Treatment and Compliance After successful completion of the screening visit and run-in period, eligible patients were randomly assigned to receive either zolpidem extended-release More common Drowsiness headache muscle aches sleepiness or unusual drowsiness stuffy or runny nose. Do not drink alcoholic beverages. Properly discard this product when it is expired or no longer needed. GoodRx is not sponsored by or affiliated with any of the pharmacies identified in its price comparisons. Zolpidem Immediate-Release The recommended zolpidem immediate-release dose for adult men is 10 mg once daily immediately before bedtime. Information last revised July
During the treatment period, patients received either zolpidem extended-release Patients were instructed to take the medication on those nights when they judged it to be necessary, with the caveat that they were required to self-administer study medication at least 3 nights per week. Patients were given sleep hygiene instructions, which included a directive to refrain from alcohol.
Patients were scheduled to report to their study center every 4 weeks for clinical evaluation; those who completed the trial were evaluated at a total of 9 study center visits Figure 1. Each patient signed an informed consent form before the conduct of any study-related procedure. The appropriate Institutional Review Board at each investigative site approved the protocol. Eligible study participants included male and female patients, 18 to 64 years of age, who met criteria for chronic primary insomnia from the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition DSM-IV.
Women of childbearing potential were required to have a negative serum pregnancy test at the screening visit and to agree to use an acceptable form of contraception throughout the study. Patients were excluded if they were shift workers or if they napped more than 3 times per week. Also excluded were patients who consumed more than 5 xanthine-containing beverages per day, as well as patients who had been using over-the-counter sleep remedies or prescription sleep medications within 2 weeks or 5 half-lives whichever was longer before screening.
In addition, patients were ineligible if they had primary hypersomnia, narcolepsy, breathing-related sleep disorders, circadian-rhythm sleep disorders, parasomnia, or dyssomnia not otherwise specified i. Patients who had a current severe neuropsychiatric disorder i. Women who were lactating or pregnant were also excluded, as were any patients who had participated in another clinical trial within the 2 months prior to screening.
After successful completion of the screening visit and run-in period, eligible patients were randomly assigned to receive either zolpidem extended-release Placebo tablets were the same size, shape, color, and taste as zolpidem extended-release tablets and were therefore indistinguishable from active treatment. Patients were instructed to take no more than 1 tablet per night of study medication immediately before bedtime with a glass of water, for a minimum of 3 tablets and a maximum of 7 tablets per week.
The 3-tablet minimum was judged to be necessary to produce a minimum drug-treatment effect in this chronically ill population. During week 25, the run-out period, patients took no medication. Patient kits contained blister packages of the study medication sufficient for 4 weeks of treatment. At each visit, patients returned the packet from the previous 4 weeks, and the study staff recorded the number of remaining tablets along with the dates on which the patient omitted dosing, as noted on the questionnaire that patients completed each morning.
The investigator reviewed the patient questionnaire at each study visit to determine drug compliance and the recording of daily sleep parameters. Patients were considered compliant with treatment if they took between 3 and 7 tablets per week. Patients could withdraw from the study at any time and for any reason. Study staff recorded the reasons for withdrawal or early discontinuation and made every effort to have the patients complete an early termination visit.
The PGI is a 4-item, subjective, patient self-report that assesses treatment aid to sleep Item 1 , treatment benefit to sleep induction Item 2 , treatment benefit to sleep duration Item 3 , and appropriateness of study medication strength Item 4. Each patient completed the PGI at every 4-week study center visit during the week treatment period and at the final visit at week 25 during the run-out period.
PGI assessments at each visit were based on the patient's global perception of the effects of treatment on sleep during that treatment period including nights with and without dosing , as compared to their sleep prior to entering the study. The CGI is a clinician-rated scale composed of two subscales that measure disease severity and degree of improvement, respectively. CGI-Severity CGI-S is a single-item, global scale of disease severity that requires the investigator to compare the patient's symptoms with those of all other patients who have the disorder.
