Divalproex sodium dosing

The enteric-coated tablet divalproex sodium causes fewer GI side effects. It is metabolized in the gut to valproic acid. When switching from Depakote to Depakote-ER, the dose should be increased by 14% to 20%. Depakote ER may be given once daily. 

Valproic acid/divalproex sodium 500-1,500 mg/day in divided doses... 

Side effects of valproic acid and divalproex sodium include nausea (less common with divalproex sodium and gradual dosing titration), tremor,... 

Oral products Bedtime administration may minimize effects of CNS depression. Gl irritation may be minimized by taking with food or by slowly increasing the dose. Delayed-release divalproex sodium may reduce the incidence of irritative Gl effects. Swallow the extended-release tablets whole do not crush or chew. Swallow the valproic acid capsules without chewing to avoid local irritation of the mouth and throat. 

Adjunctive therapy - Divalproex sodium or valproic acid may be added to the patient s regimen at a dosage of 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/wk to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses less than 60 mg/kg/day. If satisfactory clinical response has not been achieved, measure plasma levels to determine whether they are in the usually accepted therapeutic range (50 to 100 mcg/mL). If the total daily dose exceeds 250 mg, administer in divided doses. 

In epileptic patients previously receiving valproic acid therapy, initiate divalproex sodium at the same daily dose and dosing schedule. After the patient is stabilized on divalproex tablets, a dosing schedule of 2 or 3 times/day may be elected in selected patients. 

Mania (divalproex sodium delayed-release tablets) 750 mg/day in divided doses increase as rapidly as possible to achieve the lowest therapeutic dose that produces the desired clinical effect or the desired range of plasma concentrations (trough plasma concentrations 50 to 125 mcg/mL). Maximum concentrations generally were achieved within 14 days. Maximum recommended dosage is 60 mg/kg/day. 

Divalproex sodium delayed-release tablets-The starting dose is 250 mg orally twice/day. Some patients may benefit from doses up to 1,000 mg/day. There is no evidence that higher doses lead to greater efficacy. 

Divalproex sodium (DVP) provided a significant reduction in manic symptoms in 54% of patients from three controlled studies. Especially when an oral loading dose of 20 mg/kg/day is used, rapid antimanic effects may be observed between 3 and 5 days. Mixed episodes and the presence of depressive symptoms are associated with better response to DVP than to lithium. 

Increase dose by 10%-20% when converting from valproate, divalproex, or valproic acid to tiie extended-release (ER) formulation of divalproex sodium. 

Indigestion, heartburn, and nausea are common side effects of valproate therapy. Use of the divalproex sodium preparation will help mitigate these effects. Patients may also be encouraged to take their doses with food. The symptomatic use of histamine H2 blockers, such as famotidine, is sometimes warranted. In most cases, however, dyspepsia is transient and not severe. Pancreatitis is a rare occurrence in patients receiving relatively high doses of valproate. If vomiting and severe abdominal pain develop during valproate therapy, serum amylase levels should be determined immediately. 

For example, a test dose may identify a fast metabolizer, who may require a higher dose there is no evidence, however, that this approach could accelerate response, an issue that needs to be tested in controlled trials. Further, only limited evidence exists that high doses will shorten the lag period for any psychotropic agent (e.g., divalproex sodium loading dose strategy). 

Dutta S, Zhang Y, Selness DS, Lee LL, Williams LA, Sommerville KW. Comparison of the bioavailability of unequal doses of divalproex sodium extended-release formulation relative to the delayed-release formulation in healthy volunteers. Epilepsy Res 2002 49(1) 1-10. 

Valproic acid (divalproex sodium) 40-100 mcg/mL Trough Immediately prior to next dose Check 2-4 d after first dose or change in dose... 

Case Conclusion Phenytoin was discontinued and JJ was started on valproic acid. She received an initial IV dose, followed by oral maintenance therapy of divalproex sodium. She was monitored closely for resolution of her reaction, which took several weeks. 

Divalproex sodium extended-release (Depakote ER) is a once daily (QD) formulation for VPA that was developed to improve patient compliance and reduce side effects compared to the standard twice-daily (BID) delayed release (DR) formulation (Depakote tablets). However, there are concerns of potential subthera-peutic concentrations following delayed or missed doses or toxic concentrations with replacement doses for the ER and DR formulations. 

Predictors of a positive response with valproate include rapid cycling, mixed episodes, comorbid panic disorder, organic mental disorders (e.g., head trauma), and mental retardation. " Low-dose valproate (125 to 500 mg/day) has been reported to be effective in reducing mood cycling in bipolar II disorder and cyclothymia. Oral loading with divalproex sodium, 20 mg/kg per day, may produce a rapid reduction in manic and psychotic symptoms within 4 days without causing major side effects, although there may be a lag time to obtain full antimanic efficacy. Development of tolerance and loss of efficacy with valproate occurs in some patients after several years of treatment." ... 

The most commonly observed side effects for valproate are gastrointestinal (anorexia, nausea, and Indigestion). These effects can be minimized by selecting divalproex sodium, which is enterically coated, and by Initiating therapy at a low dose. More Importantly, however, valproate is associated with the development of fatal hepatotoxicity, especially in children or when coadministered with other AEDs. Frequent monitoring of liver function tests is mandatory for determining the onset of toxicity. 

Aripiprazole 30 mg daily was given to 6 healthy subjects for 5 weeks, with valproate semisodium (divalproex sodium) daily in doses to achieve a serum valproate level of 50 to 125 mg/L, for weeks 3 to 5 of the study. The mean AUC and maximum plasma concentrations of aripiprazole were found to decrease by 24% and 26%, respectively, and the time to maximum aripiprazole levels was extended by 2 hours. Since aripiprazole and valproate share the same protein binding sites, it was considered likely that the valproate displaced bound aripiprazole leading to increased... 

Analysis of plasma quetiapine levels of 94 patients, 9 of whom were also taking valproate, found a 77% increase in the concentration dose ratio compared with those patients not taking valproate. The US manufacturers report that valproate semisodium (divalproex sodium) increases the maximum plasma levels of quetiapine by 17%, and the UK manufacturers state that these changes are not clinically relevant. ... 

However, there is one report of a possible decrease in valproate levels in a 30-year-old man after starting lopinavir/ritonavir. This patient, who had been taking valproic acid 375 mg daily as divalproex sodium for 7 months after an episode of mania, had a subtherapeutic valproic acid level of 197 micromol/L, and the dose was increased to 250 mg three times daily. After 25 days his trough valproic acid level was 495 micromol/L, and an antiretroviral regimen of lamivudine, zidovudine, lopinavir/ritonavir was started, and paroxetine for depression. Four days later he was hy-pomanic and the paroxetine was replaced with sertraline, which the patient discontinued. Twenty-one days later he had become increasingly manic, and the valproic acid level was found to be 238 micromol/L, about 50% lower than the previous level. An increase in valproic acid dose to 1.5 g daily was eventually required to achieve a therapeutic level of 392 micromol/L. 

A 50-year-old male with previous history of priapism and prior use of sildenafil presented with ischaemic priapism requiring surgical intervention. The patient had been on ziprasidone and sodium divalproex for 6 years. There was no change in dose but within 24 h of switching to co-ingesting ziprasidone with food he experienced... 

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