Getting Through the Night – A focus on middle-of-the-night awakenings

 

The first prescription sleep drug approved for the treatment of patients with middle-of-the-night (MOTN) insomnia remains the only one on the market. A year after its release, Intermezzo® from Purdue Pharma still finds itself alone as it continues to help patients who wake up in the wee hours unable to get back to sleep.

With all the attention lavished on traditional insomnia, Intermezzo occupies a middle-of-the-night niche that specifically addresses those who toss and turn—as long as they have 4 or more hours of planned time in bed remaining. Margaret Moline, PhD, co-authored a paper about the drug’s effectiveness in an outpatient setting, which she says is based on a buffered sublingual formulation of zolpidem.

Built on the premise that patients who get to sleep don’t necessarily stay asleep, Intermezzo has resonated with primary care physicians (PCPs) and sleep physicians looking for new solutions. Any clinician with a DEA license can prescribe the drug, but Moline agrees that board-certified sleep physicians may be the ones who usually make it their business to take a closer look.

“This is even more relevant to sleep specialists,” says Libby Holman, associate director of Public Affairs for Stamford, Conn-based Purdue Pharma, “since they are in the trenches and regularly address sleep disorders.”

Moline explains that Intermezzo is not supposed to be used if another medication is being taken at bedtime. The “as needed” nature of the drug is also an attraction for consumers. “A lot of people don’t like taking something every night,” she says. “They want something they can take as needed. And for those who do wake up with more than 4 hours of bedtime left, there are sex- specific dosage requirements.”

Poster Presentation Examines the Why

While the sex-specific doses (1.75 milligrams for women and 3.5 milligrams for men) are straightforward enough, Moline says many clinicians may not understand the clinical reasons behind the dosages. “Women metabolize zolpidem differently than men,” she says. “Women clear the zolpidem from their bodies more slowly. That means, for a given dose, women would have higher plasma concentrations.”

Moline set about to address the “why” of dosage in a more detailed fashion last year in Boston with a poster presentation at SLEEP 2012—the 26th Annual Meeting of the Associated Professional Sleep Societies (APSS). The poster was a new set of analyses performed on data that were already published. Moline explains that in November 2011, when the FDA approved the drug, they stipulated sex-specific dosing, but few clinicians understood the reasoning behind the government’s decision.

“When you are evaluating drugs for approval, it’s important to take into consideration the entire package of efficacy and safety,” explains Moline, in reference to her poster titled Gender Effects of 1.75 mg and 3.5 mg Zolpidem Tartrate Sublingual Tablets Formulated with a Carbonate-Bicarbonate Buffer on Sleep Onset Following Middle-of-the-Night Awakening and on Next-Day Residual Effects. “There were two pivotal trials, and this trial that we reported on for the poster tested two different doses — 1.75 milligrams and 3.5 mg.”

Moline’s analyses specifically investigated the 1.75mg and 3.5mg zolpidem tartrate sublingual tablets (Intermezzo®), formulated with a carbonate-bicarbonate buffer. Post-hoc analysis was performed to examine response by sex in this double-blind, placebo-controlled 3-way cross-over study in patients with a diagnosis of primary insomnia as defined by the DSM-IV-TR and a history of prolonged middle-of-the-night (MOTN) awakenings. Patients had a history of MOTN awakening with difficulty returning to sleep and had to demonstrate polysomnographic (PSG) average (mean) latency to persistent sleep of ≥20 minutes following scheduled awakenings on screening nights.

Treatments consisted of 2 nights of dosing followed by a 5- to 12-day washout. Fifty-eight female and 24 male patients were randomized. Patients were awakened and dosed with 3.5 mg, 1.75 mg or placebo 4 hours after lights out, kept awake for 30 minutes, then returned to bed for 4 hours. Time to return to sleep was assessed by PSG and post-sleep questionnaires. Daytime residual effects were measured by objective/subjective measures.

In both sexes, compared to placebo, both the 3.5 mg and 1.75 mg doses of Intermezzo significantly decreased sleep latency based on PSG and post-sleep questionnaires. Following the 1.75 mg dose, 60% and 44% of the females and males, respectively, were asleep within 20 minutes. The rates following the 3.5 mg dose were 80% and 63% in females and males, respectively. Placebo response rates were significantly lower: 26% (females) and 33% (males).

The 20-minute value is important since this was the inclusion criterion for the study based on the 2-night PSG screening period. Neither dose in either sex showed significant residual effects compared to placebo based on the daytime assessments performed during the study.

These data demonstrated that Intermezzo was effective in reducing time to return to sleep in MOTN insomnia without producing residual effects. Further, the effects of 1.75 mg in females and 3.5 mg in males were comparable. This sex-specific related dosing is consistent with previously reported differences in zolpidem pharmacokinetics.

PSG and patient-reported measures indicate that Intermezzo doses of 1.75 mg and 3.5 mg significantly shortened time to return to sleep and improved total sleep time in patients with MOTN insomnia, and that the effects of 1.75 mg in females and 3.5 mg in males were comparable.

Minimal residual sedative or other adverse effects were observed with Intermezzo versus placebo in this study, and there were no differences between females and males on any parameter.

Intermezzo in DetailAccording to the FDA, zolpidem tartrate, the active ingredient inIntermezzo, was first approved in the United States in 1992 as the drug Ambien. Intermezzo is a lower dose formulation of zolpidem. The recommended and maximum dose of Intermezzo is 1.75 milligrams for women and 3.5 mg for men, taken once per night. The recommended dose for women is lower because women clear zolpidem from the body at a lower rate than men.

Intermezzo was studied in two clinical trials involving more than 370 patients. In the studies, patients taking the drug had a shorter time to fall back asleep after waking compared to people taking an inactive pill (placebo). The most commonly reported adverse reactions in the clinical trials were headache, nausea, and fatigue.

Like other sleep medicines, Intermezzo may cause serious side effects, including getting out of bed while not fully awake and doing an activity that you do not know you are doing or do not remember having done. Reported activities while under the influence of sleep medicines include driving a car, making and eating food, having sex, talking on the phone, and sleep walking — without knowing at the time or remembering later.

Margaret Moline, PhD is director of Clinical Research in Medical Research at Purdue, Stamford, CT.

Margaret Moline, PhD is director of Clinical Research in Medical Research at Purdue, Stamford, CT.

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