you are looking [2:<2 years of age in whom there is a clinical suspicion of a mitochondrial disorder. 179 182 183 185 In children> 2 years of age with suspected hereditary mitochondrial disease, use only if other anticonvulsant therapies have failed; closely monitor such patients with regular clinical assessments and liver function tests. 179 182 183 185 Perform POLG mutation screening according to current clinical practice. 179 182 183 185 222 223 Fetal Risk Risk of major congenital malformations, particularly neural tube defects (NTDs). 182 183 184 185 188 189 190 191 192 193 194 Risk of decreased IQ scores following in utero exposure. 182 196 197 198 199 200 201 202 203 204 205 206 207 212 Contraindicated in pregnant women for migraine prophylaxis. 182 205 In pregnant women with epilepsy or bipolar disorder, use only if other therapies fail or are otherwise unacceptable. 182 205 Do not use in women of childbearing potential unless the drug is essential to their medical condition. 182 183 184 185 This is particularly important when contemplating treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine headaches). 182 183 184 185 (See Pregnancy under Cautions.) A medication guide describing the risks of valproic acid is available for patients. 182 183 188 (See Advice to Patients.) Pancreatitis Life-threatening pancreatitis has occurred both in children and adults. 179 182 183 184 185 Some cases described as hemorrhagic with rapid progression from initial symptoms to death. 179 182 183 184 185 Can occur shortly after initial use as well as after several years of use. 179 182 183 184 185 Warn patients and caregivers that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. 179 182 183 184 185 Usually discontinue the drug and initiate alternative therapy if pancreatitis is diagnosed. 179 182 183 184 185 Introduction Valproic acid (the active moiety), valproate sodium, and divalproex sodium are carboxylic acid-derivative anticonvulsants; also antimanic, other psychotherapeutic, and antimigraine agents. 182 183 184 185 b Uses for Divalproex Sodium Valproic acid (ionized form: valproate) is the active moiety for valproate sodium and divalproex sodium. b Absence (Petit Mal) Seizures Alone or with other anticonvulsants (e.g., ethosuximide) as first-line therapy in the prophylactic management of simple and complex absence (petit mal) seizures. 179 182 183 184 185 224 b In conjunction with other anticonvulsants in the management of multiple seizure types that include absence seizures. b Complex Partial Seizures Alone or with other anticonvulsants (e.g., carbamazepine, phenytoin) as first-line therapy in the prophylactic management of complex partial seizures that occur either by themselves or in association with other seizure types. 179 182 183 184 185 b Generalized Seizures First-line therapy for generalized seizures, including primary generalized tonic-clonic , primary generalized tonic-clonic absence , myoclonic , or atonic seizures , especially when more than one type of generalized seizure is present. b Simple Partial Seizures First-line therapy for the management of simple partial seizures . b Status Epilepticus Has been administered rectally or by intragastric drip with some success in the management of status epilepticus refractory to IV diazepam. b A parenteral formulation of valproic acid has been studied and has been effective when administered IV in the management of status epilepticus. b Bipolar Disorder Alone or as a component of combination therapy (e.g., with lithium, antipsychotic agents [e.g., olanzapine], antidepressants, carbamazepine) for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. 182 183 214 American Psychiatric Association (APA) currently recommends combined therapy with valproic acid plus an antipsychotic agent or with lithium plus an antipsychotic agent as first-line drug therapy for the acute treatment of more severe manic or mixed episodes and monotherapy with one of these drugs for less severe episodes. b Valproic acid or lithium also is recommended for the initial acute treatment of rapid cycling. b Some clinicians recommend that valproic acid therapy be used in patients with bipolar disorder or schizoaffective disorder, bipolar type, who have responded inadequately to or have been unable to tolerate treatment with lithium salts or other therapy (e.g., carbamazepine), particularly if the patient displays residual manic symptoms, or in the presence of rapid-cycling, dysphoric mania or hypomania, associated neurologic abnormalities, or organic brain disorder. b Migraine Prophylaxis of migraine headache. 170 182 183 214 b Because valproic acid poses a hazard to the fetus (see Fetal Risk in Boxed Warning and also see Pregnancy under Cautions), do not use in pregnant women for migraine prophylaxis; in such patients, the risks of the drug outweigh any possible benefits. 182 183 184 185 205 Use in women of childbearing potential only if the drug is essential. 