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Keywords:

  • efficacy;
  • gender;
  • insomnia;
  • middle-of-the-night awakening;
  • safety;
  • sublingual zolpidem tartrate

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Objective

Evaluate potential gender effects on efficacy and safety of a buffered zolpidem sublingual tablet (ZST) formulation.

Methods

Post hoc analysis of the pivotal sleep laboratory and outpatient studies, per gender.

Results

In the sleep laboratory study, polysomnography-derived latency to persistent sleep after middle-of-the-night was significantly improved for both genders at both 1.75 mg and 3.5 mg ZST (females: 15.7 and 8.6 min, respectively, vs. 27.7 min [placebo]; males: 19.0 and 12.7 min vs. 29.0 min [placebo]) with no significant gender differences. In the outpatient study, subjective sleep onset latency after middle-of-the-night was significantly shorter for both genders treated with ZST 3.5 mg versus placebo over the 4-week average (females: 37.3 vs. 59.4 min, p < 0.0001; males: 38.6 vs. 55.1 min, p ≤ 0.01). There were no gender differences in subjective sleep onset latency after middle-of-the-night awakening. In the outpatient study, weekly usage of ZST and placebo by both genders declined throughout the study. Morning alertness following dosing nights improved in both genders, although significant only in females. In both studies, there were no gender differences in adverse events.

Conclusion(s)

Time to return to sleep after middle-of-the-night dosing with ZST improved in both genders, with no gender differences in efficacy and safety. Copyright © 2013 John Wiley & Sons, Ltd.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Insomnia is common and more prevalent in females (Ohayon, 2002; Krishnan and Collop, 2006; Phillips et al., 2008). A meta-analysis reported a 41% greater prevalence of insomnia in females than in males, with this higher risk increasing to 73% among females >65 years old (Zhang and Wing, 2006). A subsequent survey of 3450 adults 18 to 64 years old reported insomnia in 10% of females versus 6% of males (p < 0.001), with frequent use of medication treatments for insomnia in 7.4% of females and 4.5% of males (p < 0.001; Peretti-Watel et al., 2009). A female predominance for insomnia and use of sedative-hypnotic medications is also present among seniors ≥65 years old (Jaussent et al., 2011).

The Diagnostic and Statistical Manual of Mental Disorders, Fourth edition Text Revision diagnostic criteria for primary insomnia include: (i) difficulty initiating or maintaining sleep or having non-restorative sleep; (ii) difficulty in sleeping is present for at least 1 month; (iii) disturbance causes distress or functional impairment; and (iv) sleep disturbance is not caused by an identified medical condition or treatment (American Psychiatric Association, 2000). Middle-of-the-night (MOTN) awakening is a common phenotype of insomnia. Ohayon and Roth (2001) surveyed 24 600 people ≥15 years old in Europe and found that difficulty maintaining sleep for at least three nights per week was the most commonly reported insomnia symptom, affecting 18% of the sample and 9% of the sample reporting difficulty returning to sleep once having awoken. The Consumer Omnibus Survey conducted in Europe reported difficulty initiating sleep (51%) and interrupted sleep (47%) to be the two most common symptoms among individuals with insomnia, with most people reporting more than one symptom (Estivill, 2002). However, these surveys did not focus on gender differences in prevalence.

Zolpidem tartrate sublingual tablet (ZST) buffered formulation is approved for patients with insomnia with difficulty returning to sleep after MOTN awakenings (Intermezzo® prescribing information, 2012). When ZST was approved in 2011, it was the only hypnotic with gender-specific dosing, based primarily on gender differences in zolpidem pharmacokinetics (PK) (Greenblatt et al., 2000; Olubodun et al., 2003; Greenblatt and Roth, 2012).

Plasma concentrations produced by dosing with immediate release (IR) formulations of zolpidem are higher, and clearance is slower in females compared with males (Greenblatt et al., 2000; Olubodun et al., 2003). At the same dose, zolpidem plasma levels from ZST are about 45% higher in females than in males (Greenblatt and Roth, 2012). In addition, pharmacodynamic responses showed a greater decrease in the digits correctly substituted in females (worse performance) than in males administered the same daytime dose of ZST, which may be at least partly associated with higher zolpidem plasma concentrations (Roth et al., 2008a). Review of data from a driving study following dosing with 10 mg IR zolpidem 3 or 4 h prior to the driving test identified significantly more impairment among females than males (Verster and Roth, 2012). In fact, previous studies of several medications, including hypnotics, have also found gender differences in therapeutic response. For example, greater efficacy has been reported for females treated with serotonin antagonists in the treatment of irritable bowel syndrome (Heitkemper et al., 2003). Conversely, males showed a greater response to propofol for use as an analgesic or anesthetic (Campesi et al., 2012). Finally, gaboxadol has been shown to be more effective in improving sleep in females relative to males insomniacs (Roth et al., 2010).

