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General Information

Stavzor is an enteric, anticonvulsant, delayed-release, softgel capsule formulation of valproic acid. The exact mechanism of action is unknown, however, valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor). GABA plays a role in regulating neuronal excitability throughout the nervous system. GABA is also directly responsible for the regulation of muscle tone. Valproic acid also blocks the voltage-gated sodium channels and T-type Calcium channels and is an inhibitor of the enzyme histone deacetylase 1 (HDAC1).

Stavzor is specifically indicated for the treatment of the manic episodes associated with bipolar disorder, as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures, for the treatment of simple and complex absence seizures and for prophylaxis of migraine headaches.

Stavzor is supplied as 125-mg, 250-mg or 500-mg capsules designed for oral administration. The recommended initial dose of the drug is:

Mania
750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations. The maximum recommended dosage is 60 mg/kg/day.

Seizures-Complex Partial Seizures
For adults and children 10 years of age or older
Monotherapy
Initial therapy should be 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. The recommended maximum dose is 60 mg/kg/day.
Conversion to Monotherapy
Therapy should be initiated at at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. The maximum recommended dose is 60 mg/kg/day.
Adjunctive Therapy
Therapy should be initiated at 10 to 15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. The maximum recommended dose is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in 2 to 3 doses.

Simple and Complex Absence Seizures
Therapy should be initiated at 15 mg/kg/day, increasing at 1-week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases. The maximum recommended dosage is 60 mg/kg/day. If the total daily dose exceeds 250 mg, it should be given in 2 to 3 doses.

Migraine
The recommended starting dose is 250 mg twice daily. Some patients may benefit from doses up to 1000 mg/day.

Clinical Results

FDA Approval
FDA approval of Stavzor was based on the following clinical trials:

Mania
Stavzor was evaluated in two 3-week, placebo controlled, parallel group studies.

Study One
This study enrolled adult subjects who received valproate at a dose of 250 mg TID and adjusted to achieve serum valproate concentrations in a range of 50-100 mcg/mL by day 7. The treatment period was three weeks (21 days). The subjects were subsequently assessed on the Young Mania Rating Scale (YMRS; score ranges from 0-60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS). Valproate was statistically significantly superior to placebo on all three measures of outcome. Sixty percent of the subjects showed at least a 30% reduction in symptom score from baseline compared to 26% of the placebo group (p<0.05).

Study Two
This study enrolled adult subjects who received valproate at a dose of 250 mg TID and adjusted within a dose range of 750-2500 mg/day to achieve serum valproate concentrations in a range of 40-150 mcg/mL. The treatment duration was three weeks (21 days). Study 2 also included a lithium group for which lithium doses for completers were 1312, 1869, and 1984 mg/day at Days 7, 14, and 21, respectively. Subjects were assessed on the Manic Rating Scale (MRS; score ranges from 11-63), and the primary outcome measures were the total MRS score, and scores for 2 subscales of the MRS. Valproate was statistically significantly superior to placebo on all three measures of outcome. Fifty-eight percent of the subjects showed at least a 30% reduction in symptom score from baseline compared to 29% of the placebo group (p<0.05).

Epilepsy
Stavzor was evaluated in two clinical trials.

Study One
This multiclinic, placebo-controlled study employing an add-on design, (adjunctive therapy), enrolled 144 subjects who continued to suffer 8 or more controlled partial seizures (CPS) per 8 weeks during an 8week period of monotherapy with doses of either carbamazepine or phenytoin. The subjects were randomized to receive either valproate or placebo in addition to their original antiepilepsy drug. They were followed for 16 weeks. The results are as follows: the median baseline incidence of CPS per 8 weeks was 16.0 for the valproate arm and 14.5 for the placebo arm. Following treatment, the median was reduced to 8.9 for the valproate arm and 11.5 for the placebo arm. The reduction from baseline was statistically significantly greater for valproate than placebo (p < 0.05).

Study Two
This study was designed to assess the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. All enrolled subjects experienced 2 or more CPS per 4 weeks during an 8- to 12 weeklong period of monotherapy with adequate doses of an AED and made a successful transition over a 2 week interval to valproate. The subjects gradually tapered off their concomitant AED, were randomized to either a high dose or low dose valproate group (mean total of 71 and 123 mcg/mL) and followed for as long as 22 weeks. The monotherapy study median incidence of CPS per 8 weeks at baseline was 13.2 in the high dose arm and 14.2 in the low dose arm. Following treatment, the median CPS incidence was reduced to 10.7 in the high dose arm and 13.8 in the low dose arm. The reduction from baseline was statistically significantly greater for high dose than low dose (p = 0.05).