It is scored from 1 normal to 7 among the most extremely ill. CGI-S was assessed at the baseline visit. CGI-Improvement CGI-I is a single-item scale of symptomatic improvement or worsening that requires the investigator to compare the patient's status at the time of assessment with baseline severity baseline CGI-S.
CGI-I is scored from 1 very much improved to 7 very much worsened. CGI-I was assessed at each 4-week study center visit during the week treatment period and at the final visit at week 25 during the run-out period. Patients completed the PMQ each morning upon awakening and recorded their responses via the interactive voice response system or Internet. The PMQ asks the respondent whether he or she took the study medication the previous evening and assesses the following subjective sleep measures: QOS was measured using a 4-point categorical scale scored as excellent 1 , good 2 , fair 3 , and poor 4.
In addition, each respondent assessed the level of next-day functioning by rating the level of morning sleepiness using numerical values from 0 very sleepy to 10 not at all sleepy and by rating ability to concentrate using a 4-point categorical scale scored as excellent 1 , good 2 , fair 3 , and poor 4. The PMQ was completed daily beginning after the screening visit and continuing through to study termination. Data from this questionnaire were used in various assessments: The ESS was used to determine daytime sleepiness and was completed by each patient at each 4-week study center visit during the week treatment period and at the final visit at week 25 of the run-out period.
The scale consisted of 8 items assessing the degree of sleepiness during the performance of everyday activities, each item being scored from 0 would never fall asleep to 3 high chance of falling asleep. The primary efficacy variable was the score on the PGI Item 1, treatment aid to sleep, assessed at week 12 of the treatment period in the intent-to-treat ITT population. The ITT population consisted of all randomized patients who had received at least one dose of study medication and had undergone at least one post-baseline efficacy assessment.
The PGI Item 1 included three ordered categories related to the patient's impression that treatment 1 helped me sleep, 2 did not affect my sleep, or 3 worsened my sleep. The main secondary efficacy variables were the scores on the following additional assessments performed every fourth week during the treatment period: Tablet-taking behavior was analyzed over each 4-week period of treatment.
Measures of daytime ability to function and sleepiness in the morning, provided daily as part of the PMQ, were analyzed on a monthly basis. Safety was assessed by physical examination during screening and at the last visit, by measurement of vital signs heart rate, supine and standing systolic and diastolic blood pressure during each visit, and by documentation of spontaneously reported or observed adverse events AEs throughout the study. A rebound insomnia effect was defined as a worsening of sleep from baseline values.
Rebound effect was assessed by patients' TST and WASO scores as recorded in the patient's daily questionnaire during the run-out period. A sample size of patients was required in a ratio of 2: Efficacy assessments were analyzed in the ITT population. Safety assessments were analyzed in the population of randomized patients who had received at least one dose of study medication.
In the event of missing assessments of the primary endpoint at week 12, data from the week 16 assessments were used, and for missing assessments of the main secondary PMQ endpoints at month 3, data from the month 4 assessments were used. If assessments were not available for week 12 and week 16, then week 8 values were used, and for missing assessments for month 3 and month 4, month 2 values were used.
No other replacements were performed. Unless otherwise noted, all statistical analyses were performed at the 0. For PGI Item 4, a chi-square test on proportion favorable ratings was used. On the PMQ, for all measurements, the change from baseline was averaged over each month each 4-week period during the treatment period up to week The change from baseline for each PMQ measurement and ESS total score was assessed using analysis of covariance ANCOVA , with treatment group as a fixed factor and the baseline value centered on the grand mean for each group as covariate.
Analysis for a rebound effect was conducted on data from patients who took at least one tablet on the last night of the treatment period. Rebound was also assessed for patients who permanently discontinued the study during the treatment period i. There were no post-baseline data for 2 randomized patients in the zolpidem extended-release group, and thus the ITT population totaled patients. In the zolpidem extended-release group, patients In the placebo group, patients Demographic characteristics of the 2 treatment groups were similar Table 1.