182 183 184 185 188 190 196 205 The US Headache Consortium states that valproic acid has medium to high efficacy for the prophylaxis of migraine headache. 170 b Has also been used IV for the acute management (i.e., abortive therapy) of migraine headache; 157 158 160 161 162 163 164 166 however, role of drug relative to other acute therapies requires further elucidation. 156 166 170 172 173 Schizophrenia As an adjunct to antipsychotic drugs in the symptomatic management of schizophrenia in patients who fail to respond sufficiently to an adequate trial of an antipsychotic agent alone. 146 147 148 APA 146 and some clinicians 148 state that anticonvulsant agents such as valproic acid and divalproex sodium may be useful adjuncts in schizophrenic patients with prominent mood lability or in those with agitated, aggressive, hostile, or violent behavior. 146 148 APA states that, with the exception of patients with schizophrenia whose illness has strong affective components, monotherapy with valproic acid or divalproex sodium has not been shown to be substantially effective in the long-term treatment of schizophrenia. 146 Divalproex Sodium Dosage and Administration General Do not abruptly discontinue anticonvulsants, including valproic acid, in patients with seizure disorders; withdraw gradually to minimize the potential for increased seizure frequency. 182 183 184 Closely monitor patients for marked changes in behavior that could indicate emergence or worsening of suicidal thoughts or behavior or depression. 176 177 178 180 183 184 (See Suicidality Risk under Cautions.) Distribute medication guide explaining risks and benefits of therapy to patients receiving oral formulations of the drug. 188 Administration Administer valproate sodium orally or by IV infusion; administer valproic acid and divalproex sodium orally. 182 183 184 185 b Valproic acid also has been administered rectally by enema or in wax-based suppositories, but a rectal dosage form is not commercially available in the US. b Oral Administration Valproic acid, valproate sodium, and divalproex sodium are administered orally. 182 183 184 b If GI irritation occurs, may administer with food or gradually increase dosage from an initial low dosage. 179 182 183 184 b Patients unable to tolerate the GI effects of valproic acid or valproate sodium may tolerate divalproex sodium. b If a dose is missed, take as soon as possible unless it is almost time for the next dose. 182 183 184 Do not double a dose to make up for a missed dose. 182 183 184 Divalproex sodium extended-release tablets are not bioequivalent to the delayed-release tablets. 182 Although the extent of GI absorption of valproic acid from capsules containing coated particles or delayed-release tablets of divalproex sodium is equivalent, peak and trough plasma concentrations achieved may vary (e.g., peak valproic acid concentrations generally are higher with the delayed-release tablets); increased monitoring of plasma valproic acid concentrations is recommended if one dosage form is substituted for the other. b Formulation-specific Administration Instructions Administer divalproex sodium extended-release tablets (e.g., Depakote ER) once daily; for other oral formulations, administer in divided doses if total daily dosage >250 mg. 179 182 183 184 214 Valproic acid capsules: Swallow capsules whole, not chewed, in order to prevent mouth and throat irritation. 184 b Valproate sodium oral solution: Do not administer in carbonated beverages. b Valproic acid delayed-release capsules (Stavzor ): Swallow capsules whole; do not crush, chew, or break. 214 Divalproex sodium delayed-release (e.g., Depakote ) or extended-release (e.g., Depakote ER) tablets: Swallow tablets intact; do not chew or crush. 182 183 Capsules containing coated particles of divalproex sodium (e.g., Depakote Sprinkle Capsules): Swallow capsules intact or sprinkle entire contents of capsule(s) on a small amount (about 5 mL) of soft food (e.g., applesauce, pudding) and swallow (not chew) immediately. 179 Do not store the mixture for future use. 179 IV Administration For solution and drug compatibility information, see Compatibility under Stability. Valproate sodium injection is intended for IV use only. 185 Dilution For IV use, dilute the appropriate dose of valproate sodium injection with at least 50 mL of a compatible IV solution (e.g., 5% dextrose injection, 0.9% sodium chloride injection, lactated Ringer s injection). 185 b (See Solution Compatibility under Stability.) Rate of Administration Infuse diluted IV solutions over 60 minutes; the manufacturer recommends that the rate not exceed 20 mg/minute. 185 Rapid IV infusion has been associated with an increased risk of adverse effects. b Experience from clinical studies of rates >20 mg/minute or infusion periods <60 minutes is limited. b In a study of the safety of initial 5- to 10-minute IV infusions of valproate sodium (1.5 3 mg/kg per minute of valproic acid), patients generally tolerated such rapid infusions; however, the study was not designed to assess the efficacy of the regimen. 