The current report is a post hoc analysis of data from two clinical trials evaluating ZST for treating MOTN awakenings. The first study used a crossover design in sleep laboratory setting, enrolling adults with insomnia. Patients were treated after scheduled MOTN awakenings with ZST 1.75 mg, ZST 3.5 mg, or placebo (Roth et al., 2008b). Polysomnographic (PSG) data (p < 0.001) and subject estimates for time to return to sleep (p < 0.05) were statistically significant favoring ZST. In addition, total sleep time and total sleep time after MOTN awakening were significantly improved with both doses. The second study was a double-blind, placebo-controlled, and parallel group outpatient trial in 295 adults with MOTN awakenings (Roth et al., 2013). Over 4 weeks of treatment, subjects reported sleep onset latency decreased significantly more with ZST 3.5 mg versus placebo.

The previously published manuscripts on these studies provided aggregate results (Roth et al., 2008b; Roth et al., 2013). The current report presents data from both studies analyzed by gender.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Full methods and combined outcome data for each study have been previously published (Roth et al., 2008; Roth et al., 2013). Both studies were performed in accordance with guidelines of the International Conference on Harmonization for Good Clinical Practice and were approved by local institutional review boards (ClinicalTrials.gov identifiers: NCT00380081 and NCT00466193, respectively).

Both studies enrolled adults 18–64 years old diagnosed with primary insomnia using the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition Text Revision criteria (American Psychiatric Association, 2000) as listed in the Introduction.

Sleep laboratory study

The study was a randomized, double-blind, placebo-controlled, and crossover study. Difficulty returning to sleep was confirmed with a 2-night PSG, single-blind, placebo screening period that included a 30-minute scheduled awakening occurring 4 h after initial lights out. Subjects were eligible for randomization if PSG recordings showed a mean latency to persistent sleep after the scheduled MOTN awakening (LPSMOTN) ≥ 20 min across the 2 nights, and a LPSMOTN of not less than 15 min on either night.

Subjects were treated during three 2-night PSG, periods in the sleep laboratory with ZST 1.75 mg, ZST 3.5 mg, or placebo in a double-blind fashion. Subjects were awakened 4 h after initial lights out (between approximately 02:15 and 03:15), treated with study drug, and kept awake for 30 min before trying to go back to sleep for up to 4 more hours. There were washout periods of 5 to 12 days between each of the three treatment periods. PSG recordings were obtained each treatment night. Following treatment with each study drug, subjects were assessed in the morning about 30 min after waking with the Treatment Morning Sleep Questionnaire asking for subjects' estimates of time to sleep onset, sleep duration, and sleep quality. Efficacy was assessed by measuring LPSMOTN from PSG data and Treatment Morning Sleep Questionnaire subjective SOL (sSOLMOTN). Effects of gender and treatment*gender interactions were evaluated for primary and secondary outcome measures.

Outpatient study

In this randomly-assigned, double-blind study, subjects treated spontaneously-occurring MOTN awakenings with ZST 3.5 mg or placebo over 4 weeks. Eligible candidates participated in a 14 -day, single-blind screening. They were instructed to call an interactive voice response system (IVRS) when they experienced a MOTN awakening of at least 10 min duration. After calling the IVRS and responding to qualification questions regarding the duration of the MOTN awakening and having at least 4 h of time remaining in bed, participants were given permission to take study medication. Upon arising each morning, regardless of whether study medication had been taken, subjects were also required to call the IVRS and report their estimates of the previous night's sleep in terms of time to sleep onset, sleep duration, and quality of sleep. Participants were eligible for randomization if their screening showed that they experienced at least three MOTN awakenings per week followed by at least 4 h in bed. They were also required to have at least one awakening per week of a duration of at least 60 min and two awakenings per week of a duration of at least 30 min. Participants who met these criteria and complied with the IVRS instructions were randomized using a 1:1 randomization schedule to double-blind ZST 3.5 mg or placebo. Participants were instructed to follow the same IVRS system instructions for MOTN awakenings that were used during the single-blind placebo screening period.

