Ambien

Mechanism Of Action

Zolpidem, the active moiety of zolpidem tartrate, is a hypnotic agent with a chemical structure unrelated to benzodiazepines, barbiturates, or other drugs with known hypnotic properties. It interacts with a GABA-BZ receptor complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which non-selectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ1 receptor preferentially with a high affinity ratio of the a subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

Pharmacokinetics

The pharmacokinetic profile of AMBIEN is characterized by rapid absorption from the gastrointestinal tract and a short elimination half-life (T1/2) in healthy subjects.

In a single-dose crossover study in 45 healthy subjects administered 5 and 10 mg zolpidem tartrate tablets, the mean peak concentrations (Cmax) were 59 (range: 29 to 113) and 121 (range: 58 to 272) ng/mL, respectively, occurring at a mean time (Tmax) of 1.6 hours for both. The mean AMBIEN elimination half-life was 2.6 (range: 1.4 to 4.5) and 2.5 (range: 1.4 to 3.8) hours, for the 5 and 10 mg tablets, respectively. AMBIEN is converted to inactive metabolites that are eliminated primarily by renal excretion. AMBIEN demonstrated linear kinetics in the dose range of 5 to 20 mg. Total protein binding was found to be 92.5 ± 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL. Zolpidem did not accumulate in young adults following nightly dosing with 20 mg zolpidem tartrate tablets for 2 weeks.

A food-effect study in 30 healthy male subjects compared the pharmacokinetics of AMBIEN 10 mg when administered while fasting or 20 minutes after a meal. Results demonstrated that with food, mean AUC and Cmax were decreased by 15% and 25%, respectively, while mean Tmax was prolonged by 60% (from 1.4 to 2.2 hr). The half-life remained unchanged. These results suggest that, for faster sleep onset, AMBIEN should not be administered with or immediately after a meal.

Special Populations

In the elderly, the dose for AMBIEN should be 5 mg [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. This recommendation is based on several studies in which the mean Cmax, T1/2, and AUC were significantly increased when compared to results in young adults. In one study of eight elderly subjects (> 70 years), the means for Cmax, T1/2, and AUC significantly increased by 50% (255 vs. 384 ng/mL), 32% (2.2 vs. 2.9 hr), and 64% (955 vs. 1,562 ng·hr/mL), respectively, as compared to younger adults (20 to 40 years) following a single 20 mg oral dose. AMBIEN did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

The pharmacokinetics of AMBIEN in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20 mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng·hr/mL) higher, respectively, in hepatically-compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normal subjects of 2.2 hr (range: 1.6 to 2.4 hr) [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS, Use In Specific Populations].

The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean ClCr = 6.5 ± 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally impaired patients. No dosage adjustment is necessary in patients with compromised renal function.

Drug Interactions

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].

Following five consecutive nightly doses at bedtime of oral zolpidem tartrate 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.

A single-dose interaction study with zolpidem tartrate 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 were given at steady state and the concentrations evaluated in healthy females, an increase in the zolpidem half-life (17%) was observed.

There was no evidence of an additive effect in psychomotor performance.

Some compounds known to inhibit CYP3A may increase exposure to zolpidem. The effect of inhibitors of other P450 enzymes on the pharmacokinetics of zolpidem is unknown.

A single-dose interaction study with zolpidem tartrate 10 mg and itraconazole 200 mg at steady-state levels in male volunteers resulted in a 34% increase in AUC0–∞ of zolpidem tartrate. There were no pharmacodynamic effects of zolpidem detected on subjective drowsiness, postural sway, or psychomotor performance.

A single-dose interaction study with zolpidem tartrate 10 mg and rifampin 600 mg at steady-state levels in female subjects 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 tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamic effects of zolpidem [see DRUG INTERACTIONS].

A single-dose interaction study with zolpidem tartrate 5 mg and ketoconazole, a potent CYP3A4 inhibitor, given as 200 mg twice daily for 2 days increased Cmax of zolpidem (30%) and the total AUC of zolpidem (70%) compared to zolpidem alone and prolonged the elimination half-life (30 %) along with an increase in the pharmacodynamic effects of zolpidem [see DRUG INTERACTIONS].

Additionally, fluvoxamine (a strong inhibitor of CYP1A2 and a weak inhibitor of CYP3A4 and CYP2C9) and ciprofloxacin (a strong inhibitor of CYP1A2 and a moderate inhibitor of CYP3A4) are also likely to inhibit zolpidem’s metabolic pathways, potentially leading to an increase in zolpidem exposure.

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

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

Clinical Studies

Transient Insomnia

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).

Chronic Insomnia

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 AMBIEN.

Studies Pertinent To Safety Concerns For Sedative/Hypnotic Drugs

Next-day residual effects of AMBIEN 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 AMBIEN 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 AMBIEN (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 AMBIEN. 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 AMBIEN, predominantly at doses above 10 mg.

In studies that measured the percentage of sleep time spent in each sleep stage, AMBIEN 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.

• Sanofi-Aventis U.S. LLC

On January 10, 2013 the FDA (U.S. Food and Drug Administration) lowered the recommended Ambien dose for women from 10 mg to 5 mg because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. Women appear to be more susceptible to this risk because they eliminate Ambien from their bodies more slowly than men.

After taking Ambien, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You should be aware that impairment from sleep drugs can be present despite feeling fully awake. You have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Ambien.

Reported activities include:

• driving a car ("sleep-driving")
• making and eating food
• talking on the phone
• having sex
• sleep-walking

Call your doctor right away if you find out that you have done any of the above activities after taking Ambien.

