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The following serious adverse reactions in zolpidem-treated patients are discussed in greater detail in other sections of the labeling:
- CNS-depressant effects and next-day impairment [see WARNINGS AND PRECAUTIONS]
- Serious anaphylactic and anaphylactoid reactions [see WARNINGS AND PRECAUTIONS]
- Abnormal thinking and behavioral changes, and complex behaviors [see WARNINGS AND PRECAUTIONS]
- Withdrawal effects [see WARNINGS AND PRECAUTIONS]
Clinical Trials Experience
The safety data described below are based on two double-blind placebo-controlled trials of Intermezzo in adult patients with insomnia characterized by difficulty returning to sleep after a middle-of-the-night awakening [see Clinical Studies]. These two trials included 230 and 82 patients treated with 3.5 mg and 1.75 mg of Intermezzo, respectively. The first study was a 3way crossover sleep-laboratory study in 82 patients (58 female and 24 male; median age 47 years; 51% Caucasian, 44% African-American) of 1.75 mg and 3.5 mg of Intermezzo compared to placebo (Study 1). The second study was a 4-week, parallel-group at-home study in 295 patients (201 female and 94 male; median age 43 years) of 3.5 mg of Intermezzo compared to placebo, used on an as-needed basis after spontaneous middle-of-the-night awakenings (Study 2). In Study 2, patients took Intermezzo during the night on 62% of study nights.
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in actual practice.
Table 1 shows the incidence of adverse reactions reported in Study 2 that occurred in 2% or more of Intermezzo-treated (3.5 mg) patients in which the incidence was greater than the incidence in placebo-treated patients. For women and other patients taking the 1.75 mg dose in Study 1, the incidence of adverse reactions was similar to the incidence seen with 3.5 mg of Intermezzo in Table 1.
The most commonly reported adverse reactions in all treatment groups were headache, nausea, and fatigue.
Table 1: Summary of Adverse Reactions ( ≥ 2%) in
Outpatient, Double-Blind, Parallel-Group, Placebo-Controlled Study (Study 2)
|MedDRA System Organ Class
|3.5 mg Intermezzo
|General Disorders and Administration Site Conditions||3%||0%|
|Nervous System Disorders||5%||3%|
The following adverse reactions have been identified during post-approval use of Intermezzo. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to establish a causal relationship to drug exposure.
- Application site reactions, primarily in the sublingual area, have been reported. These application site reactions included oral ulcers, blisters, and mucosal inflammation.
Read the Intermezzo (zolpidem tartrate) Side Effects Center for a complete guide to possible side effects
Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see WARNINGS AND PRECAUTIONS]. Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.
Imipramine in combination with zolpidem produced no pharmacokinetic interaction other than a 20% decrease in peak levels of imipramine, but there was an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced no pharmacokinetic interaction, but there was an additive effect of decreased alertness and psychomotor performance.
A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict the absence of an effect following chronic administration.
An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see WARNINGS AND PRECAUTIONS].
Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem.
After multiple doses of zolpidem tartrate and fluoxetine, an increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance [see CLINICAL PHARMACOLOGY].
Drugs That Affect Drug Metabolism Via Cytochrome P450
Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of other P450 enzymes on the exposure to zolpidem is not known.
Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem. Use of rifampin in combination with zolpidem may decrease the efficacy of zolpidem.
Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.
Drug Abuse And Dependence
Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.
Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.
Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.
Studies of abuse potential in former drug abusers found that the effects of single doses of 40 mg of oral zolpidem tartrate were similar, but not identical, to diazepam 20 mg, while 10 mg of oral zolpidem tartrate was difficult to distinguish from placebo.
Because persons with a history of addiction to or abuse of drugs or alcohol are at increased risk for misuse, abuse and addiction of zolpidem, they should be monitored carefully when receiving Intermezzo.
Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist.
Sedative-hypnotics have produced withdrawal signs and symptoms following abrupt discontinuation. These reported symptoms range from mild dysphoria and insomnia to a withdrawal syndrome that may include abdominal and muscle cramps, vomiting, sweating, tremors, and convulsions. The following adverse events which are considered to meet the DSMIII-R criteria for uncomplicated sedative-hypnotic withdrawal were reported during U.S. clinical trials with other oral zolpidem formulations following placebo substitution occurring within 48 hours following the last zolpidem treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence, and withdrawal resulting from use of oral zolpidem tartrate have been received.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 3/20/2017
Additional Intermezzo Information
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You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
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