Efficacy was evaluated by sSOLMOTN (determined by response to the IVRS question: “How long did it take you to fall asleep after taking your study medication?”). Effects of gender and treatment*gender interactions were evaluated on dosing and non-dosing nights.

Safety

Safety was evaluated by a review of adverse event (AE) reporting, physical exam, and laboratory testing. Morning sleepiness/alertness was rated each morning on a 9-point Likert scale on dosing and non-dosing nights in both studies.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Subjects

Subject characteristics for the sleep laboratory and outpatient studies are shown in Table 1.

Table 1. Patient demographics
 Sleep laboratory studyOutpatient study
CharacteristicFemales (N = 58a)Males (N = 24a)Females (N = 201)Males (N = 94)
   ZST 3.5 mgPlaceboZST 3.5 mgPlacebo
   n = 107n = 94n = 43n = 51
  1. SD, standard deviation and ZST, zolpidem sublingual tablet.

  2. a

    All were treated with ZST 1.75 mg, ZST 3.5 mg, and placebo.

Age, years      
Mean ± SD46.6 ± 11.542.5 ± 12.842.3 ± 11.343.3 ± 11.642.3 ± 11.843.5 ± 10.8
Range20–6419–6418–6418–6421–6021–64
Race, n (%)      
White24 (41.4)18 (75.0)66 (61.7)56 (59.6)30 (69.8)38 (74.5)
Black30 (51.7)6 (25.0)37 (34.6)34 (36.2)10 (23.3)11 (21.6)
Asian2(2.4)02 (1.9)1 (1.1)1 (2.3)1 (2.0)
Other2 (2.4)02 (1.9)3 (3.2)2 (4.7)1 (2.0)
Weight, kg      
Mean ± SD73.9 ± 12.488.7 ± 13.169.3 ± 12.071.7 ± 12.186.7 ± 14.883.1 ± 12.7
Range48.6–100.565.9–111.449.0–95.348.3–104.363.5–122.253.5–115.0
Body mass index, kg/m2      
Mean ± SD26.9 ± 4.127.4 ± 2.725.8 ± 3.926.5 ± 4.027.1 ± 3.626.7 ± 3.4
Range18.6–33.621.7–32.118.0–33.919.2–33.819.4–33.818.5–33.9

Efficacy analyses

Sleep laboratory study

Significant improvements in PSG-derived sleep measure (LPSMOTN) were noted for females (least squares [LS] mean for ZST 1.75 mg, ZST 3.5 mg, and placebo was 15.7, 8.6, and 27.7 min, respectively) and for males (LS mean for ZST 1.75 mg, ZST 3.5 mg, and placebo was 19.0, 12.7, and 29.0 min, respectively) treated with ZST at both 1.75 mg and 3.5 mg versus placebo (Figure 1A). In both females and males, the decrease in LPS was dose-dependent, with a significantly greater decrease seen after the 3.5 mg dose relative to the 1.75 mg dose (p < 0.0001 and p = 0.04, respectively). Subjective estimates of latency to return to sleep (sSOLMOTN) were also statistically significant with 1.75 mg and 3.5 mg ZST compared with placebo in both females (LS mean 28.4 and 26.8 min, respectively, vs. 38.5 min for placebo) and males (26.4 and 21.9 min, respectively, vs. 38.0 min for placebo) (Figure 1B). There were no differences between the genders.

image

Figure 1. Sleep laboratory study: time to sleep onset. (A) LPSMOTN and (B) sSOLMOTN. *p < 0.05; **p < 0.01; and ***p < 0.001. LPSMOTN, latency to persistent sleep after middle-of-the-night awakening; sSOLMOTN, subjective sleep onset latency after middle-of-the-night awakening; and ZST, zolpidem sublingual tablet

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Outpatient study

There were no gender differences in sSOLMOTN during the baseline 2-week screening with placebo treatment (Figure 2). sSOLMOTN was significantly shorter among females treated with ZST 3.5 mg versus placebo (LS mean 37.3 min vs. 59.4 min) during double-blind treatment at each week and over the 4-week average (p < 0.0001). Among males, sSOLMOTN was significantly shorter at treatment weeks 1–3 and over the 4-week average (LS mean 38.6 min vs. 55.1 min p ≤ 0.01). There were no significant differences between genders at any time point in the study.

