thrombocytopenia; monitor platelet counts and coagulation tests ( 5.8 ) • Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy ( 5.6 , 5.9 , 5.10 ) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate ( 5.11 ) • Multi-organ hypersensitivity reaction; discontinue divalproex sodium extended-release tablets ( 5.12 ) • Somnolence in the elderly can occur. Divalproex sodium extended-release tablets dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.14 ) 5.1 Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first 6 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 6 months. However, healthcare providers 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 2 years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium extended-release tablets are used in this patient group, they 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 [see Boxed Warning and Contraindications (4) ] . 5.2 Birth Defects Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations and malformations involving various body systems). The rate of congenital malformations among babies born to mothers using valproate is about 4 times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. 5.3 Decreased IQ Following in utero Exposure Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest of these studies 1 Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252. is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n = 62) had lower IQ scores at age 6 (97 [95% C.I. 94 to 101]) than children with prenatal exposure to the other antiepileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105 to 110]), carbamazepine (105 [95% C.I. 102 to 108]), and phenytoin (108 [95% C.I. 104 to 112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed. Although all of the available studies have methodological limitations, the weight of the evidence supports the conclusion that valproate exposure in utero can cause decreased IQ in children. In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1) ]. Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant should not be treated with valproate unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. 5.4 Use in Women of Childbearing Potential Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural tube defects), which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate. Women who are planning a pregnancy should be counseled regarding the relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1) ]. To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate. 5.5 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 two cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, divalproex sodium extended-release tablets should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed Warning ]. 5.6 Urea Cycle Disorders Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders (UCD). 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 divalproex sodium extended-release tablets 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 (4) and Warnings and Precautions (5.10) ]. 5.7 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including divalproex sodium extended-release tablets, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1,000 Patients Drug Patients with Events Per 1,000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1,000 Patients Epilepsy 1 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing divalproex sodium extended-release tablets or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. 5.8 Thrombocytopenia The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose related. In a clinical trial of valproate 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. Because of reports of thrombocytopenia, 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 extended-release tablets be monitored for platelet count and coagulation parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy. 5.9 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. Hyperammonemia should also be considered in patients who present with hypothermia [see Warnings and Precautions (5.11) ]. 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 Contraindications (4) and Warnings and Precautions (5.6 , 5.10) ] . During the placebo-controlled pediatric mania trial, one (1) in twenty (20) adolescents (5%) treated with valproate developed increased plasma ammonia levels compared to no (0) patients treated with placebo. 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. 5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of hyperammonemia [see Warnings and Precautions (5.11) ] . 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 valproate 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 Contraindications (4) and Warnings and Precautions (5.6 , 5.9) ]. 5.11 Hypothermia Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug Interactions (7.3) ] . Consideration should be given to stopping valproate in patients who develop hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy, confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and respiratory systems. Clinical management and assessment should include examination of blood ammonia levels. 5.12 Multi-Organ Hypersensitivity Reactions 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), 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. 5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1) ] . 5.14 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 reactions. 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 (2.4) ] . 5.15 Monitoring: Drug Plasma Concentration 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 [see Drug Interactions (7) ] . 5.16 Effect on Ketone and Thyroid Function Tests 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. 5.17 Effect on HIV and CMV Viruses Replication There are in vitro 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 in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically. 5.18 Medication Residue in the Stool There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.

<table ID="_Refid_23ecb7a6-c35e-4501-8d2c-8ccb79f9c"> <caption>Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis</caption> <col width="13%"/> <col width="22%"/> <col width="21%"/> <col width="34%"/> <col width="26%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph>Indication</paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>Placebo Patients with Events Per 1,000 Patients</paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>Drug Patients with Events Per 1,000 Patients</paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients</paragraph> </td> <td styleCode="Rrule Botrule Toprule " valign="top"> <paragraph>Risk Difference: Additional Drug Patients with Events Per 1,000 Patients</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Epilepsy</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>3.4</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>3.5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Psychiatric</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>5.7</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>8.5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.5</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Other</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.8</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>0.9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Total</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>2.4</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>4.3</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.8</paragraph> </td> <td styleCode="Rrule Botrule " valign="top"> <paragraph>1.9</paragraph> </td> </tr> </tbody> </table>

