ADVERSE REACTIONS
Epilepsy
The data described in the following section were obtained using DEPAKOTE (divalproex sodium) tablets.
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 2 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 a placebo-controlled trial of adjunctive therapy for the 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 2. 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 3 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 3. 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) |
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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 (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose-related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes in other liver function tests. These results may reflect potentially serious hepatotoxicity (see WARNINGS).
Endocrine
Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests (see PRECAUTIONS).
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
Pancreatic
Acute pancreatitis, including fatalities (see WARNINGS).
Metabolic
Hyperammonemia (see PRECAUTIONS), hyponatremia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.
Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent nonketotic hyperglycinemia.
Genitourinary
Enuresis and urinary tract infection.
Special Senses
Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect relationship has not been established. Ear pain has also been reported.
Other
Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia.
Mania
Although DEPAKENE has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE tablets.
Body as a Whole
Chills, neck pain, neck rigidity.
Cardiovascular System
Hypotension, postural hypotension, vasodilation.
Digestive System
Fecal incontinence, gastroenteritis, glossitis.
Musculoskeletal System
Arthrosis.
Nervous System
Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
Skin and Appendages
Furunculosis, maculopapular rash, seborrhea.
Special Senses
Conjunctivitis, dry eyes, eye pain.
Urogenital System
Dysuria.
Migraine
Although DEPAKENE has not been evaluated for safety and efficacy in the treatment of prophylaxis of migraine headaches, the following adverse events not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of DEPAKOTE tablets.
Body as a Whole
Face edema.
Digestive System
Dry mouth, stomatitis.
Urogenital System
Cystitis, metrorrhagia, and vaginal hemorrhage.
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