• Take Ambien right before you get in bed, not sooner.
• Do not take Ambien if you drink alcohol.
• Do not take Ambien with other medicines that can make you sleepy. 
• Do not take Ambien if you cannot get a full night's sleep or stay in bed 7 or 8 hours before being active again.
• Do not take Ambien if you are allergic to anything in it. Severe allergic reactions have occurred with Ambien use. Seek emergency medical attention if you have unexplained rash, itching, hives, wheezing or trouble breathing, or unexplained swelling (especially of the throat, lips, or mouth).

Ambien can cause dizziness or drowsiness. Do not drive or operate heavy machinery until you know how Ambien affects you.

Before receiving Ambien, tell your doctor about all of your medical conditions, including if you:

• have a history of depression, mental illness, or suicidal thoughts
• have a history of drug or alcohol abuse or addiction
• have kidney or liver disease
• have a lung disease or breathing problems
• are pregnant, planning to become pregnant, or breastfeeding

Tell your doctor about all of the medicines you take including prescription and nonprescription medicines, vitamins and herbal supplements.

Take Ambien exactly as your doctor has prescribed it. Follow the directions on your prescription label carefully. 

The recommended Ambien dose for adult men is 10 mg once daily immediately before bedtime. The total Ambien dose should not exceed 10 mg per day.

For women, the recommended Ambien dose is 5 mg once daily immediately before bedtime. The FDA lowered the recommended dose for women from 10 mg to 5 mg for immediate-release products on January 10, 2013 because new data show that blood levels in some patients may be high enough the morning after use to impair activities that require alertness, including driving. Women appear to be more susceptible to this risk because they eliminate Ambien from their bodies more slowly than men.

Ambien is a federally controlled substance (C-IV) because it can be abused or lead to dependence. Keep Ambien in a safe place to prevent misuse and abuse. Selling or giving away Ambien may harm others, and is against the law. Tell your doctor if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.

Metabolized principally by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6.88

Drugs Affecting Hepatic Microsomal Enzymes

Some drugs that inhibit CYP3A may increase systemic exposure to zolpidem.1 89

Effect of inhibitors of other CYP isoenzymes on pharmacokinetics (e.g., systemic exposure) of zolpidem not known.1 89

Specific Drugs

Storage

Oral

20–25°C.1

15–25°C (may be exposed to temperatures up to 30°C).89

25°C (may be exposed to 15–30°C); avoid prolonged exposure to temperatures >30°C.92 Store upright.92 Do not freeze.92

Sublingual

20–25°C.93 Protect from light and moisture.93

20–25°C (may be exposed to 15–30°C).94 Protect from moisture.94

Store tablet in pouch until just prior to administration.94

• It is used to treat sleep problems.

Ambien (zolpidem tartrate) is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Ambien has been shown to decrease sleep latency for up to 35 days in controlled clinical studies [see Clinical Studies (14)].

The clinical trials performed in support of efficacy were 4–5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment.

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 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.

Transient Insomnia

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).

Chronic Insomnia

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 Ambien.

Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Next-day residual effects: Next-day residual effects of Ambien 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 Ambien 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.

Rebound effects: There was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation of Ambien (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.

Memory impairment: Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration of Ambien. 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 Ambien, predominantly at doses above 10 mg.

Effects on sleep stages: In studies that measured the percentage of sleep time spent in each sleep stage, Ambien 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.

Mechanism of Action

Imidazopyridine; modulates omega-1 type GABA receptor via selective antagonism, resulting in increased chloride conductance, neuronal hyperpolarization, inhibition of action potential, and a decrease in neuronal excitability that in turn produce sedative and hypnotic effects

Absorption

Bioavailability: 70%

Peak plasma time: 1.6 hr (immediate-release); 1.5 hr (extended-release); 0.9 hr (spray); 1.4 hr (sublingual Edluar); 0.6-1.3 hr (sublingual Intermezzo)

Peak plasma time delayed by food intake

Peak plasma concentration: (5 mg dose) 59 ng/mL; (10 mg) 121 ng/mL; (12.5 mg CR) 134 ng/mL

Distribution

Protein bound: 92.5%

Metabolism

Metabolized by CYP3A4 (60%), CYP2C9 (22%), CYP1A2 (14%), CYP2D6 (3%), CYP2C (3%)

Metabolized to inactive metabolites

Elimination

Half-life

• Immediate release: 2.5 hr (normal liver function); 9.9 hr (cirrhosis)
• Spray: 1.7-8.4 hr
• Sublingual: 1.4-6.7 hr

Excretion

• Urine (48-67%)
• Feces (29-42%)

Oral Administration

Extended-release tablet: Swallow whole; do not chew, crush, or split

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Ambien may cause a severe allergic reaction. Stop taking Ambien and get emergency medical help if you have any signs of an allergic reaction to zolpidem: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: depression, anxiety, aggression, agitation, confusion, unusual thoughts, hallucinations, memory problems, changes in personality, risk-taking behavior, decreased inhibitions, no fear of danger, or thoughts of suicide or hurting yourself.

Stop using Ambien and call your doctor at once if you have:

• chest pain, fast or irregular heartbeat, feeling short of breath;

• trouble breathing or swallowing; or

• feeling like you might pass out.

Common Ambien side effects may include:

• daytime drowsiness, dizziness, weakness, feeling "drugged" or light-headed;

• tired feeling, loss of coordination;

• stuffy nose, dry mouth, nose or throat irritation;

• nausea, constipation, diarrhea, upset stomach; or

• headache, muscle pain.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.