185 b Use of rapid infusions as a parenteral replacement for oral valproic acid has not been established. b Dosage Dosage of valproate sodium and divalproex sodium is expressed in terms of valproic acid. b Must adjust dosage carefully and slowly according to individual requirements and response. b An anticonvulsant therapeutic range of 50 100 mcg/mL has been suggested; seizure control occasionally may occur with lower or higher concentrations, but> 150 mcg/mL usually is toxic. b For acute manic or mixed episodes in bipolar disorder, usually dosed to clinical response with trough plasma concentrations of 50 125 mcg/mL. 182 183 Frequency of adverse effects (particularly elevated liver enzyme concentrations and thrombocytopenia) may be dose related; carefully weigh the benefit of improved therapeutic effect that may accompany higher dosages against the risk of adverse effects. 182 183 b (See Thrombocytopenia under Cautions.) When switching to divalproex sodium delayed-release tablets or valproic acid delayed-release capsules in patients receiving conventional valproic acid, use same daily dosage and schedule. 183 214 After stabilization with the delayed-release formulation, may divide daily dosage and administer 2 or 3 times daily in selected patients. 183 214 Pediatric Patients Seizure Disorders Complex Partial Seizures (Monotherapy and Adjunctive Therapy) Oral (conventional, delayed-, and extended-release preparations) Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium. 179 182 183 184 214 Children 10 years of age: Initially, 10 15 mg/kg daily. 179 182 183 184 214 Increase dosage by 5 10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily. 179 182 183 184 214 When used adjunctively, may continue concurrent anticonvulsant therapy, adjusting dosages according to response and tolerability. 182 183 184 (See Interactions.) Alternatively, may attempt to decrease dosage of the current anticonvulsant by 25% every 2 weeks, either starting concomitantly with initiation of valproic acid therapy or delayed by 1 2 weeks if there is a concern that seizures are likely to occur with a reduction. b Speed and duration of withdrawal of the current anticonvulsant can be highly variable; monitor patients closely during this period for increased seizure frequency. b When converting a patient from a current anticonvulsant to valproic acid therapy for the treatment of complex partial seizures, initiate valproic acid therapy at usual starting dosages. b IV May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible. 185 b IV administration can be used for monotherapy or as adjunctive therapy in the management of seizure disorders. 185 b The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary. 185 b Administer daily dosages >250 mg in divided doses. 185 Use of IV therapy for >14 days not established. 185 b Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy. 185 b Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly. b Simple or Complex Absence Seizures Oral (conventional, delayed-, and extended-release preparations) Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium. 179 182 183 184 214 Initially, 15 mg/kg daily. 179 182 183 184 214 Increase dosage by 5 10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily. 179 182 183 184 214 IV May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible. 185 b The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary. 185 b Administer daily dosages >250 mg in divided doses. 185 Use of IV therapy for >14 days has not been studied to date. 185 b Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy. 185 b Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly. 185 b Adults Seizure Disorders Complex Partial Seizures Oral (conventional, delayed-, and extended-release preparations) Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium. 182 183 184 214 Initially, 10 15 mg/kg daily. 183 184 214 Increase dosage by 5 10 mg/kg daily at weekly intervals until seizures are controlled or adverse effects prevent further dosage increases, usually up to 60 mg/kg daily according to response and tolerability. b When used adjunctively, may continue concurrent anticonvulsant therapy, adjusting dosages according to response and tolerability. 182 183 184 (See Interactions.) Alternatively, may attempt to decrease dosage of the current anticonvulsant by 25% every 2 weeks, either starting concomitantly with initiation of valproic acid therapy or delayed by 1 2 weeks if there is a concern that seizures are likely to occur with a reduction. b Speed and duration of withdrawal of the current anticonvulsant can be highly variable; monitor patients closely during this period for increased seizure frequency. b IV May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible. 185 b IV administration can be used for monotherapy or as adjunctive therapy in the management of seizure disorders. b The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary. 185 b Administer daily dosages >250 mg in divided doses. 