The patients ranged in age from 18 to 64 years, and the majority were white and female. Mean weight of all patients was Baseline disease characteristics were comparable between treatment groups. Mean baseline CGI-S score was 4. Baseline insomnia characteristics recorded from the PMQ during the run-in period were similar between groups Table 2. In the zolpidem extended-release group, The percentage of patients who reported a treatment benefit on the PGI was higher in the zolpidem extended-release group than in the placebo group for all four PGI items at the conclusion of the first 4-week treatment period, and this difference was sustained throughout the entire study.
The percentage of patients who obtained a positive evaluation on the CGI-I scale i. The magnitude of these improvements generally increased over the week treatment period. At baseline, both groups had a mean baseline ESS of 7. ESS was overall statistically significantly lower in the zolpidem extended-release group than the placebo group during the double-blind treatment period. Univariate analyses indicated that the groups were statistically significantly different at all time points except month 6 and month 1 trend for significance Table 4.
Over the 6-month period, the mean number of nights per month that tablets were reported as taken was stable in each treatment group. The mean value was slightly higher for patients in the zolpidem extended-release group than for those in the placebo group Table 5. Of note, each patient's average tablet intake per month was based on a minimum required dosing of 3 tablets per week, with the option to take up to a maximum of 7 tablets per week.
Of the patients who received at least one dose of study drug, treatment-emergent AEs were reported by patients The majority of AEs were mild or moderate in severity. The most common AEs occurring at a slightly higher frequency in the zolpidem extended-release group than in the placebo group were headache, anxiety, somnolence, dizziness, fatigue, disturbance in attention, irritability, nausea, and sinusitis Table 6.
These AEs were similar in nature to those reported in previous studies and to the known safety profile of zolpidem extended-release. Overall, 57 patients 8. The AEs most commonly leading to discontinuation in the zolpidem extended-release and placebo groups were psychiatric disorders 3. A total of 30 serious AEs occurred in 25 patients in 2. Potential rebound insomnia was assessed by examining the mean change in TST and WASO scores from baseline on each of the first 3 nights after abrupt discontinuation of study medication during the run-out period.
In neither the zolpidem extended-release group nor the placebo group was any worsening from baseline i. However, no differences between these groups were observed on nights 2 and 3. This study assessed the efficacy and safety of zolpidem extended-release A review of the current literature suggests that this is the longest placebo-controlled study completed thus far of intermittent dosing of an insomnia agent.
Non-nightly dosing may offer many advantages over nightly dosing, including decreased drug exposure, increased patient control over therapy, and reduced medication expense. It is consistent with the prevailing prescribing recommendations for medications in this class and is also the preferred dosing pattern among many patients. Results of the present study confirm the sleep maintenance efficacy of zolpidem extended-release With respect to QOS, the largest benefit obtained in the placebo group 0.
Furthermore, the absolute magnitude of the benefits obtained with zolpidem extended-release The primary efficacy parameter, aid to sleep PGI Item 1 , was chosen to capture patients' overall impressions of the medication's ability to improve sleep. One of the main concerns with developing a longer-acting formulation of a sedative or hypnotic drug is the potential for continuing drug effects after the patient awakens in the morning.
Therefore, it is encouraging to note that patient-reported daily measures of morning sleepiness and ability to concentrate were significantly better in the zolpidem extended-release group than in the placebo group for each 4-week interval throughout the entire study. This is consistent with the pharmacokinetic profile of zolpidem extended-release, which provides higher plasma concentrations beyond 3 h, compared to original zolpidem 10 mg, yet retains a similar elimination half-life, thereby presenting low plasma concentrations at 8 h post-dose.
Scores on the ESS were significantly improved with zolpidem extended-release versus placebo in months 2 to 5, and there was a trend for this effect in month 1. As far as we are aware, this is the first double-blind, placebo-controlled trial demonstrating significant efficacy of an insomnia medication on this measure. This finding lends further support to the conclusion that zolpidem extended-release treatment improved subjective daytime sleepiness in this study.
