Bristol-Myers Squibb's Serzone (nefazadone) has complementary actions on serotonin (5HT). The antidepressant works as an antagonist at the 5HT2 receptors and inhibits the 5HT uptake carrier. Preclinical studies have demonstrated that Serzone also inhibits norepinephrine uptake.

Serzone, designated by FDA as a "1S", a new molecular entity given a standard review, was approved Dec. 22 after more than three years in FDA's review queue. The NDA (20-152) has been "approvable" since Nov. 7. BMS will launch Serzone in the "very near future." The drug was first launched in Canada in 1994.

The phenylpiperazine antidepressant will join the market presumably as a direct competitor to Wyeth-Ayerst's antidepressant Effexor (venlafaxine). Effexor, which became available in the first half of 1994, has been hailed by Wyeth as the first of a new class of serotonin-norepinephrine reuptake inhibitors. Serzone also will compete against the selective serotonin reuptake inhibitors: Pfizer's Zoloft (sertraline), SmithKline Beecham's Paxil (paroxetine) and Lilly's Prozac (fluoxetine).

Published studies have shown Serzone's beneficial effects on sleep quality, sexual function and anxiety symptoms compared to other antidepressants. BMS VP-CNS Research Donald Robinson, MD, told FDA's Psychopharmacologic Drugs Advisory Committee during its July 1993 review of the NDA that "weight and appetite were not adversely affected during long-term treatment and there was little, if any, sexual dysfunction and no treatment-emergent anxiety symptoms associated with nefazodone therapy in these controlled trials."

According to Serzone physician labeling, the incidence of insomnia in the trials was 11% in patients taking Serzone. The incidence of insomnia with the SSRIs ranges from 13.3% to 16.4%, and 18% with Effexor.

A study by J. Ware et al. of Sleep Disorders Center, Sentara Norfolk General Hospital, Norfolk, Va., looked at the effects of nefazodone, trazodone and buspirone (Mead Johnson's anxiolytic BuSpar) on sleep and sleep-related penile tumescence in a double-blind, placebo-controlled crossover study in 12 healthy subjects. Nefazodone, a structural analog of trazodone, increased rapid-eye-movement (REM) sleep, while trazodone and buspirone suppressed REM sleep. Nefazodone increased total tumescence time insofar as it increased REM sleep; trazodone increased tumescence time by delaying onset of detumescence; and buspirone did not change total tumescence time. Serzone labeling states: "While priapism did not occur during premarketing experience with nefazodone, priapism has been reported with...trazodone."

The incidence of male sexual dysfunction with Serzone is less than the occurrence in patients taking Effexor, Paxil and Zoloft. Abnormal ejaculation is listed as an infrequent event in Serzone labeling. Abnormal ejaculation and impotence occurred in 12% and 6% of Effexor patients, respectively, ejaculatory disturbance was 12.9% with Paxil and 15.5% with Zoloft. Prozac, however, has a low incidence of dysfunction (1.9%).

Based on labeling, Serzone appears to have lower incidences of nervousness, anxiety and tremor than either Effexor or the SSRIs. A study filed in the NDA comparing nefazodone, imipramine and placebo, shows patients reporting an improvement in anxiety symptoms associated with depression with nefazodone that was evident as early as the first week of treatment.

Unlike treatment with Effexor, which is associated with sustained increases in blood pressure, Serzone has been associated with postural hypotension. Physician labeling notes that "nefazodone was shown to antagonize alpha-1 adrenergic receptors, a property which may be associated with postural hypotension."

"A pooled analysis of the vital signs monitored during placebo-controlled premarketing studies revealed that 5.1% of nefazodone patients compared to 2.5% of placebo patients (pó.01) met criteria for a potentially important decrease in blood pressure at some time during treatment," labeling states. "The rates for adverse events characterized as `postural hypotension' were as follows: nefazodone (2.8%), tricyclic antidepressants (10.9%), SSRI (1.1%), and placebo (0.8%). Thus, the prescriber should be aware that there is some risk of postural hypotension in association with nefazodone use." Effexor's labeling carries an extensive warning about blood pressure increases and recommends regular blood pressure monitoring.

Proper dosage of Serzone was a concern for the advisory committee when it met to discuss the drug. Then-committee Chair Carol Tamminga, MD, University of Maryland, noted the group's "considerable uneasiness" over which doses showed effectiveness ("The Pink Sheet" July 26, 1993, p. 17).

The recommended starting dose for Serzone is "200 mg/day, administered in two divided doses," physician labeling states. In controlled clinical trials establishing Serzone's efficacy, "the effective dose range was generally 300 to 600 mg/day. Consequently, most patients depending on tolerability and the need for further clinical effect, should have [their] dose increased."

Five Phase IV commitments were made in an NDA amendment submitted to the agency Nov. 17, 1994, including an agreement to "further explore the dose response of nefazodone for effectiveness."

Serzone treatment "should be initiated at half the usual dose in elderly patients, especially in women, but the therapeutic dose range is similar in younger and older patients," physician labeling states. "After single doses of 300 mg to younger and older patients, Cmax and AUC for nefazodone and hydroxynefazodone [a metabolite] were up to twice as high in the older patients. With multiple doses, however, differences were much smaller, 10%-20%." A similar effect was seen in women, labeling notes. Approximately, two-thirds of patients in the clinical trials were women.

The company also has committed to "conduct and submit results from studies to evaluate the use of nefazodone in children and adolescents with depression," in keeping with FDA's Dec. 13 publication of a pediatric labeling final rule.

Phase IV commitments also include Bristol's agreement to "complete and submit results from...two ongoing studies of nefazodone in the maintenance treatment of depression." Labeling notes that "the effectiveness of Serzone in long-term use, that is, for more than 6 to 8 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use Serzone for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient."

Bristol also has committed to "conduct a clinical study to explore the possible effect of the combined use of nefazodone and terfenadine on parent terfenadine levels and/or QT intervals." Serzone labeling states that "co-administration of terfenadine or astemizole with Serzone is contraindicated." Nefazodone has been shown in vitro to be an inhibitor of the P450111A4 isozyme and other inhibitors. Specifically, the antifungal ketoconazole and macrolide antibiotics can block metabolism of terfenadine (Marion Merrell Dow's Seldane) and astemizole (Janssen's Hismanal), resulting in life-threatening cardiac events.

Finally, Bristol has committed to "consider conducting a crossfostering study in the rat" with the understanding that "if this experiment clearly establishes that the adverse effect on pup weight and survival is occurring as a result of a postnatal effect rather than an in utero effect of drug on the fetus, the labeling may be changed from pregnancy category C to pregnancy category B," the letter states. "We recommend that you submit the protocol for this study for our concurrence before initiating it."

A bold-faced warning on Serzone labeling noting the "potential for interaction with monoamine oxidase inhibitors" is similar to ones found on physician labeling for SSRIs. The warnings section also discusses "interaction with triazolobenzodiazepines," in which it is noted that "interaction studies" with Upjohn's Xanax (alprazolam) and Halcion (triazolam) "metabolized by cytochrome P450111A4 have revealed substantial and clinically important increases in plasma concentration of these compounds when administered concomitantly with nefazodone."

BRISTOL-MYERS SQUIBB SERZONE HAS COMPLEMENTARY ACTIONS ON SEROTONIN; MAY PROVIDE BENEFICIAL EFFECTS ON SLEEP, SEXUAL FUNCTION, ANXIETY -- APPROVAL

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