185 Use of IV therapy for >14 days not established. 185 b Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy. b Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly. b Simple or Complex Absence Seizures Oral (conventional, delayed-, and extended-release preparations) Dosages apply to conventional (capsules and solution), delayed-release (capsules and tablets), and extended-release (tablets) dosage forms of valproic acid (active moiety), valproate sodium, and divalproex sodium. 182 183 184 214 Initially, 15 mg/kg daily. 183 184 b Increase dosage by 5 10 mg/kg daily at weekly intervals, according to response and tolerability, up to maximum recommended dosage of 60 mg/kg daily. 183 184 214 IV May employ IV therapy in patients in whom oral therapy temporarily is not feasible, but switch to oral administration as soon as clinically possible. 185 b The usual total daily dosages are equivalent for IV or oral administration, and the doses and frequency of administration employed with oral therapy in seizure disorders are expected to be the same with IV therapy, although plasma concentration monitoring and dosage adjustment may be necessary. 185 b Administer daily dosages >250 mg in divided doses. 185 Use of IV therapy for >14 days not established. 185 b Use of IV valproate sodium for initial monotherapy has not been systematically studied; however, usual dosages and titration employed with oral therapy can be employed with parenteral therapy. b Monitor patients receiving dosages near the usual maximum recommended dosage of 60 mg/kg daily closely, particularly when enzyme-inducing drugs are not used concomitantly. b Seizure Disorders Conversion from Divalproex Sodium Delayed-release (e.g., Depakote ) to Extended-release (e.g., Depakote ER) Tablets Oral When converting a patient whose seizure disorder is controlled with divalproex sodium delayed-release tablets to the extended-release tablets, give the drug once daily using a total daily dose that is 8 20% higher than the corresponding delayed-release dosage that the patient was receiving. 182 For patients whose delayed-release daily dosage cannot be directly converted to a corresponding commercially available extended-release dosage, consider increasing the delayed-release total daily dosage to the next higher dosage before converting to the appropriate extended-release total daily dosage at the clinician s discretion. 182 Refractory Status Epilepticus Rectally 400 600 mg of valproic acid has been administered by enema or in wax-based suppositories at 6-hour intervals. b Bipolar Disorder Manic or Mixed Episodes Oral Initially, 750 mg daily in divided doses as delayed-release tablets (e.g., Depakote ) or delayed-release capsules (Stavzor ) or 25 mg/kg once daily as extended-release tablets (e.g., Depakote ER) for acute episodes. 182 183 214 For acute episodes, increase dosage as quickly as possible to achieve the lowest therapeutic dosage producing the desired clinical effect or desired plasma concentration; however, the manufacturers recommend that the dosage not exceed 60 mg/kg daily. 182 183 214 b In clinical studies, dosed to clinical response with trough plasma concentrations of 50 125 mcg/mL. 182 183 Efficacy beyond 3 weeks not systematically evaluated; if continued, periodically reevaluate long-term usefulness and risk for the individual patient. 182 183 214 Safety for longer-term antimanic therapy is supported by data from record reviews involving approximately 360 patients treated for >3 months. 183 214 Dosing guidelines for maintenance therapy are less evidence-based than those for acute therapy, and dosages lower than those employed for acute therapy occasionally have been used. b Migraine Prophylaxis of Chronic Attacks Oral Initially, 250 mg twice daily as delayed-release tablets (e.g., Depakote ) 183 or delayed-release capsules (Stavzor ) 214 or 500 mg once daily as extended-release tablets (e.g., Depakote ER). 182 Maintenance: After 1 week at the initial dosage of extended-release tablets, may increase dosage to 1 g daily. 182 Some patients may benefit from dosages up to 1 g daily. 183 214 No evidence of additional benefit with higher dosages. 183 214 If a patient requires smaller dosage adjustment than that available using the extended-release tablets, use the delayed-release tablets instead. 182 Schizophrenia Oral In general, for adjunctive therapy, administer in the same dosages, and with the same resulting therapeutic plasma concentrations, as those for the management of seizure disorders. 146 147 148 Prescribing Limits Pediatric Patients Seizure Disorders Oral Usual maximum recommended dosage is 60 mg/kg daily; 182 183 b if therapeutic response not achieved, monitor plasma concentrations. 