VALPROIC ACID

WARNING: LIFE THREATENING ADVERSE REACTIONS WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1) ]. Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Valproic acid oral solution is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications (4) ]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, valproic acid oral solution should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with valproic acid oral solution for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions (5.1) ]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate should only be used to treat pregnant women with epilepsy if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [ see Warnings and Precautions (5.2, 5.3, 5.4) ]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17) ]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions (5.5) ]. See full prescribing information for complete boxed warning. Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4) Pancreatitis, including fatal hemorrhagic cases (5.5)

5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in association with other organ system involvement, such as hepatitis, nephritis, haematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an alternative etiology for the signs or symptoms cannot be established.

5.13 Interaction with Carbapenem Antibiotics Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1) ].

5.14 Somnolence in the Elderly In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years), doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion of valproate patients had somnolence compared to placebo, and although not statistically significant, there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also significantly higher than with placebo. In some patients with somnolence (approximately one-half), there was associated reduced nutritional intake and weight loss. There was a trend for the patients who experienced these events to have a lower baseline albumin concentration, lower valproate clearance, and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence [see Dosage and Administration (2.2) ].

5.15 Monitoring: Drug Plasma Concentration Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy [see Drug Interactions (7) ] .

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, 5.9, 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 (5.14) ] 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. Most common adverse reactions (reported >5%) are 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, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss. (6.1) The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4) To report SUSPECTED ADVERSE REACTIONS, contact Quagen Pharmaceuticals LLC at 1-888-344-9603 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 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 3: 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 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. Table 4: Adverse Reactions Reported by 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures 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. Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) 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 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. 6.2 Mania Although valproic acid oral solution 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 oral solution 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 3: 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 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. Table 4: Adverse Reactions Reported by 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Monotherapy for Complex Partial Seizures 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. Body System/Reaction High Dose (%) (n = 131) Low Dose (%) (n = 134) 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 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.

6.2 Mania Although valproic acid oral solution 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 oral solution 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.