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Ambien CR

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Ambien CR

Ambien CR

SIDE EFFECTS

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

  • Serious anaphylactic and anaphylactoid reactions [seeWARNINGS AND PRECAUTIONS)
  • Abnormal thinking, behavior changes, and complex behaviors [seeWARNINGS AND PRECAUTIONS]
  • Withdrawal effects [seeWARNINGS AND PRECAUTIONS]
  • CNS-depressant effects [seeWARNINGS AND PRECAUTIONS]

Clinical trials experience

Associated with discontinuation of treatment: In 3-week clinical trials in adults and elderly patients ( > 65 years), 3.5% (7/201) patients receiving Ambien CR (zolpidem tartrate) 6.25 or 12.5 mg discontinued treatment due to an adverse reaction as compared to 0.9% (2/216) of patients on placebo. The reaction most commonly associated with discontinuation in patients treated with Ambien CR (zolpidem tartrate) was somnolence (1%).

In a 6-month study in adult patients (18-64 years of age), 8.5% (57/669) of patients receiving Ambien CR (zolpidem tartrate) 12.5 mg as compared to 4.6% on placebo (16/349) discontinued treatment due to an adverse reaction. Reactions most commonly associated with discontinuation of Ambien CR (zolpidem tartrate) included anxiety (anxiety, restlessness or agitation) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo, and depression (depression, major depression or depressed mood) reported in 1.5% (10/669) of patients as compared to 0.3% (1/349) of patients on placebo.

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 treatment with Ambien CR (zolpidem tartrate) in adults and elderly at daily doses of 12.5 mg and 6.25 mg, respectively, each for three weeks, the most commonly observed adverse reactions associated with the use of Ambien CR (zolpidem tartrate) were headache, next-day somnolence, and dizziness.

In the 6-month trial evaluating Ambien CR (zolpidem tartrate) 12.5 mg, the adverse reaction profile was consistent with that reported in short-term trials, except for a higher incidence of anxiety (6.3% for Ambien CR (zolpidem tartrate) versus 2.6% for placebo).

Adverse reactions observed at an incidence of ≥ 1% in controlled trials: The following tables enumerate treatment-emergent adverse reaction frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received Ambien CR (zolpidem tartrate) in placebo-controlled trials. Events reported by investigators were classified utilizing the MedDRA dictionary 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 tables were derived from results of two placebo-controlled efficacy trials involving Ambien CR (zolpidem tartrate) . These trials involved patients with primary insomnia who were treated for 3 weeks with Ambien CR (zolpidem tartrate) at doses of 12.5 mg (Table 1) or 6.25 mg (Table 2), respectively. The tables include only adverse reactions occurring at an incidence of at least 1% for Ambien CR (zolpidem tartrate) patients and with an incidence greater than that seen in the placebo patients.

Table 1. Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Adults (percentage of patients reporting)

Body System/Adverse Reaction* Ambien CR (zolpidem tartrate)
12.5 mg
(N = 102)
Placebo
(N = 110)
Infections and infestations
  Influenza 3 0
  Gastroenteritis 1 0
  Labyrinthitis 1 0
Metabolism and nutrition disorders
  Appetite disorder 1 0
Psychiatric disorders
  Hallucinations** 4 0
  Disorientation 3 2
  Anxiety 2 0
  Depression 2 0
  Psychomotor retardation 2 0
  Binge eating 1 0
  Depersonalization 1 0
  Disinhibition 1 0
  Euphoric mood 1 0
  Mood swings 1 0
  Stress symptoms 1 0
Nervous system disorders
  Headache 19 16
  Somnolence 15 2
  Dizziness 12 5
  Memory disorders*** 3 0
  Balance disorder 2 0
  Disturbance in attention 2 0
  Hypoesthesia 2 1
  Ataxia 1 0
  Paresthesia 1 0
Eye disorders
  Visual disturbance 3 0
  Eye redness 2 0
  Vision blurred 2 1
  Altered visual depth perception 1 0
  Asthenopia 1 0
Ear and labyrinth disorders
  Vertigo 2 0
  Tinnitus 1 0
Respiratory, thoracic and mediastinal disorders
  Throat irritation 1 0
Gastrointestinal disorders
  Nausea 7 4
  Constipation 2 0
  Abdominal discomfort 1 0
  Abdominal tenderness 1 0
  Frequent bowel movements 1 0
  Gastroesophageal reflux disease 1 0
  Vomiting 1 0
Skin and subcutaneoustissuedisorders
  Rash 1 0
  Skin wrinkling 1 0
  Urticaria 1 0
Musculoskeletal and connective tissue disorders
  Back pain 4 3
  Myalgia 4 0
  Neck pain 1 0
Reproductive system and breast disorders
  Menorrhagia 1 0
General disorders and administration site conditions
  Fatigue 3 2
  Asthenia 1 0
  Chest discomfort 1 0
Investigations
  Blood pressure increased 1 0
  Body temperature increased 1 0
Injury, poisoning and procedural complications
  Contusion 1 0
Social circumstances
  Exposure to poisonous plant 1 0
*Reactions reported by at least 1% of patients treated with Ambien CR (zolpidem tartrate) and at greater frequency than in the placebo group.
**Hallucinations included hallucinations NOS as well as visual and hypnogogic hallucinations.
***Memory disorders include: memory impairment, amnesia, anterograde amnesia.