182 183 Adults Seizure Disorders Oral Usual maximum recommended dosage is 60 mg/kg daily; 182 183 b if therapeutic response not achieved, monitor plasma concentrations. 182 183 Bipolar Disorder Manic or Mixed Episodes Oral Maximum recommended dosage is 60 mg/kg daily. 182 183 b Migraine Prophylaxis of Chronic Attacks Oral Maximum recommended dosage is 1 g daily. 182 183 214 Special Populations Hepatic Impairment Because of substantially decreased protein binding, monitoring total (bound + unbound) drug concentrations may be misleading. 183 185 Renal Impairment Dosage adjustment does not appear necessary. 183 184 Because of substantially decreased protein binding, monitoring total (bound + unbound) drug concentrations may be misleading. 183 184 Geriatric Patients Reduce initial dosage because of a decrease in clearance of unbound valproic acid and possibility of greater sensitivity to adverse effects (e.g., somnolence); increase subsequent dosage more slowly. 182 183 184 185 Consider dosage reduction or discontinuance in geriatric patients with reduced food or fluid intake and in those with excessive somnolence. 182 183 184 185 (See Somnolence in Geriatric Patients under Cautions and also see Geriatric Use under Cautions.) Determine ultimate therapeutic dosage on the basis of tolerability and clinical response. b Gender No dosage adjustment necessary based solely on gender. 183 Cautions for Divalproex Sodium Contraindications Hepatic disease or substantial hepatic dysfunction. 182 183 184 185 Patients with mitochondrial disorders caused by POLG mutations and children <2 years of age suspected of having a POLG -related disorder. 179 182 183 185 Known hypersensitivity to valproic acid, valproate sodium, divalproex sodium, or any ingredient in the respective formulation. 182 183 184 185 b Urea cycle disorders. 182 183 184 185 (See Urea Cycle Disorders [UCD] under Cautions.) Use for prophylaxis of migraine headache in pregnant women. 182 183 (See Pregnancy under Cautions.) Warnings/Precautions Warnings Hepatotoxicity May cause serious and potentially fatal hepatotoxicity. 182 183 184 185 221 222 223 (See Hepatotoxicity in Boxed Warning.) Children and patients receiving multiple anticonvulsants or those with congenital metabolic disorders, severe seizure disorders accompanied by mental retardation, or organic brain disease may be at particular risk. 182 183 184 185 221 Higher incidence of acute liver failure and resultant deaths reported in patients with hereditary neurometabolic syndromes caused by POLG mutations than in those without such disorders; most cases identified in children and adolescents. 182 221 222 223 Use with caution in patients with a history of hepatic disease. 182 Immediately discontinue valproic acid if substantial hepatic dysfunction, suspected or apparent, is present. 182 183 184 185 In some cases, hepatic dysfunction has progressed despite discontinuance of the drug. 182 183 184 185 Pancreatitis May cause life-threatening pancreatitis. 182 183 184 185 (See Pancreatitis in Boxed Warning.) Urea Cycle Disorders (UCD) Potentially fatal hyperammonemic encephalopathy can occur following initiation of therapy in patients with UCD, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency. 182 183 184 185 (See Contraindications under Cautions.) Plasma ammonia concentrations not systematically studied following IV administration; however, hyperammonemia with encephalopathy reported in at least 2 patients who received IV infusions of valproate sodium. 185 Advise patients to contact a clinician promptly if symptoms of this disorder (e.g., lethargy, vomiting, changes in mental status) develop. 182 183 184 185 If such symptoms are present, determine plasma ammonia concentrations, and, if increased, discontinue therapy. 182 183 184 185 Initiate appropriate treatment for hyperammonemia and evaluate the patient for an underlying UCD. 182 183 184 185 Prior to the initiation of therapy, consider evaluating for UCD in patients with: a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine concentrations; patients with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN concentration, or protein avoidance; patients with a family history of UCD or unexplained infant deaths (particularly males); or those with other signs or symptoms of UCD. 182 183 184 185 Asymptomatic elevation of ammonia concentrations is more common than symptomatic hyperammonemia. 182 183 184 185 In patients with asymptomatic elevations, closely monitor plasma ammonia concentrations and, if elevations persist, consider discontinuance of the drug. 182 183 184 185 Fetal Risk Can produce NTDs and other structural malformations (e.g., craniofacial defects, cardiovascular malformations, anomalies involving various body systems) following in utero exposure. 182 183 184 185 188 189 190 191 192 193 194 In addition, decreased IQ and other cognitive impairments observed in children exposed in utero. 