6 ADVERSE REACTIONS Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Information on pediatric adverse reactions is presented in section 8. • Most common adverse reactions (reported > 5%) reported in adult studies are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred vision, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus ( 6.1 , 6.2 , 6.3 , 6.4 ). • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ). To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch. 6.1 Mania The incidence of treatment-emergent events has been ascertained based on combined data from two 3-week placebo-controlled clinical trials of divalproex sodium extended-release tablets in the treatment of manic episodes associated with bipolar disorder. Table 3 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the divalproex sodium extended-release tablet-treated group was greater than 5% and greater than the placebo incidence. Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-release Tablet-Treated Patients During Placebo-Controlled Trials of Acute Mania The following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex sodium extendedrelease tablets: headache Adverse Event Divalproex Sodium Extended-release Tablets (n = 338) Placebo (n = 263) Somnolence 26% 14% Dyspepsia 23% 11% Nausea 19% 13% Vomiting 13% 5% Diarrhea 12% 8% Dizziness 12% 7% Pain 11% 10% Abdominal pain 10% 5% Accidental injury 6% 5% Asthenia 6% 5% Pharyngitis 6% 5% The following additional adverse reactions were reported by greater than 1% but not more than 5% of the divalproex sodium extended-release tablet-treated patients in controlled clinical trials: Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal. Cardiovascular System: Hypertension. Digestive System: Constipation, Dry Mouth, Flatulence. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral Edema. Musculoskeletal System: Myalgia. Nervous System: Abnormal Gait, Hypertonia, Tremor. Respiratory System: Rhinitis. Skin and Appendages: Pruritus, Rash. Special Senses: Conjunctivitis. Urogenital System: Urinary Tract Infection, Vaginitis. 6.2 Epilepsy Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium delayed-release tablets were generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium delayed-release tablet-treated patients (6%), compared to 1% of placebo-treated patients. Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium delayed-release tablet-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 reactions can be ascribed to divalproex sodium delayed-release tablets alone, or the combination of divalproex sodium delayed-release tablets and other antiepilepsy drugs. Table 4 Adverse Reactions Reported by > 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Event Divalproex Sodium Delayed- release Tablets (%) (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 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium delayed-release tablets 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 reactions can be ascribed to divalproex sodium delayed-release tablets alone, or the combination of valproate and other antiepilepsy drugs. Table 5 Adverse Reactions Reported by > 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 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 System/Event High Dose (%) (n = 131) Low Dose (%) (n = 134) 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 reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate 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. 6.3 Migraine Based on two placebo-controlled clinical trials and their long-term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate 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 reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-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%). Table 6 includes those adverse reactions reported for patients in the placebo-controlled trial where the incidence rate in the divalproex sodium extended-release tablets-treated group was greater than 5% and was greater than that for placebo patients. Table 6 Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-release Tablet-Treated Patients During the Migraine Placebo-Controlled Trial with a Greater Incidence than Patients Taking Placebo The following adverse reactions occurred in greater than 5% of divalproex sodium extended-release tablet-treated patients and at a greater incidence for placebo than for divalproex sodium extended-release tablets: asthenia and flu syndrome. Body System Event Divalproex Sodium Extended-release Tablets (n = 122) Placebo (n = 115) Gastrointestinal System Nausea 15% 9% Dyspepsia 7% 4% Diarrhea 7% 3% Vomiting 7% 2% Abdominal Pain 7% 5% Nervous System Somnolence 7% 2% Other Infection 15% 14% The following additional adverse reactions were reported by greater than 1% but not more than 5% of divalproex sodium extended-release tablet-treated patients and with a greater incidence than placebo in the placebo-controlled clinical trial for migraine prophylaxis: Body as a Whole: Accidental injury, viral infection. Digestive System: Increased appetite, tooth disorder. Metabolic and Nutritional Disorders: Edema, weight gain. Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo. Respiratory System: Pharyngitis, rhinitis. Skin and Appendages: Rash. Special Senses: Tinnitus. Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials where the incidence rate in the valproate-treated group was greater than 5% and was greater than that for placebo patients. Table 7 Adverse Reactions Reported by > 5% of Valproate-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence than Patients Taking Placebo The following adverse events occurred in greater than 5% of divalproex sodium delayed-release tablet-treated patients and at a greater incidence for placebo than for divalproex sodium delayed-release tablets: flu syndrome and pharyngitis. Body System Reaction Divalproex Sodium Delayed-release Tablets (n = 202) Placebo (n = 81) 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% The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 valproate-treated patients in the controlled clinical trials: Body as a Whole: Chest pain. Cardiovascular System: Vasodilatation. Digestive System: Constipation, dry mouth, flatulence, and stomatitis. Hemic and Lymphatic System: Ecchymosis. Metabolic and Nutritional Disorders: Peripheral edema. Musculoskeletal System: Leg cramps. Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking abnormalities. Respiratory System: Dyspnea, and sinusitis. Skin and Appendages: Pruritus. Urogenital System: Metrorrhagia. 6.4 Other Patient Populations Mania The following adverse reactions not listed previously were reported by greater than 1% of divalproex sodium delayed-release tablet treated patients and with a greater incidence than placebo in placebo-controlled trials of manic episodes associated with bipolar disorder: Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity. Cardiovascular System: Arrhythmia, hypotension, postural hypotension. Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage, mouth ulceration. Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia. Metabolic and Nutritional Disorders: Hypoproteinemia. Musculoskeletal System: Arthrosis. Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, psychosis, reflexes increased, sleep disorder, tardive dyskinesia. Respiratory System: Hiccup. Skin and Appendages: Discoid lupus erythematosus, erythema nodosum, furunculosis, maculopapular rash, seborrhea, sweating, vesiculobullous rash. Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion. Urogenital System: Cystitis, menstrual disorder. Epilepsy Adverse reactions 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. 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 and Precautions (5.6) ]. 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 Drug Interactions (7.2) ]. 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 Warnings and Precautions (5.8) and Drug Interactions (7) ]. 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 and Precautions (5.1) ]. Endocrine Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests [see Warnings and Precautions (5.16) ]. 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 and Precautions (5.5) ]. Metabolic Hyperammonemia [see Warnings and Precautions (5.9 , 5.10) ] , 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 [see Warnings and Precautions (5.11) ] . There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.

