Valproate sodium adverse reactions

# Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Hepatic failure (5.1)
- Birth defects (5.2)
- Decreased IQ following in utero exposure (5.3)
- Pancreatitis (5.5)
- Thrombocytopenia (5.8)
- Hyperammonemic encephalopathy (5.9, 5.10)
- Multi-organ hypersensitivity reactions (5.12)
- Somnolence in the elderly (5.14)
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.
The adverse reactions that can result from Depacon use include all of those associated with oral forms of valproate. The following describes experience specifically with Depacon. Depacon has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6,000 mg (total daily dose). A total of 2% of patients discontinued treatment with Depacon due to adverse reactions. The most common adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse reactions leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min.
Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of Depacon are summarized in Table 1.
In a separate clinical safety trial, 112 patients with epilepsy were given infusions of Depacon (up to 15 mg/kg) over 5 to 10 minutes (1.5-3.0 mg/kg/min). The common adverse reactions (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse reactions was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot be made because of differences in patient populations and study designs.
Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV Depacon cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of Depacon.

### Epilepsy
Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote (divalproex sodium) was generally well tolerated with most adverse reactions 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 reactions 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 reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.
Table 3 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 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 reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.
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.

### Mania
Although Depacon has not been evaluated for safety and efficacy in the treatment of manic episodes associated with bipolar disorder, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium) tablets.
- Body as a Whole: Chills, neck pain, neck rigidity.
- Cardiovascular System: Hypotension, postural hypotension, vasodilation.
- Digestive System: Fecal incontinence, gastroenteritis, glossitis.
- Musculoskeletal System: Arthrosis.
- Nervous System: Agitation, catatonic reaction, hypokinesia, reflexes increased, tardive dyskinesia, vertigo.
- Skin and Appendages: Furunculosis, maculopapular rash, seborrhea.
- Special Senses: Conjunctivitis, dry eyes, eye pain.
- Urogenital: Dysuria.

### Migraine
Although Depacon has not been evaluated for safety and efficacy in the prophylactic treatment of migraine headaches, the following adverse reactions not listed above were reported by 1% or more of patients from two placebo-controlled clinical trials of Depakote (Divalproex Sodium) tablets.
- Body as a Whole: Face edema.
- Digestive System: Dry mouth, stomatitis.
- Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

### Other Patient Populations
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 using oral therapy.
- CNS Effects: Sedative effects have occurred in patients receiving valproate alone but occur most often in patients receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication. Tremor (may be dose-related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots before eyes," dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without fever has developed shortly after the introduction of valproate monotherapy without evidence of hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been described following drug withdrawal, there have been fatalities in patients with hyperammonemic encephalopathy, particularly in patients with underlying urea cycle disorders .
There have been postmarketing reports of reversible and irreversible cerebral and cerebellar atrophy temporally associated with the use of valproate products. In some cases the patients recovered with permanent sequelae . Cerebral atrophy has been reported in children exposed to valproate in utero.
- 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 .
- 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 . Relative lymphocytosis, macrocytosis, hypofibrinogenemia, leucopenia, 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 .
- Endocrine: Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling. Abnormal thyroid function tests .
There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship has not been established.
- Pancreatic: Acute pancreatitis including fatalities .
- Metabolic: Hyperammonemia , 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.
There have been reports of developmental delay, autism and/or autism spectrum disorder in the offspring of women exposed to valproate during pregnancy.