Divalproex: uses, dosing, side effects & brands

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 ) ] Serious Dermatologic Reactions [see Warnings and Precautions ( 5.13 ) ] Angioedema [see Warnings and Precautions ( 5.14 ) ] Somnolence in the Elderly [see Warnings and Precautions ( 5.16 ) ] 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 ≥15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness,…

Depakote is contraindicated in patients: • with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1 ) ] . • known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions ( 5.1 ) ] . • with known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema [see Warnings and Precautions ( 5.12 , 5.13 , 5.14 ) ] . • with known urea cycle disorders [see Warnings and Precautions ( 5.6 ) ] . • being treated for prophylaxis of migraine headaches who are pregnant or in women of childbearing potential who are not using effective contraception [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 ) ] . Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) Known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid ( 4 , 5.12 , 5.13 , 5.14 ) Urea cycle disorders ( 4 , 5.6 ) Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives, methotrexate: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g., diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2 ) Dosage adjustment of amitriptyline/nortriptyline, propofol, warfarin, and zidovudine may be necessary if used concomitantly with Depakote ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 ) Cannabidiol: ALT and/or AST elevation ( 7.4 ) 7.1 Effects of Co-Administered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs. In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the co-administration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions ( 5.15 ) ] . Estrogen-Containing Hormonal Contraceptives Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products. Felbamate A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy (n=10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 mg/day increased the mean valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage may be necessary when felbamate therapy is initiated. Methotrexate Methotrexate may decrease serum valproate levels and potentially result in increased frequency of seizures or bipolar symptoms. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing methotrexate and adjust valproate dosage, if necessary. Rifampin A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate. Valproate dosage adjustment may be necessary when it is co-administered with rifampin. 7.2 Effects of Valproate on Other Drugs Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases. The following list provides information about the potential for an influence of valproate co-administration on the pharmacokinetics or pharmacodynamics of several commonly prescribed medications. The list is not exhaustive, since new interactions are continuously being reported. Drugs for which a potentially important valproate interaction has been observed Amitriptyline/Nortriptyline Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (10 males and 5 females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate. Carbamazepine/carbamazepine-10,11-Epoxide Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients. Clonazepam The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures. Diazepam Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism. Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers (n=6). Plasma clearance and volume of distribution for free diazepam were reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of diazepam remained unchanged upon addition of valproate. Ethosuximide Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of 500 mg with valproate (800 to 1,600 mg/day) to healthy volunteers (n=6) was accompanied by a 25% increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs. Lamotrigine In a steady-state study involving 10 healthy volunteers, the elimination half-life of lamotrigine increased from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine dosing with concomitant valproate administration. Phenobarbital Valproate was found to inhibit the metabolism of phenobarbital. Co-administration of valproate (250 mg BID for 14 days) with phenobarbital to normal subjects (n=6) resulted in a 50% increase in half-life and a 30% decrease in plasma clearance of phenobarbital (60 mg single-dose). The fraction of phenobarbital dose excreted unchanged increased by 50% in presence of valproate. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate. Phenytoin Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism. Co-administration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n=7) was associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and apparent volume of distribution of free phenytoin were reduced by 25%. In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the clinical situation. Propofol The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression. Rufinamide Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate). Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose [see Dosage and Administration ( 2.5 ) ] . Similarly, patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients) or 400 mg per day (adults). Tolbutamide From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate. The clinical relevance of this displacement is unknown. Warfarin In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is instituted in patients taking anticoagulants. Zidovudine In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was decreased by 38% after administration of valproate (250 or 500 mg q8h); the half-life of zidovudine was unaffected. 7.3 Topiramate Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy [see Contraindications ( 4 ) and Warnings and Precautions ( 5.6 , 5.9 , 5.10 ) ] . Concomitant administration of topiramate with valproate has also been associated with hypothermia in patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in patients in whom the onset of hypothermia has been reported [see Warnings and Precautions ( 5.9 , 5.11 ) ] . 7.4 Cannabidiol Concomitant administration of valproate and cannabidiol has been associated with an increased risk of ALT and/or AST elevation. This has been manageable by dose reduction or, in more severe cases, by discontinuation of one or both drugs. Liver function, including serum transaminase and total bilirubin levels, should be monitored during concomitant treatment [see Warnings and Precautions ( 5.1 ) ] .