Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2.5, 10, and 50 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area and in rats, these doses are approximately 5, 20, and 100 times the MRHD based on mg/m2 body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.
Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.
Impairment of Fertility
Zolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, prior to and during mating, and continuing in females through postpartum day 25. Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose tested, which is approximately 120 times the MRHD based on mg/m2 body surface area. The NOAEL for these effects is 25 times the MRHD based on a mg/m2 body surface area. There was no impairment of fertility at any dose tested.
Normal adults experiencing transient insomnia (n=462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem (7.5 and 10 mg) and placebo. Both zolpidem doses were superior to placebo on objective (polysomnographic) measures of sleep latency, sleep duration, and number of awakenings. Normal elderly adults (mean age 68) experiencing transient insomnia (n=35) during the first two nights in a sleep laboratory were evaluated in a double-blind, crossover, 2-night trial comparing four doses of zolpidem (5, 10, 15 and 20 mg) and placebo. All zolpidem doses were superior to placebo on the two primary PSG parameters (sleep latency and efficiency) and all four subjective outcome measures (sleep duration, sleep latency, number of awakenings, and sleep quality).
Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV™). Adult outpatients with chronic insomnia (n=75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.
Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.
Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.
Next-Day Residual Effects
Next-day residual effects of zolpidem tartrate were evaluated in seven studies involving normal subjects. In three studies in adults (including one study in a phase advance model of transient insomnia) and in one study in elderly subjects, a small but statistically significant decrease in performance was observed in the Digit Symbol Substitution Test (DSST) when compared to placebo. Studies of zolpidem tartrate in non-elderly patients with insomnia did not detect evidence of next-day residual effects using the DSST, the Multiple Sleep Latency Test (MSLT), and patient ratings of alertness.
There was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation of zolpidem tartrate. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg.
Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration of zolpidem tartrate. However, in one study involving zolpidem doses of 10 and 20 mg, there was a significant decrease in next-morning recall of information presented to subjects during peak drug effect (90 minutes post dose), i.e., these subjects experienced anterograde amnesia. There was also subjective evidence from adverse event data for anterograde amnesia occurring in association with the administration of zolpidem tartrate, predominantly at doses above 10 mg.
Effects on Sleep Stages
In studies that measured the percentage of sleep time spent in each sleep stage, zolpidem tartrate has generally been shown to preserve sleep stages. Sleep time spent in stages 3 and 4 (deep sleep) was found comparable to placebo with only inconsistent, minor changes in REM (paradoxical) sleep at the recommended dose.
NDC: 50090-3878-0 10 TABLET, FILM COATED in a BOTTLE
NDC: 50090-3878-1 30 TABLET, FILM COATED in a BOTTLE
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients and their families about the benefits and risks of treatment with zolpidem tartrate. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with zolpidem tartrate and with each prescription refill. Review the zolpidem tartrate Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that zolpidem tartrate should be taken only as prescribed.
Complex Sleep Behaviors
Instruct patients and their families that zolpidem tartrate may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue zolpidem tartrate and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions (5.1)].
CNS-Depressant Effects and Next-Day Impairment
Tell patients that zolpidem tartrate has the potential to cause next-day impairment, and that this risk is increased if dosing instructions are not carefully followed. Tell patients to wait for at least 8 hours after dosing before driving or engaging in other activities requiring full mental alertness. Inform patients that impairment can be present despite feeling fully awake. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.2)].
Severe Anaphylactic and Anaphylactoid Reactions
Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur [see Warnings and Precautions (5.4)].
Tell patients to immediately report any suicidal thoughts.
Alcohol and other Drugs
Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use zolpidem tartrate if they drank alcohol that evening or before bed.
Concomitant Use with Opioids
Inform patients and caregivers that potentially serious additive effects may occur if zolpidem tartrate is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.2, 5.7), Drug Interactions (7.1)].
Tolerance, Abuse, and Dependence
Tell patients not to increase the dose of zolpidem tartrate on their own, and to inform you if they believe the drug “does not work.”
Patients should be counseled to take zolpidem tartrate right before they get into bed and only when they are able to stay in bed a full night (7 to 8 hours) before being active again. Zolpidem tartrate tablets should not be taken with or immediately after a meal. Advise patients NOT to take zolpidem tartrate if they drank alcohol that evening.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with zolpidem tartrate. Advise patients that use of zolpidem tartrate late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used zolpidem tartrate during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness [see Use in Specific Populations (8.1)].
Advise breastfeeding mothers using zolpidem tartrate to monitor infants for increased sleepiness, breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after zolpidem tartrate administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations (8.2)].
Dispense with Medication Guide available at: www.aurobindousa.com/medication-guides
This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2022
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