image

Figure 2. Outpatient study: sSOLMOTN. Significant differences were seen between ZST versus placebo: **p < 0.01 and ****p < 0.0001. sSOLMOTN, subjective sleep onset latency after middle-of-the-night awakening; ZST, zolpidem sublingual tablet

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Safety analyses

Sleep laboratory study

Zolpidem sublingual tablet was generally well tolerated by both genders. No individual AE was reported by more than one woman or man treated with either dose of ZST or placebo. There were no clinically relevant changes in vital signs, physical examinations, or laboratory testing in either gender. There was no significant impairment on digit symbol substitution test with either dose in either gender.

Outpatient study

Adverse events occurring in at least two subjects were headache (n = 3, 2.8%) and nausea (n = 2, 1.9%) in females treated with ZST 3.5 mg; nasopharyngitis (n = 2, 2.1%) and joint sprain (n = 2, 2.1%) in females with placebo; and nasopharyngitis (n = 3, 5.9%) and somnolence (n = 2, 3.9%) in males with placebo. In the male ZST 3.5 mg group, there were no AEs that occurred in more than one subject. Weekly usage of ZST and placebo declined significantly over the course of the study, although more so in females (Figure 3).

image

Figure 3. Outpatient study: mean number of tablets self-administered per week. ZST, zolpidem sublingual tablet

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Morning alertness in the total patient population was statistically significantly improved in the ZST 3.5 mg group versus placebo (LS mean ± SE: ZST 5.6 ± 0.09 and placebo 5.2 ± 0.09; p = 0.0041). Female ZST subjects also reported being significantly more alert than female placebo patients following dosing nights (Table 2). Although the ratings of alertness were numerically higher in the male ZST group, the differences between the male ZST 3.5 mg and placebo groups were not statistically significant. There were no differences in daytime alertness ratings following non-dosing nights in the overall patient population or between gender groups.

Table 2. Outpatient study: morning sleepiness/alertness after dosing and non-dosing nights, least square means ± SE
Morning sleepiness/alertnessFemalesMales
ZST 3.5 mgPlaceboZST 3.5 mgPlacebo
  1. SE, standard error and ZST, zolpidem sublingual tablet.

  2. Significant between-treatment differences: *p < 0.05.

Dosing nights    
Baseline4.7 ± 0.154.8 ± 0.175.2 ± 0.284.6 ± 0.25
Double-blind treatment5.6 ± 0.11*5.2 ± 0.125.6 ± 0.155.3 ± 0.13
Non-dosing nights    
Baseline4.8 ± 0.194.7 ± 0.215.1 ± 0.334.9 ± 0.31
Double-blind treatment5.2 ± 0.144.9 ± 0.155.2 ± 0.225.3 ± 0.20

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

In the present analyses results of both PSG and patient reported measures demonstrate that ZST was effective in reducing time to return to sleep after a MOTN awakening. Importantly, this significant improvement in sleep reinitiation was seen in both males and females, with no systematic differences between genders.

The possibility of gender differences in efficacy was hypothesized for three reasons. First, there have been demonstrated differences in sleep biology between males and females. For example, females have longer sleep latencies, and they spend more time in slow wave sleep relative to males (Ehlers and Kupfer, 1997). Second, gaboxadol, a GABAA agonist studied for the treatment of insomnia, showed significantly greater efficacy in females than males (Roth et al., 2010). Finally, PK studies with zolpidem have shown that females have a higher Cmax and a greater AUC than males (Greenblatt and Roth, 2012). However, for zolpidem, there were no differences in efficacy despite differences in PK parameters.

In terms of safety, neither of the present studies found a difference in the number of AEs or the frequency of any given AE in terms of gender. It is interesting to note that zolpidem at 10 mg has been shown to have greater negative effects on driving in females relative to males (Verster and Roth, 2012). This inconsistency calls for studies examining the interaction between dose and gender-related efficacy and safety.