205 206 207 208 212 (See Fetal Risk in Boxed Warning.) In animal studies, adverse fetal effects, including structural malformations (e.g., skeletal, cardiac, urogenital), neural tube closure defects, intrauterine growth retardation, neurobehavioral abnormalities, and death, observed. 182 183 184 190 Do not use in pregnant women for prevention of migraine headaches; use only in pregnant women with epilepsy or bipolar disorder if absolutely necessary. 182 183 184 185 188 196 205 (See Pregnancy under Cautions.) Suicidality Risk Increased risk of suicidality (suicidal ideation or behavior) observed in an analysis of studies using various anticonvulsants in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain); risk in patients receiving anticonvulsants (0.43%) was approximately twice that in patients receiving placebo (0.24%). 176 177 178 179 180 183 184 Increased suicidality risk was observed 1 week after initiation of anticonvulsant therapy and continued through 24 weeks. 176 177 178 179 183 184 Risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions. 176 178 179 183 184 Closely monitor all patients currently receiving or beginning anticonvulsant therapy for changes in behavior that may indicate emergence or worsening of suicidal thoughts or behavior or depression. 177 178 179 180 183 184 Anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality. 176 Balance risk of suicidality with the risk of untreated illness. 176 179 183 184 Epilepsy and other illnesses treated with anticonvulsants are themselves associated with morbidity and mortality and an increased risk of suicidality. 179 183 184 If suicidal thoughts or behavior emerge during anticonvulsant therapy, consider whether these symptoms may be related to the illness itself. 179 183 184 (See Advice to Patients.) Brain Atrophy Cerebral and cerebellar atrophy (or pseudoatrophy) reported during postmarketing experience; may be irreversible or reversible. 182 183 215 216 217 218 219 220 Some patients recovered with permanent sequelae. 182 183 Monitor patients routinely for motor and cognitive impairments during therapy; if any manifestations of brain atrophy develop or are suspected, evaluate whether therapy should be continued. 182 183 Cerebral atrophy also reported in children exposed in utero to valproic acid. 182 183 (See Pregnancy under Cautions.) Interaction with Carbapenem Antibiotics Carbapenem antibiotics (e.g., ertapenem, imipenem, meropenem) may reduce plasma valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. 179 182 184 185 186 187 (See Specific Drugs and Laboratory Tests under Interactions.) Somnolence in Geriatric Patients Somnolence reported, particularly in geriatric patients. 182 183 184 185 (See Advice to Patients.) In geriatric patients with dementia, somnolence occurred in a significantly higher proportion of patients receiving valproic acid compared with those receiving placebo. 182 183 184 185 Dehydration also occurred in more valproic acid-treated patients, although the difference was not clinically significant. 182 183 184 185 In some patients (approximately half) with somnolence, associated reduced nutritional intake and weight loss occurred. 182 183 184 185 (See Geriatric Use under Cautions.) In geriatric patients, increase dosage more slowly and monitor patients regularly for fluid and nutritional intake, dehydration, somnolence, and other adverse effects. 182 183 184 185 (See Geriatric Patients under Dosage and Administration.) Thrombocytopenia Frequency of valproic acid-associated adverse effects, particularly elevated liver enzyme concentrations and thrombocytopenia, may be dose-related. 182 183 b The probability of thrombocytopenia appears to increase substantially at total plasma valproic acid concentrations 110 mcg/mL (females) or 135 mcg/mL (males). 182 183 184 185 Weigh the therapeutic benefit of relatively high dosages with the possibility of dose-related thrombocytopenia and other adverse effects. 182 183 Monitor platelet counts and coagulation tests before initiating valproic acid therapy and periodically during therapy. 182 183 b Such monitoring is also recommended prior to planned (i.e., elective) surgery. 182 183 b Consider thromboelastography as a more reliable method to assess the effects of valproic acid on coagulation. b If clinical evidence of hemorrhage, bruising, or a disorder of hemostasis/coagulation occurs during therapy, reduce dosage or withdraw the drug pending further evaluation. 182 183 184 185 Hypothermia Hypothermia (unintentional drop in body core temperature to> <35 C) reported in association with valproic acid therapy both in conjunction with and in the absence of hyperammonemia (see Hyperammonemia under Cautions). 182 183 184 185 May also occur in patients receiving concurrent topiramate and valproic acid after starting topiramate therapy or increasing the daily topiramate dosage. 182 183 184 185 (See Hyperammonemia and Encephalopathy associa keep at bay
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