Valproic Acid
Generic: VALPROIC ACID
Basic Information
Manufacturer
Xttrium Laboratories Inc.
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
3b124a29-30bd-d30e-e063-6294a90ac4ca
Indications & Usage
1 INDICATIONS AND USAGE 1.1 Epilepsy Valproic acid is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures.
Valproic acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precautions ( 5.1 ) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 )] .
For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] .
Valproic acid is indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
See Warnings and Precautions ( 5.1 ) for statement regarding fatal hepatic dysfunction.
1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 )] .
For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] .
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Hepatic failure [see Warnings and Precautions ( 5.1 )] • Birth defects [see Warnings and Precautions ( 5.2 )] • Decreased IQ and Neurodevelopmental Disorders following in utero exposure [see Warnings and Precautions ( 5.3 )] • Pancreatitis [see Warnings and Precautions ( 5.5 )] • Hyperammonemic encephalopathy [see Warnings and Precautions ( 5.6 , 5.9 , 5.10 )] • Suicidal behavior and ideation [see Warnings and Precautions ( 5.7 )] • Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.8 )] • Hypothermia [see Warnings and Precautions ( 5.11 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.12 )] • Somnolence in the elderly [see Warnings and Precautions ( 5.12 )] 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.
6.1 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 reactions 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 3 lists treatment-emergent adverse reactions 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 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
Table 4 lists treatment-emergent adverse reactions 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 reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
1 Headache was the only adverse reaction 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 reactions 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.
Adverse reactions adverse reactions reported 6.2 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 reactions 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.
6.3 Migraine Although valproic acid 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 divalproex sodium tablets.
Body as a Whole : Face edema.
Digestive System : Dry mouth, stomatitis.
Urogenital System : Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of divalproex sodium.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic : Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.
Psychiatric : Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic : Paradoxical convulsion, parkinsonism There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.
There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes.
The encephalopathy reversed partially or fully after valproate discontinuation.
Musculoskeletal : Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.
Hematologic : Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine : Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Metabolism and nutrition : Weight gain.
Reproductive : Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.
Genitourinary : Enuresis and urinary tract infection.
Special Senses : Hearing loss.
Other : Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.
6.1 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 reactions 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 3 lists treatment-emergent adverse reactions 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 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
Table 4 lists treatment-emergent adverse reactions 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 reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
1 Headache was the only adverse reaction 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 reactions 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.
Adverse reactions adverse reactions reported 6.2 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 reactions 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.
6.3 Migraine Although valproic acid 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 divalproex sodium tablets.
Body as a Whole : Face edema.
Digestive System : Dry mouth, stomatitis.
Urogenital System : Cystitis, metrorrhagia, and vaginal hemorrhage.
6.4 Post-Marketing Experience The following adverse reactions have been identified during post approval use of divalproex sodium.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Dermatologic : Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.
Psychiatric : Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.
Neurologic : Paradoxical convulsion, parkinsonism There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.
There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes.
The encephalopathy reversed partially or fully after valproate discontinuation.
Musculoskeletal : Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.
Hematologic : Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.
Endocrine : Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.
There have been rare reports of Fanconi's syndrome occurring chiefly in children.
Metabolism and nutrition : Weight gain.
Reproductive : Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.
Genitourinary : Enuresis and urinary tract infection.
Special Senses : Hearing loss.
Other : Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.