Despite differences in ZST pharmacokinetics between genders, there were no between-gender differences in efficacy and tolerability in these two pivotal trials. Although previously reported data have shown about a 45% higher plasma concentrations in females than in males (Greenblatt and Roth, 2012), efficacy in returning to sleep after MOTN awakening and tolerability were similarly demonstrated in both females and males treated with ZST 3.5 mg in both the sleep laboratory and the outpatient studies. Significantly faster sleep onset was also seen in females, as well as in males, treated with 1.75 mg.

Interpreting results from these data is limited by factors inherent to post hoc analyses. Thus, these studies were not powered to detect difference as a function of gender.

In summary, ZST is an effective and well-tolerated therapy for the management of MOTN awakenings for both females and males with insomnia. Specifically, post hoc analyses of both PSG and patient-reported data demonstrated that ZST at 1.75 and 3.5 mg were equally effective in males and in females and did not demonstrate any gender-related differences in safety. Given the results of these two clinical trials, it can be concluded that differential dosing recommendations for ZST, 1.75 mg in females and 3.5 mg in males, is driven by PK rather than pharmacodynamic differences.

CONFLICT OF INTEREST

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Thomas Roth has received grants/research support from Apnex Medical, Inc., Aventis Pharmaceuticals, Inc., Cephalon, Inc., GlaxoSmithKline plc, Merck & Co., Inc., Neurocrine Biosciences, Inc., Pfizer, Inc., Sanofi U.S., Schering-Plough Corp., Sepracor, Inc., Somaxon Pharmaceuticals, Inc., Somnus Therapeutics, Inc., Syrex Corp., Takeda Pharmaceutical Co., Ltd, Transcept Pharmaceuticals, Inc., Ventus Medical, Inc., Wyeth, LLC, and Xenoport, Inc. He has acted as a consultant for Abbott Laboratories, Acadia Pharmaceuticals, Inc., Acologix, Inc., Acorda Therapeutics, Inc., Actelion Pharmaceuticals Ltd, Addrenex Pharmaceuticals, Inc., Alza Corp., Ancile, Arena Pharmaceuticals, Inc., AstraZeneca plc, Aventis Pharmaceuticals, Inc., Aver Pharmaceuticals Pvt. Ltd, Bayer AG, Bristol-Myers Squibb Company, BTG International Ltd, Cephalon, Inc., Cypress Pharmaceutical, Inc., Dove Pharmaceuticals, Eisai Co., Ltd, Elan Corp., Eli Lilly and Company, Evotec AG, Forest Laboratories, Inc., GlaxoSmithKline plc, Hypnion, Inc., Impax Laboratories, Inc., Intec Pharma Ltd, Intra-Cellular Therapies, Inc., Jazz Pharmaceuticals plc, Johnson & Johnson, Inc., King Pharmaceuticals, Inc., Lundbeck A/S, McNeil Consumer Healthcare, MediciNova, Inc., Merck & Co., Inc., Neurim Pharmaceuticals Ltd, Neurocrine Biosciences, Inc., Neurogen Corp., NovaDel Pharma, Inc., Novartis AG, Ocera Therapeutics, Inc., Orexo AB, Organon Pharmaceuticals, Inc., Otsuka Pharmaceutical Co., Ltd, Prestwick Pharmaceuticals, Inc., Procter & Gamble, Pfizer, Inc., Purdue Pharma L.P., Teva, Hoffman-La Roche, Inc., Sanofi S.A., Schering-Plough Corp., Sepracor, Inc., Servier, Shire plc, Somaxon Pharmaceuticals, Inc., Syrex Corp., Takeda Pharmaceutical Co., Ltd, Transcept Pharmaceuticals, Inc., Vanda Pharmaceuticals, Inc., Ventus Medical, Inc., VivoMetrics, Inc., Wyeth, LLC, Yamanuchi Pharmaceutical Co., Ltd, and Xenoport, Inc. In the last 12 months he has participated in speaking engagements supported by Purdue Pharma L.P.

ACKNOWLEDGEMENTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES

Funding for this study was provided by Purdue Pharma L.P. and Transcept Pharmaceuticals, Inc. The authors received editorial/writing support in the preparation of this manuscript, funded by Purdue Pharma L.P. Tam Vo, PhD and a team from Excerpta Medica, and Margi Goldstein, PhD, an employee of Purdue Pharma L.P., provided editorial and writing assistance. The authors are fully responsible for all content, editorial decisions, and opinions expressed in this study.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONFLICT OF INTEREST
  8. ACKNOWLEDGEMENTS
  9. REFERENCES
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