Side Effects of Intermezzo (zolpidem)

Intermezzo (zolpidem) is a sedative/hypnotic used to treat insomnia in the middle of the night (awakening and experiencing difficulty returning to sleep). 

Intermezzo contains the same active ingredient as in Ambien. Intermezzo shares some characteristics of a family of sedatives called benzodiazepines which includes diazepam. 

Benzodiazepines cause sedation, muscle relaxation, act as anticonvulsants (antiseizure medications), and reduce anxiety. Intermezzo has selectivity in that it has little of the muscle relaxant and antiseizure effects and more of the sedative effect. Therefore, it is used primarily as a medication for sleep.

Common side effects of Intermezzo include

• headache,
• nausea,
• drowsiness,
• dizziness, and
• diarrhea.

Serious side effects of Intermezzo include

• confusion,
• insomnia,
• euphoria,
• balance problems, and
• visual changes.

When abruptly discontinued, Intermezzo can cause abnormal behavior with confusion, paradoxical insomnia or "complex sleep-related behaviors," which may include sleep-driving (driving with no memory of having done so). 

Drug interactions of Intermezzo include alcohol, which has an additive effect with Intermezzo and the two should not be combined. 

Intermezzo should not be combined with other sedative drugs because of the additive effects. 

Itraconazole and ketoconazole may increase the blood concentration of Intermezzo by reducing the activity of the enzymes that break down Intermezzo in the liver. Conversely, rifampin may reduce the concentration of Intermezzo by increasing the activity of the enzymes that break down Intermezzo. 

There are no adequate studies of Intermezzo use in pregnant women.

Intermezzo is excreted in human breast milk and may adversely affect the infant. Consult your doctor before breastfeeding.

The most common side effects of zolpidem are:

• headache,
• nausea,
• drowsiness,
• dizziness, and
• diarrhea.

Other important side effects include:

• confusion,
• insomnia,
• euphoria,
• ataxia (balance problems), and
• visual changes.

When the drug is abruptly discontinued. Zolpidem can cause abnormal behavior with confusion, paradoxical insomnia or "complex sleep-related behaviors," which may include sleep-driving (driving with no memory of having done so). If these side effects occur, zolpidem should be discontinued. Zolpidem is a controlled substance because it is likely to be abused and may cause dependence.

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
• Serious anaphylactic and anaphylactoid reactions
• Abnormal thinking and behavioral changes, and complex behaviors
• Withdrawal effects

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.

• 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)

Postmarketing Experience

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.

CNS-active Drugs

• Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression.
• Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.

Imipramine

• 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.

Haloperidol

• 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.

Alcohol

• An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated.

Sertraline

• Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamic effect of zolpidem.

Fluoxetine

• 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.

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

• 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

• 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

Controlled Substance

• Zolpidem tartrate is classified as a Schedule IV controlled substance by federal regulation.

Abuse

• 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.

Dependence

• 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.