This result is intriguing, however, given that ESS measures were not elevated in this population at baseline and are generally not elevated in adult insomnia patients. Rebound insomniaŚdefined as an acute worsening of insomnia symptoms upon discontinuation of medication to a level of severity greater than baselineŚwas not observed in this study.
This result occurred despite the fact that rebound was assessed only in the subset of subjects who had taken study medication on the last night of the double-blind phase, in order to decrease the likelihood that a rebound effect might have been missed by a drug-free period before the run-out phase. However, it is notable that on the first night of the discontinuation phase, there appeared to be a worsening of TST and WASO compared with the second and third nights in those receiving zolpidem extended-release tablets.
The mean number of days that pills were taken was stable over the 6-month period in both treatment groups. This lack of increase over time in the number of pill-taking nights strongly supports the intermittent dosing model examined in this trial. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:.
Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional. Call your doctor for medical advice about side effects. This medicine helps you to fall asleep and sleep through the night. Enter a custom quantity Set. You can only add a maximum of 25 drugs to MyRx. Please remove another drug before adding this one.
Zolpidem ER Side Effects. What should I watch for? Common and Rare Side Effects Along with its needed effects, a medicine may cause some unwanted effects. Check with your doctor immediately if any of the following side effects occur: Less common Chest pain confusion confusion about identity, place, and time discouragement false or unusual sense of well-being fast, irregular, pounding, or racing heartbeat or pulse feeling sad or empty fever general feeling of discomfort or illness irritability lack of appetite lightheadedness loss of interest or pleasure shakiness and unsteady walk tiredness trouble concentrating trouble sleeping unsteadiness, trembling, or other problems with muscle control or coordination unusual tiredness or weakness.
Less common or rare Anxiety bladder pain bloody or cloudy urine burning, crawling, itching , numbness, prickling, "pins and needles", or tingling feelings chills cold sweats crying decreased awareness or responsiveness depersonalization difficult, burning, or painful urination dizziness, faintness, or lightheadedness when getting up from lying or sitting position dry mouth dysphoria euphoria fainting frequent urge to urinate hyperventilation irregular heartbeats irritability lower back or side pain paranoia quick to react or overreact emotionally rapidly changing moods restlessness seeing, hearing, or feeling things that are not there severe sleepiness shakiness in the legs, arms, hands, or feet shortness of breath trembling or shaking of the hands or feet.
Rare Attack, assault, or force black, tarry stools change in walking and balance clumsiness or unsteadiness cough delusions dementia difficulty swallowing dizziness hives , itching , or skin rash lack of feeling or emotion pale skin puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue sore throat sores, ulcers, or white spots on the lips or in the mouth swollen glands thoughts of killing oneself or changes in behavior tightness in the chest troubled breathing with exertion uncaring unusual bleeding or bruising.
Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them: More common Drowsiness headache muscle aches sleepiness or unusual drowsiness stuffy or runny nose. Less common Abdominal or stomach discomfort acid or sour stomach back pain being forgetful belching body aches or pain congestion diarrhea difficulty having a bowel movement stool difficulty with moving double vision feeling of constant movement of self or surroundings heartburn hoarseness indigestion longer or heavier menstrual periods loss of memory muscle pain or stiffness nausea pain or tenderness around the eyes and cheekbones seeing double sensation of spinning tender, swollen glands in the neck unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness voice changes.
Less common or rare Bad, unusual, or unpleasant after taste breast pain change in taste changes in patterns and rhythms of speech increased sweating itching of the vagina or genital area pain during sexual intercourse paleness of the skin slurred speech thick, white vaginal discharge with no odor or with a mild odor vomiting. Rare Blemishes on the skin blindness blurred vision change in near or distance vision decreased interest in sexual intercourse difficulty in focusing eyes eye pain feeling of warmth frequent urge to defecate inability to have or keep an erection increased appetite increased sensitivity of the skin to sunlight lack or loss of strength loss in sexual ability, desire, drive, or performance pimples redness of the face, neck, arms, and occasionally, upper chest redness or other discoloration of the skin severe sunburn stomach upset straining while passing stool tearing weight loss.
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