Drug Information for VALPROIC ACID SYRUP (Valproic Acid Oral Solution, USP) 250 mg/5 mL (Morton Grove Pharmaceuticals, Inc.): ADVERSE REACTIONS

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  • Epilepsy

    The data described in the following section were obtained using divalproex sodium tablets.

    Based 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 1 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 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.

    Table 1 Adverse Events Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
    Body System/EventDivalproex Sodium (%)(n = 77)Placebo (%)(n = 70)
    Body as a Whole
    Headache3121
    Asthenia277
    Fever64
    Gastrointestinal System
    Nausea4814
    Vomiting277
    Abdominal Pain236
    Diarrhea136
    Anorexia120
    Dyspepsia84
    Constipation51
    Nervous System
    Somnolence2711
    Tremor256
    Dizziness2513
    Diplopia169
    Amblyopia/Blurred Vision129
    Ataxia81
    Nystagmus81
    Emotional Lability64
    Thinking Abnormal60
    Amnesia51
    Respiratory System
    Flu Syndrome129
    Infection126
    Bronchitis51
    Rhinitis54
    Other
    Alopecia61
    Weight Loss60

    Table 2 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 2 Adverse Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial SeizuresHeadache 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/EventHigh Dose (%)(n = 131)Low Dose (%)(n = 134)
    Body as a Whole
    Asthenia2110
    Digestive System
    Nausea3426
    Diarrhea2319
    Vomiting2315
    Abdominal Pain129
    Anorexia114
    Dyspepsia1110
    Hemic/Lymphatic System
    Thrombocytopenia241
    Ecchymosis54
    Metabolic/Nutritional
    Weight Gain94
    Peripheral Edema83
    Nervous System
    Tremor5719
    Somnolence3018
    Dizziness1813
    Insomnia159
    Nervousness117
    Amnesia74
    Nystagmus71
    Depression54
    Respiratory System
    Infection2013
    Pharyngitis82
    Dyspnea51
    Skin and Appendages
    Alopecia2413
    Special Senses
    Amblyopia/Blurred Vision84
    Tinnitus71

    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 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 the 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 valproic acid 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 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 System: Dysuria.

    Migraine

    Although valproic acid 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 divalproex sodium tablets.

    Body as a Whole: Face edema.

    Digestive System: Dry mouth, stomatitis.

    Urogenital System: Cystitis, metrorrhagia, and vaginal hemorrhage.

  • Drug Information Provided by National Library of Medicine (NLM).
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