ADVERSE REACTIONS
Mania
The incidence of treatment-emergent events has been ascertained based on combined data from two placebo-controlled clinical trials of DEPAKOTE 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, DEPAKOTE, and lithium carbonate. A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, DEPAKOTE, and lithium carbonate groups, respectively.
Table 1 summarizes those adverse events reported for patients in these trials where the incidence rate in the DEPAKOTE-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the DEPAKOTE-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 DEPAKOTE compared to placebo.
Table 1. Adverse Events Reported by > 5% of DEPAKOTE-Treated Patients During Placebo-Controlled Trials of Acute Mania1 | Adverse Event | DEPAKOTE
(n = 89) | Placebo
(n = 97) |
|
1. The following adverse events occurred at an equal or greater incidence for placebo than for DEPAKOTE: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
|
| 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% |
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.
Migraine
Based on two placebo-controlled clinical trials and their long term extension, DEPAKOTE was generally well tolerated with most adverse events rated as mild to moderate in severity. Of the 202 patients exposed to DEPAKOTE 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 DEPAKOTE-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 2 includes those adverse events reported for patients in the placebo-controlled trials where the incidence rate in the DEPAKOTE-treated group was greater than 5% and was greater than that for placebo patients.
Table 2. Adverse Events Reported by > 5% of DEPAKOTE-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1 | Body System Event | Depakote
(N = 202) | Placebo
(N = 81) |
|
1. The following adverse events occurred in at least 5% of DEPAKOTE-treated patients and at an equal or greater incidence for placebo than for DEPAKOTE: flu syndrome and pharyngitis.
|
| 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 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.
Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, DEPAKOTE was generally well tolerated with most adverse events rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the DEPAKOTE-treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse events which were reported by ≥ 5% of DEPAKOTE-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 DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.
Table 3. Adverse Events Reported by ≥ 5% of Patients Treated with DEPAKOTE During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures | Body System/Event | Depakote (%)
(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 4 lists treatment-emergent adverse events which were reported by ≥ 5% of patients in the high dose DEPAKOTE group, and for which the incidence was greater than in the low dose group, in a controlled trial of DEPAKOTE 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 DEPAKOTE alone, or the combination of DEPAKOTE and other antiepilepsy drugs.
Table 4. Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of DEPAKOTE Monotherapy for Complex Partial Seizures1 | 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 DEPAKOTE 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.
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 (eg, 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.
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