Migraine
Stavzor was evaluated in two multicenter, randomized, double-blind, placebo-controlled clinical trials. Both studies enrolled subjects with a history of migraine with or without aura (of at least 6 months in duration) who were experiencing at least 2 migraine headaches a month during the 3 months prior to enrollment. Each study was comprised of a 4-week single-blind placebo baseline period after which they were randomized, under double blind conditions, to valproate or placebo for a 12-week treatment phase, comprised of a 4-week dose titration period followed by an 8-week maintenance period.

Study One
This study enrolled 107 subjects, 90 of whom completed the 8-week maintenance period. Valproate doses ranged from 500 to 2500 mg a day. Doses over 500 mg were given in three divided doses (TID). The mean dose during the treatment phase was 1087 mg/day. The mean 4-week migraine headache rate during the treatment phase was 5.7 in the placebo group compared to 3.5 in the valproate group, a significant difference.

Study Two
This study enrolled 176 subjects, 137 of whom completed the 8-week maintenance period. The subjects were randomized equally to one of three valproate dose groups (500, 1000, or 1500 mg/day) or placebo. The treatments were given in two divided doses (BID). The initial dose was 250 mg daily. The regimen was advanced by 250 mg every 4 days (8 days for 500 mg/day group), until the randomized dose was achieved. Efficacy was determined by a comparison of the 4-week migraine headache rate in the combined 1000/1500 mg/day group and placebo group. The mean 4-week migraine headache rates during the treatment phase, adjusted for differences in baseline rates, were 4.5 in the placebo group, compared to 3.3, 3.0, and 3.3 in the valproate 500, 1000, and 1500 mg/day groups, respectively. The rates in the combined valproate 1000/1500 mg group were significantly lower than in the placebo group.

Side Effects

Adverse events associated with the use of Stavzor may include, but are not limited to, the folowing:

nausea
somnolence
dizziness
vomiting
asthenia
abdominal pain
dyspepsia
rash
diarrhea
increased appetite
tremor
weight gain

Mechanism of Action

Stavzor is an enteric, anticonvulsant, delayed-release, softgel capsule formulation of valproic acid, a carboxylic acid designated as 2- propylpentanoic acid. It is also known as dipropylacetic acid. The exact mecahnism of action is unknown, however, valproate is believed to affect the function of the neurotransmitter GABA (as a GABA transaminase inhibitor). GABA plays a role in regulating neuronal excitability throughout the nervous system. GABA is also directly responsible for the regulation of muscle tone. In addition to blocking transamination of GABA, Valproate is believed to reverse the transamination process to form more GABA. Valproic acid also blocks the voltage-gated sodium channels and T-type Calcium channels and is an inhibitor of the enzyme histone deacetylase 1 (HDAC1).

Literature References

Jedrzejczak J, Kuncíková M, Magureanu S; VIPe Study Group An observational study of first-line valproate monotherapy in focal epilepsy. European Journal of Neurology : the official journal of the European Federation of Neurological Societies 2008 Jan;15(1):66-72.

Yurekli VA, Akhan G, Kutluhan S, Uzar E, Koyuncuoglu HR, Gultekin F The effect of sodium valproate on chronic daily headache and its subgroups. The Journal of Headache and Pain 2008 Feb;9(1):37-41

Bowden C, Gögüs A, Grunze H, Häggström L, Rybakowski J, Vieta E A 12-week, open, randomized trial comparing sodium valproate to lithium in patients with bipolar I disorder suffering from a manic episode. International Clinical Psychopharmacology 2008 Sep;23(5):254-262

Deleu D, Al-Hail H, Mesraoua B, Mahmoud HA, Gulf Vipe Study Group Short-term efficacy and safety of valproate sustained-release formulation in newly diagnosed partial epilepsy VIPe-study. A multicenter observational open-label study. Saudi Medical Journal 2007 Sep;28(9):1402-7

Shinohara K, Okamoto Y, Jitsuiki H, Yamashita H, Morinobu S, Yamayaki S The tolerability of oral-loaded valproate after remission of acute mania in Japanese patients with bipolar disorder. Primary care companion to the Journal of clinical psychiatry 2007;9(3):241

Herranz JL, Arteaga R, Adín J, Armijo JA Conventional and sustained-release valproate in children with newly diagnosed epilepsy: a randomized and crossover study comparing clinical effects, patient preference and pharmacokinetics. European Journal of Neurology : the official journal of the European Federation of Neurological Societies 2006 Oct;62(10):805-15

Bazinet RP, Weis MT, Rapoport SI, Rosenberger TA Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology 2006 Jan;184(1):122-9

Kinze S, Clauss M, Reuter U, Wolf T, Dreier JP, Einhäupl KM, Arnold G Valproic acid is effective in migraine prophylaxis at low serum levels: a prospective open-label study. Headache 2001 Sep;41(8):774-8.