Table 2. Incidences of Treatment-Emergent Adverse Reactions in a 3-Week Placebo-Controlled Clinical Trial in Elderly (percentage of patients reporting)

Body System/Adverse Reaction* Ambien CR (zolpidem tartrate)
6.25 mg
(N=99)
Placebo
(N=106)
Infections and infestations
  Nasopharyngitis 6 4
  Lower respiratory tract infection 1 0
  Otitis externa 1 0
  Upper respiratory tract infection 1 0
Psychiatric disorders
  Anxiety 3 2
  Psychomotor retardation 2 0
  Apathy 1 0
  Depressed mood 1 0
Nervous system disorders
  Headache 14 11
  Dizziness 8 3
  Somnolence 6 5
  Burning sensation 1 0
  Dizziness postural 1 0
  Memory disorders** 1 0
  Muscle contractions involuntary 1 0
  Paresthesia 1 0
  Tremor 1 0
Cardiac disorders
  Palpitations 2 0
Respiratory, thoracic and mediastinal disorders
  Dry throat 1 0
Gastrointestinal disorders
  Flatulence 1 0
  Vomiting 1 0
Skin and subcutaneoustissuedisorders
  Rash 1 0
  Urticaria 1 0
Musculoskeletal and connective tissue disorders
  Arthralgia 2 0
  Muscle cramp 2 1
  Neck pain 2 0
Renal and urinary disorders
  Dysuria 1 0
Reproductive system andbreastdisorders
  Vulvovaginal dryness 1 0
General disorders and administration site conditions
  Influenza like illness 1 0
  Pyrexia 1 0
Injury, poisoning and procedural complications
  Neck injury 1 0
*Reactions reported by at least 1% of patients treated with Ambien CR and at greater frequency than in the placebo group. **Memory disorders include: memory impairment, amnesia, anterograde amnesia.

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.

Other adverse reactions observed during the premarketing evaluation of Ambien CR (zolpidem tartrate) : Other treatment-emergent adverse reactions associated with participation in Ambien CR (zolpidem tartrate) studies (those reported at frequencies of < 1%) were not different in nature or frequency to those seen in studies with immediate-release zolpidem tartrate, which are listed below.

Adverse Events Observed During the Premarketing Evaluation of Immediate-Release Zolpidem Tartrate: Immediate-release zolpidem tartrate 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: Frequent: dry mouth. 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: chest pain, edema, falling, 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, drowsiness, drugged feeling, euphoria, insomnia, lethargy, lightheadedness, vertigo. Infrequent: agitation, 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: diarrhea, dyspepsia, hiccup. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis. 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: Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.

Reproductive system: Infrequent: menstrual disorder, vaginitis. Rare: breast fibroadenosis, breast neoplasm, breast pain.

Respiratory system: Frequent: sinusitis. Infrequent: bronchitis, coughing, dyspnea. Rare: bronchospasm, 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.

Read the Ambien CR (zolpidem tartrate) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

CNS-active drugs

Since the systematic evaluations of zolpidem in combination with other CNS-active drugs have been limited, careful consideration should be given to the pharmacology of any CNS-active drug to be used with zolpidem. Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.

An immediate-release formulation of zolpidem tartrate was evaluated in healthy subjects 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 a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and zolpidem was demonstrated [seeWARNINGS AND PRECAUTIONS].

A single-dose interaction study with zolpidem 10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady-state concentrations were evaluated in healthy females, the only significant change was a 17% increase in the zolpidem half-life. There was no evidence of an additive effect in psychomotor performance.

Following five consecutive nightly doses of zolpidem 10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Drugs that affect drug metabolism via cytochrome P450

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes has not been carefully evaluated.

A randomized, double-blind, crossover interaction study in ten healthy volunteers between itraconazole (200 mg once daily for 4 days) and a single dose of zolpidem (10 mg) given 5 hours after the last dose of itraconazole resulted in a 34% increase in AUC0-∞ of zolpidem. There were no significant pharmacodynamic effects of zolpidem on subjective drowsiness, postural sway, or psychomotor performance.

A randomized, placebo-controlled, crossover interaction study in eight healthy female subjects between five consecutive daily doses of rifampin (600 mg) and a single dose of an immediate-release formulation of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (–73%), Cmax (–58%), and T1/2 (–36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem.

A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of immediate-release zolpidem tartrate with ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem by a factor of 1.3 and increased the total AUC of zolpidem by a factor of 1.7 compared to zolpidem alone and prolonged the elimination half-life by approximately 30% along with an increase in the pharmacodynamic effects of zolpidem. Caution should be used when ketoconazole is given with zolpidem and consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together. Patients should be advised that use of Ambien CR (zolpidem tartrate) with ketoconazole may enhance the sedative effects.

Other drugs with no interaction with zolpidem

A study involving cimetidine/zolpidem and ranitidine/zolpidem combinations revealed no effect of either drug on the pharmacokinetics or pharmacodynamics of zolpidem.

Zolpidem had no effect on digoxin pharmacokinetics and did not affect prothrombin time when given with warfarin in normal subjects.

Drug-laboratory test interactions

Zolpidem is not known to interfere with commonly employed clinical laboratory tests. In addition, clinical data indicate that zolpidem does not cross-react with benzodiazepines, opiates, barbiturates, cocaine, cannabinoids, or amphetamines in two standard urine drug screens.

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 effects were 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 DSM-III-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. Post-marketing reports of abuse, dependence and withdrawal have been received.

Read the Ambien CR Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 5/10/2010
This monograph has been modified to include the generic and brand name in many instances.

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