FDA Approvals: Symbyax and Edluar

Yael Waknine

March 26, 2009

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March 26, 2009 — The US Food and Drug Administration (FDA) has approved fluoxetine HCl plus olanzapine capsules as therapy for treatment-resistant depression, and zolpidem tartrate sublingual tablets for the temporary treatment of insomnia.

Fluoxetine HCl/Olanzapine (Symbyax) Is First Therapy Approved for Treatment-Resistant Depression

On March 19, the FDA approved an expanded indication for fluoxetine HCl plus olanzapine capsules (Symbyax; Eli Lilly and Co), allowing its use for the acute treatment of treatment-resistant depression (TRD).

TRD is a condition that affects an estimated 35% of patients with major depressive disorder (MDD) and is defined as a failure to sustain or achieve remission with 2 separate trials of different antidepressants of adequate dose and duration in the current episode. Combination treatment with fluoxetine/olanzapine is the first therapy to be approved by the FDA for use in this population.

"Living with major depressive disorder is difficult and distressing for anyone, but even more so for patients whose symptoms continue despite treatment," said Lilly medical director Dr. Sara Corya in a company news release. "Until today, there has been no approved medication for treatment-resistant depression. Now, after two failed attempts with other antidepressants, doctors and patients have a new treatment option."

Labeling changes to the monographs for olanzapine (Zyprexa) and fluoxetine (Prozac, both made by Eli Lilly) monographs also reflect the new indication, allowing clinicians the option of prescribing a combination capsule or 2 separate pills.

FDA approval was based primarily on data from 2 eight-week double-blind studies using doses ranging from 6 to 18 mg for olanzapine and 25 to 50 mg for fluoxetine.

Pooled results showed that flexible dosing with fluoxetine/olanzapine yielded a statistically significant greater reduction from baseline in mean total Montgomery-Asberg Depression Rating Scale (MADRS) scores vs fluoxetine and olanzapine alone (–12.6 vs –9.2 and –8.9; P < .001 for both comparisons); improvements relative to monotherapy were apparent within 3 to 4 days and reached significance after 1 week. The MADRS is a 10-item clinician-rated scale with total scores ranging from 0 to 60.

Also, 40% of patients receiving fluoxetine/olanzapine responded to therapy vs 30% and 26% of those receiving fluoxetine and olanzapine monotherapy, respectively.

Adverse events reported in 5% or more of patients receiving combination therapy and at twice the rate of placebo were weight gain, increased appetite, dry mouth, somnolence, and fatigue.

As with the treatment of depressive episodes of bipolar disorder, patients treated for TRD should receive fluoxetine/olanzapine once daily in the evening, generally beginning with a 6-mg/25-mg dose that can then be adjusted based on efficacy and tolerability to a maximum of 18 mg/75 mg.

The FDA notes that a starting dose of 3 mg/25 mg to 6 mg/25 mg of fluoxetine/olanzapine should be used for patients predisposed to hypotensive reactions, those with hepatic impairment, and patients with factors for slowed metabolism such as female sex, geriatric age, and nonsmoking status. Dose escalation should be performed with caution in these patients.

Potentially life-threatening serotonin syndrome and neuroleptic malignant syndrome–like reactions have been reported with use of selective serotonin reuptake inhibitors such as fluoxetine alone but particularly with concomitant use of serotonergic drugs (including triptans), agents that impair serotonin metabolism (including monoamine oxidase inhibitors), or with antipsychotics (eg, olanzapine) and other dopamine antagonists.

If these events occur, treatment with fluoxetine/olanzapine and any concomitant serotonergic or antidopaminergic agents should be discontinued immediately and supportive symptomatic treatment initiated.

Fluoxetine/olanzapine capsules previously were approved for the treatment of depressive episodes associated with bipolar disorder in adults.

Faster-Acting Sublingual Formulation of Zolpidem Tartrate (Edluar) Approved for Insomnia

On March 13, the FDA approved a sublingual formulation of zolpidem tartrate (Edluar, formerly known as Sublinox; made by Orexo AB and marketed by Meda AB) for the temporary treatment of insomnia. The tablets will be available in 5- and 10-mg strengths.

According to information on the company Web site, efficacy trials have demonstrated that the sublingual formulation renders a 30% faster onset of sleep aid vs conventional zolpidem tartrate tablets (Ambien; sanofi-aventis US) and that patients are able to maintain sleep throughout the night without "day-after" residual effects.

Symbyax and Zyprexa Prescribing Information

Prozac Prescribing Information

FDA New Drug Information

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