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Divalproex sodium ER well-tolerated as migraine prophylaxis for adolescents, studies show

Thursday, January 08 2009 | Comments

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What's This? The use of daily divalproex sodium extended-release (ER) appears to be well-tolerated as migraine prophylaxis for adolescents, according to findings from 2 open-label, Phase III studies.

The first study was a 12-month extension of a double-blind, placebo-controlled trial that included 112 participants, and the second was a separate 12-month trial that included 241 participants. Both trials assessed the safety and tolerability of divalproex sodium ER. In each trial, the participants received divalproex sodium ER 500 mg/day for 15 days and then 1,000 mg/d for the remainder of the trial. Dosage adjustments to optimize response were permitted, with a possible daily dose ranging from 250 mg to 1,000 mg.

In the first study, safety assessments included adverse events, laboratory testing, physical and neurological examinations, vital signs, electrocardiograms (ECG), and reproductive endocrine analyses (in postmenarchal female subjects).

The mean duration of exposure was 300 days, and 68% of the participants were >=70% compliant with medication throughout the study. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five subjects experienced serious adverse events, including 1 event that was considered possibly related to the study drug (symptomatic hyperammonemia). Fifteen subjects (13%) prematurely discontinued treatment because of an adverse event.

The mean ammonia level for all of the subjects increased 19.2 mcM from baseline. There were no other clinically significant changes in laboratory values, vital signs, or ECGs, according to the study authors. Overall, they added, adverse events and laboratory changes associated with divalproex sodium ER use were consistent with those observed previously in adults.

The mean headache frequency per 4-week period decreased from 2.1 during the first 28 days of treatment to 1.4 during the fourth 28-day period. Similar improvements were observed in the original placebo-controlled, 3-month trial, but the differences between divalproex sodium ER and placebo were not statistically significant. (Apostol G, et al. Headache 2009;49:36-44.)

In the second trial, safety and tolerability were assessed through adverse events, laboratory assessments, physical and neurological examinations, vital signs, ECGs, the Udvalg for Kliniske Undersogelser Side Effect Rating Scale (for neurological, movement-related side effects), the Wechsler Abbreviated Scale of Intelligence, and the Behavior Assessment System for Children.

The mean duration of exposure was 251 days, and >50% of the participants were compliant with medication throughout the study. The most common adverse events were nausea (19%), vomiting (18%), weight gain (12%), nasopharyngitis (11%), migraine (worsening of pre-existing migraine, new headache types, and/or new migraine-associated symptoms; 10%), and upper respiratory tract infection (10%). Ten participants (4%) experienced serious adverse events (including 4 with psychiatric events), none of which was considered related to the study drug.

Forty subjects (17%) withdrew because of an adverse event. Events leading to withdrawal in >=2 subjects were weight gain (n=6), alopecia (n=5), nausea (n=4), increased ammonia (n=3), migraine (n=3), upper abdominal pain (n=2), depressed mood (n=2), depression (n=2), and irritability (n=2).

The laboratory values that showed the greatest degree of change from baseline--decreased platelets and alkaline phosphatase and increased uric acid and ammonia--were similar to those in the first open-label trial. Some subjects discontinued treatment because of abnormal laboratory values, including 2 subjects with increased ammonia, 1 subject with increased ammonia and increased bilirubin, 1 subject with leukopenia, and 1 subject with elevated liver enzymes and prolonged coagulation times.

There were no other clinically significant changes in laboratory values, vital signs, rating scales, or ECGs.

The median rate of headaches per 4-week period decreased 75% between the first and fourth months of the study (from 4.0 to 1.0), and this improvement was sustained for the remainder of the study. (Apostol G, et al. Headache 2009;49:45-53.)

These studies were funded by Abbott.

This information concerns a use that has not been approved by the Food and Drug Administration.

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