Valproate Sodium
Generic: VALPROATE SODIUM
Basic Information
Manufacturer
Fresenius Kabi USA, LLC
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
INTRAVENOUS
FDA Set ID
3dfb6da1-f66a-4618-9f74-d2d6c16c0b58
Indications & Usage
1 INDICATIONS AND USAGE Valproate sodium injection is indicated as an intravenous alternative in patients in whom oral administration of valproate products is temporarily not feasible in the following conditions: • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 ) 1.1 Epilepsy Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions: Valproate sodium injection 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.
Valproate sodium injection is also indicated for use as sole and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that 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 )] .
Valproate sodium injection is also indicated for use as sole and adjunctive therapy in the treatment of patients with simple and complex absence seizures, and adjunctively in patients with multiple seizure types that 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 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 , 5.8 , 5.9 )] • Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.7 )] • Hypothermia [see Warnings and Precautions ( 5.10 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.11 )] • Somnolence in the elderly [see Warnings and Precautions ( 5.13 )] 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 valproate sodium use include all of those associated with oral forms of valproate.
The following describes experience specifically with valproate sodium.
Valproate sodium 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 valproate sodium 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 valproate sodium are summarized in Table 1 .
Table 1.
Adverse Reactions Reported During Studies of Valproate Sodium Body System/Reaction N = 463 % Body as a Whole Headache 4.3 Injection Site Pain 2.6 Injection Site Reaction 2.4 Chest Pain 1.7 Pain (unspecified) 1.3 Injection Site Inflammation 0.6 Cardiovascular Vasodilation 0.9 Dermatologic Sweating 0.9 Digestive System Nausea 3.2 Vomiting 1.3 Abdominal Pain 1.1 Diarrhea 0.9 Nervous System Dizziness 5.2 Somnolence 1.7 Euphoria 0.9 Nervousness 0.9 Paresthesia 0.9 Hypesthesia 0.6 Tremor 0.6 Respiratory Pharyngitis 0.6 Special Senses Taste Perversion 1.9 In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate (up to 15 mg/kg) over 5 to 10 minutes (1.5 to 3 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 valproate sodium cannot be provided.
Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium.
Adverse reactions occurring in at least 5% of patients treated with divalproex sodium in Monotherapy or Adjunctive Complex Partial Seizures Trials: • Abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss ( 6.1 ) Additional Adverse Reactions not included above that occurred in > 0.5% of patients treated with valproate sodium: • Chest pain, euphoria, hypesthesia, injection site inflammation, injection site pain, injection site reaction, pain, sweating, taste perversion, vasodilation ( 6 ) Additional adverse reactions not included above that occurred in other clinical trials with divalproex sodium: • Accidental injury, back pain, increased appetite, rash ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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, 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 2 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 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
Table 2.
Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex Sodium % (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 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 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 valproate and other antiepilepsy drugs.
Table 3.
Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 1 Body System/Reaction High Dose % (n = 131) Low Dose % (n = 134) Body as a Whole Asthenia Digestive System 21 10 Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia Hemic/Lymphatic System 11 10 Thrombocytopenia 24 1 Ecchymosis Metabolic/Nutritional 5 4 Weight Gain 9 4 Peripheral Edema Nervous System 8 3 Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression Respiratory System 5 4 Infection 20 13 Pharyngitis 8 2 Dyspnea Skin and Appendages 5 1 Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 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 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.
6.2 Mania Although valproate sodium 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 : Dysuria.
6.3 Migraine Although valproate 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 Postmarketing 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, leucopenia, 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.
The adverse reactions that can result from valproate sodium use include all of those associated with oral forms of valproate.
The following describes experience specifically with valproate sodium.
Valproate sodium 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 valproate sodium 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 valproate sodium are summarized in Table 1 .
Table 1.
Adverse Reactions Reported During Studies of Valproate Sodium Body System/Reaction N = 463 % Body as a Whole Headache 4.3 Injection Site Pain 2.6 Injection Site Reaction 2.4 Chest Pain 1.7 Pain (unspecified) 1.3 Injection Site Inflammation 0.6 Cardiovascular Vasodilation 0.9 Dermatologic Sweating 0.9 Digestive System Nausea 3.2 Vomiting 1.3 Abdominal Pain 1.1 Diarrhea 0.9 Nervous System Dizziness 5.2 Somnolence 1.7 Euphoria 0.9 Nervousness 0.9 Paresthesia 0.9 Hypesthesia 0.6 Tremor 0.6 Respiratory Pharyngitis 0.6 Special Senses Taste Perversion 1.9 In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate (up to 15 mg/kg) over 5 to 10 minutes (1.5 to 3 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 valproate sodium cannot be provided.
Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium.
Adverse reactions occurring in at least 5% of patients treated with divalproex sodium in Monotherapy or Adjunctive Complex Partial Seizures Trials: • Abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss ( 6.1 ) Additional Adverse Reactions not included above that occurred in > 0.5% of patients treated with valproate sodium: • Chest pain, euphoria, hypesthesia, injection site inflammation, injection site pain, injection site reaction, pain, sweating, taste perversion, vasodilation ( 6 ) Additional adverse reactions not included above that occurred in other clinical trials with divalproex sodium: • Accidental injury, back pain, increased appetite, rash ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Kabi USA, LLC at 1-800-551-7176 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 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, 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 2 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 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 divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
Table 2.
Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalproex Sodium % (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 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 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 valproate and other antiepilepsy drugs.
Table 3.
Adverse Reactions Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures 1 Body System/Reaction High Dose % (n = 131) Low Dose % (n = 134) Body as a Whole Asthenia Digestive System 21 10 Nausea 34 26 Diarrhea 23 19 Vomiting 23 15 Abdominal Pain 12 9 Anorexia 11 4 Dyspepsia Hemic/Lymphatic System 11 10 Thrombocytopenia 24 1 Ecchymosis Metabolic/Nutritional 5 4 Weight Gain 9 4 Peripheral Edema Nervous System 8 3 Tremor 57 19 Somnolence 30 18 Dizziness 18 13 Insomnia 15 9 Nervousness 11 7 Amnesia 7 4 Nystagmus 7 1 Depression Respiratory System 5 4 Infection 20 13 Pharyngitis 8 2 Dyspnea Skin and Appendages 5 1 Alopecia 24 13 Special Senses Amblyopia/Blurred Vision 8 4 Tinnitus 7 1 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 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.
6.2 Mania Although valproate sodium 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 : Dysuria.
6.3 Migraine Although valproate 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 Postmarketing 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, leucopenia, 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.