<table ID="_Refid_1ad83591-39c4-4369-b399-c6b343873"> <caption>Table 3. Adverse Reactions Reported by &gt; 5% of Divalproex Sodium Extended-release Tablet-Treated Patients During Placebo-Controlled Trials of Acute Mania<footnote ID="_Refid-4b4e32f5-2963-4600-8286-331117bc1">The following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex sodium extendedrelease tablets: headache</footnote> </caption> <col width="18%"/> <col width="47%"/> <col width="11%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Adverse Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Divalproex Sodium Extended-release Tablets</content> <content styleCode="bold">(n = 338)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo</content> <content styleCode="bold">(n = 263)</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>26%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>19%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Abdominal pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Accidental injury</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph>Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph>Pharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6%</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5%</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_0626a201-f2a4-4f40-a3b2-127e84102"> <caption>Table 4 Adverse Reactions Reported by &gt; 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures</caption> <col width="30%"/> <col width="31%"/> <col width="14%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Body System/Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Divalproex Sodium Delayed-</content> <content styleCode="bold">release Tablets (%)</content> <content styleCode="bold">(n = 77)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Placebo (%)</content> <content styleCode="bold">(n = 70)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Headache</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>31</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>21</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Fever</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Gastrointestinal System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>48</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>14</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Abdominal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Constipation</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>27</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>25</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Diplopia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>16</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Amblyopia/Blurred Vision</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Ataxia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nystagmus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Emotional Lability</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Thinking Abnormal</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Amnesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Flu Syndrome</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Bronchitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Rhinitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Other</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Weight Loss</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>6</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>0</paragraph> </td> </tr> </tbody> </table>

<table ID="_Refid_57e26ada-60aa-4522-a65b-1740505ac"> <caption>Table 5 Adverse Reactions Reported by &gt; 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures<footnote ID="_Refidajtqsd">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.</footnote> </caption> <col width="30%"/> <col width="17%"/> <col width="16%"/> <tbody> <tr> <td styleCode="Rrule Botrule Lrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Body System/Event</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">High Dose (%)</content> <content styleCode="bold">(n = 131)</content> </paragraph> </td> <td align="center" styleCode="Rrule Botrule Toprule " valign="top"> <paragraph> <content styleCode="bold">Low Dose (%)</content> <content styleCode="bold">(n = 134)</content> </paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Body as a Whole</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Asthenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>21</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Digestive System </content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nausea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>34</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>26</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Diarrhea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Vomiting</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>23</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Abdominal Pain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>12</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Anorexia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dyspepsia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>10</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Hemic/Lymphatic System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Thrombocytopenia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Ecchymosis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Metabolic/Nutritional</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Weight Gain</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Peripheral Edema</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>3</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Nervous System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Tremor</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>57</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>19</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Somnolence</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>30</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>18</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dizziness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>18</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Insomnia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>15</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>9</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nervousness</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>11</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Amnesia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Nystagmus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Depression</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Respiratory System</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Infection</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>20</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Pharyngitis</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>2</paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Dyspnea</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>5</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Skin and Appendages</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Alopecia</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>24</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>13</paragraph> </td> </tr> <tr> <td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> <content styleCode="bold">Special Senses</content> </paragraph> </td> </tr> <tr> <td styleCode="Rrule Lrule Botrule " valign="top"> <paragraph> Amblyopia/Blurred Vision</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>8</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>4</paragraph> </td> </tr> <tr> <td styleCode="Rrule Botrule Lrule " valign="top"> <paragraph> Tinnitus</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>7</paragraph> </td> <td align="center" styleCode="Rrule Botrule " valign="top"> <paragraph>1</paragraph> </td> </tr> </tbody> </table>