Side Effects of Ambien (zolpidem)

Ambien (zolpidem) is a sedative/hypnotic used to treat insomnia. Ambien improves initiation of sleep and keeps patients asleep longer. Ambien shares some characteristics with benzodiazepines, which cause sedation, muscle relaxation, act as anti-convulsants (anti-seizure medications), and reduce anxiety. Ambien has selectivity in that it has little of the muscle relaxant and anti-seizure effects and more of the sedative effect. Therefore, it is used primarily as a medication for sleep. The oral spray form of zolpidem, Zolpimist, has more rapid absorption than the tablet form because it is absorbed through the lining of the mouth. 

Common side effects of Ambien include:

• drowsiness,
• headache,
• weakness,
• dizziness,
• a “drugged” feeling,
• confusion,
• insomnia,
• diarrhea,
• depression,
• dry mouth,
• rash,
• euphoria,
• balance problems, and
• visual changes.

Serious side effects of Ambien include:

• withdrawal symptoms (muscle cramps, sweats, shaking, and seizures) when abruptly discontinued, and
• 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 Ambien include alcohol and other sedative drugs which have an additive effect.

Itraconazole and ketoconazole may increase the blood concentration of Ambien by and increase its side effects.

Rifampin may reduce the concentration of Ambien and reduce its effectiveness.

There are no adequate studies of Ambien use in pregnant women. Ambien 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:

• Drowsiness
• Headache
• Weakness
• Dizziness
• A "drugged" feeling, which probably reflect the action of the drug

Other side effects include:

• Confusion
• Insomnia
• Diarrhea
• Depression
• Dry mouth
• Rash
• Euphoria
• Ataxia (balance problems), and
• Visual changes.

Zolpidem can cause withdrawal symptoms (muscle cramps, sweats, shaking, and seizures) 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.

The following serious adverse reactions are discussed in greater detail in other sections of the labeling:

• Complex Sleep Behaviors
• CNS-Depressant Effects and Next-Day Impairment
• Serious Anaphylactic and Anaphylactoid Reactions
• Abnormal Thinking and Behavior Changes
• Withdrawal effects

Clinical Trials Experience

Associated With Discontinuation Of Treatment

Approximately 4% of 1,701 patients who received zolpidem at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.

Most Commonly Observed Adverse Reactions In Controlled Trials

During short-term treatment (up to 10 nights) with Ambien at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

Adverse Reactions Observed At An Incidence Of ≥1% In Controlled Trials

The following tables enumerate treatment-emergent adverse reactions frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies.

The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following table was derived from results of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

Table 1: Incidences of Treatment-Emergent Adverse Reactions in Placebo-Controlled Clinical Trials Lasting up to 10 Nights (percentage of patients reporting)

The following table was derived from results of three placebo-controlled long-term efficacy trials involving Ambien (zolpidem tartrate). These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.

Table 2: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials Lasting up to 35 Nights (percentage of patients reporting)

Dose Relationship For Adverse Reactions

There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Adverse Event Incidence Across The Entire Preapproval Database

Ambien was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with Ambien, they were not necessarily caused by it.

Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system 

Infrequent: increased sweating, pallor, postural hypotension, syncope.

Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole

Frequent: asthenia.

Infrequent: edema, falling, fatigue, fever, malaise, trauma.

Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.

Cardiovascular system

Infrequent: cerebrovascular disorder, hypertension, tachycardia.

Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system

Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor.

Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system

Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting.

Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system 

Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system

Infrequent: infection.

Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.

Liver and biliary system 

Infrequent: abnormal hepatic function, increased SGPT.

Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional 

Infrequent: hyperglycemia, thirst.

Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.

Musculoskeletal system

Frequent: arthralgia, myalgia. Infrequent: arthritis.

Rare: arthrosis, muscle weakness, sciatica, tendinitis.

Reproductive system

Infrequent: menstrual disorder, vaginitis.

Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system

Frequent: upper respiratory infection, lower respiratory infection.

Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, respiratory depression, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages 

Infrequent: pruritus.

Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses

Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus.

Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system 

Frequent: urinary tract infection.

Infrequent: cystitis, urinary incontinence.

Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Ambien. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver and biliary system: acute hepatocellular, cholestatic or mixed liver injury with or without jaundice (i.e., bilirubin >2 x ULN, alkaline phosphatase ≥2 x ULN, transaminase ≥5 x ULN).

CNS-Active Drugs

CNS Depressants

Coadministration of zolpidem with other CNS depressants increases the risk of CNS depression. Concomitant use of zolpidem with these drugs may increase drowsiness and psychomotor impairment, including impaired driving ability.

Zolpidem tartrate was evaluated in healthy volunteers in single-dose interaction studies for several CNS drugs.

Imipramine, Chlorpromazine

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.

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 induce or inhibit CYP3A may affect exposure to zolpidem. The effect of drugs that induce or inhibit other P450 enzymes on the exposure to zolpidem is not known.

CYP3A4 Inducers

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 and is not recommended.

St. John's Wort

Use of St. John's wort, a CYP3A4 inducer, in combination with zolpidem may decrease blood levels of zolpidem and is not recommended.

CYP3A4 Inhibitors

Ketoconazole

Ketoconazole, a potent CYP3A4 inhibitor, increased the exposure to and pharmacodynamic effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when a potent CYP3A4 inhibitor 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 a 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 zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg 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 zolpidem or any other hypnotic.

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 following placebo substitution occurring within 48 hours following 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. Postmarketing reports of abuse, dependence and withdrawal have been received.