ADVERSE REACTIONS ManiaThe incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse events were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively.Table 2 summarizes those adverse events reported for patients in these trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium-treated group was statistically significantly greater than the placebo group. Vomiting was the only event that was reported by significantly (p ≤ 0.05) more patients receiving divalproex sodium compared to placebo.Table 2. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Placebo-Controlled Trials of Acute Mania1 Adverse EventDivalproex sodium(n = 89)Placebo(n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3%1 The following adverse events occurred at an equal or greater incidence for placebo than for divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.The following additional adverse events were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials:Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia, vasodilation.Digestive System: Anorexia, fecal incontinence, flatulence, gastroenteritis, glossitis, periodontal abscess.Hemic and Lymphatic System: Ecchymosis.Metabolic and Nutritional Disorders: Edema, peripheral edema.Musculoskeletal System: Arthralgia, arthrosis, leg cramps, twitching.Nervous System: Abnormal dreams, abnormal gait, agitation, ataxia, catatonic reaction, confusion, depression, diplopia, dysarthria, hallucinations, hypertonia, hypokinesia, insomnia, paresthesia, reflexes increased, tardive dyskinesia, thinking abnormalities, vertigo.Respiratory System: Dyspnea, rhinitis.Skin and Appendages: Alopecia, discoid lupus erythematosis, dry skin, furunculosis, maculopapular rash, seborrhea.Special Senses: Amblyopia, conjunctivitis, deafness, dry eyes, ear pain, eye pain, tinnitus.Urogenital System: Dysmenorrhea, dysuria, urinary incontinence.MigraineBased on two placebo-controlled clinical trials and their long term extension, divalproex sodium was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to divalproex sodium in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse events reported as the primary reason for discontinuation by ≥ 1% of 248 divalproex sodium-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).Table 3 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and was greater than that for placebo patients.Table 3. Adverse Events Reported by > 5% of Divalproex Sodium-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1Body System EventDivalproex sodium(n = 202)Placebo(n = 81)1 The following adverse events occurred in at least 5% of divalproex sodium-treated patients and at an equal or greater incidence for placebo than for divalproex sodium: flu syndrome and pharyngitis.Gastrointestinal System Nausea31%10% Dyspepsia13%9% Diarrhea12%7% Vomiting11%1% Abdominal pain9%4% Increased appetite6%4%Nervous System Asthenia20%9% Somnolence17%5% Dizziness12%6% Tremor9%0%Other Weight gain8%2% Back pain8%6% Alopecia7%1%The following additional adverse events were reported by greater than 1% but not more than 5% of the 202 divalproex sodium-treated patients in the controlled clinical trials: Body as a Whole: Chest pain, chills, face edema, fever, and malaise.Cardiovascular System: Vasodilatation.Digestive System: Anorexia, constipation, dry mouth, flatulence, gastrointestinal disorder (unspecified), and stomatitis.Hemic and Lymphatic System: Ecchymosis.Metabolic and Nutritional Disorders: Peripheral edema, SGOT increase, and SGPT increase.Musculoskeletal System: Leg cramps and myalgia.Nervous System: Abnormal dreams, amnesia, confusion, depression, emotional lability, insomnia, nervousness, paresthesia, speech disorder, thinking abnormalities, and vertigo.Respiratory System: Cough increased, dyspnea, rhinitis, and sinusitis.Skin and Appendages: Pruritus and rash.Special Senses: Conjunctivitis, ear disorder, taste perversion, and tinnitus.Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.EpilepsyBased 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 4 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 4. Adverse Events Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial SeizuresBody System/Event Divalproex sodium (%)(n = 77)Placebo (%)(n = 70)Body as a Whole Headache3121 Asthenia277 Fever64Gastrointestinal System Nausea4814 Vomiting277 Abdominal Pain236 Diarrhea136 Anorexia120 Dyspepsia84 Constipation51Nervous System Somnolence2711 Tremor256 Dizziness2513 Diplopia169 Amblyopia/Blurred Vision129 Ataxia81 Nystagmus81 Emotional Lability64 Thinking Abnormal60 Amnesia51Respiratory System Flu Syndrome129 Infection126 Bronchitis51 Rhinitis54Other Alopecia61 Weight Loss60Table 5 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 5. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures1Body System/EventHigh Dose (%)(n = 131)Low Dose (%) (n = 134)Body as a Whole Asthenia2110Digestive System Nausea3426 Diarrhea2319 Vomiting2315 Abdominal Pain129 Anorexia114 Dyspepsia1110Hemic/Lymphatic System Thrombocytopenia241 Ecchymosis54Metabolic/Nutritional Weight Gain94 Peripheral Edema83Nervous System Tremor5719 Somnolence3018 Dizziness1813 Insomnia159 Nervousness117 Amnesia74 Nystagmus71 Depression54Respiratory System Infection2013 Pharyngitis82 Dyspnea51Skin and Appendages Alopecia2413Special Senses Amblyopia/Blurred Vision84 Tinnitus711 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.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 PopulationsAdverse 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.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.