Intermezzo (zolpidem tartrate 1.75 mg) Dailymed

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of INTERMEZZO. Some of these events may result in serious injuries, including death. Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior [see Contraindications (4) and Warnings and Precautions (5.1)].

WARNING: COMPLEX SLEEP BEHAVIORS See full prescribing information for complete box warning.
Complex sleep behaviors including sleep-walking, sleep- driving, and engaging in other activities while not fully awake may occur following use of INTERMEZZO. Some of these events may result in serious injuries, including death. Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior (4, 5.1).

• Take only if 4 hours of bedtime remain before the planned time of waking (2.1, 5.1)
• INTERMEZZO should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. (2.1)
• The effect of INTERMEZZO may be slowed if taken with or immediately after a meal (2.1)
• Recommended dose is 1.75 mg for women and 3.5 mg for men, taken only once per night if needed (2.2)
• Lower doses of CNS depressants may be necessary when taken concomitantly with INTERMEZZO (2.3)
• Co-administration with CNS depressants: Recommended dose is 1.75 mg for men and women (2.3)
• Geriatric patients and patients with hepatic impairment: Recommended dose is 1.75 mg for men and women (2.4, 2.5)

2.1 Important AdministrationInstructions

INTERMEZZO is to be taken in bed when a patient wakes in the middle of the night and has difficulty returning to sleep. INTERMEZZO should only be taken if the patient has at least 4 hours of bedtime remaining before the planned time of waking [see Warnings and Precautions (5.1)] .
INTERMEZZO should be placed under the tongue and allowed to disintegrate completely before swallowing. The tablet should not be swallowed whole. For optimal effect, INTERMEZZO should not be administered with or immediately after a meal. The tablet should be removed from the pouch just prior to dosing.

2.2 Basic Dosing Information

The recommended and maximum dose of INTERMEZZO is 1.75 mg for women and 3.5 mg for men, taken only once per night as needed if a middle-of-the-night awakening is followed by difficulty returning to sleep. The recommended doses for women and men are different because women clear zolpidem from the body at a lower rate than men [see Use in Specific Populations (8.6)] .

2.3 Use with CNS Depressants

The recommended INTERMEZZO dose for men and women who are taking concomitant CNS depressants is 1.75 mg. Dose adjustment of concomitant CNS depressants may be necessary when co-administered with INTERMEZZO because of potentially additive effects. The use of INTERMEZZO with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Warnings and Precautions (5.1)] .

2.4 Use in GeriatricPatients

Geriatric patients may be especially sensitive to the effects of zolpidem. The recommended dose of INTERMEZZO in men and women over 65 years old is 1.75 mg, taken only once per night if needed [see Use in Specific Populations (8.5)] .

2.5 Use in Patients withHepatic Impairment

The recommended dose of INTERMEZZO in patients with hepatic impairment is 1.75 mg, taken only once per night if needed [see Clinical Pharmacology (12.3)] .

3dosage Forms And Strengths

INTERMEZZO is available as 1.75 mg and 3.5 mg tablets for sublingual administration.
INTERMEZZO 1.75 mg tablets are yellow, round, uncoated, biconvex, debossed with ZZ on one side.
INTERMEZZO 3.5 mg tablets are beige, round, uncoated, biconvex, debossed with ZZ on one side.

1.75 mg and 3.5 mg sublingual tablets (3)

4contraindications

INTERMEZZO is contraindicated in patients who have experienced complex sleep behaviors after taking INTERMEZZO [see Warnings and Precautions (5.1)].
INTERMEZZO is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions with zolpidem include anaphylaxis and angioedema [see Warnings and Precautions (5.4)] .

Patients who have experienced complex sleep behaviors after taking INTERMEZZO (4, 5.1)
Known hypersensitivity to zolpidem (4)

5warnings And Precautions

• CNS depressant effects: Impairs alertness and motor coordination, including risk of morning impairment. Risk increases with dose and use with other CNS depressants and alcohol. Instruct patients on correct use (5.2)
• Evaluate for co-morbid diagnoses: Re-evaluate if insomnia persists after 7 to 10 days of use (5.2)
• Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not re-challenge if such reactions occur (5.3)
• Abnormal Thinking and Behavioral Changes: Changes including decreased inhibition, bizarre behavior, agitation and depersonalization have been reported. Immediately evaluate any new onset behavioral changes (5.5)
• Depression: Worsening of depression or suicidal thinking may occur. Prescribe the least number of tablets feasible to avoid intentional overdose (5.6)
• Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function (5.7)

5.1 Complex Sleep Behaviors

Complex sleep behaviors including sleep-walking, sleep-driving, and engaging in other activities while not fully awake may occur following use of zolpidem. Serious injuries and death have occurred during a complex sleep behavior episode. Other complex sleep behaviors (e.g., preparing and eating food, making phone calls, or having sex) have also been reported. Patients usually do not remember these events. Post-marketing reports have shown that complex sleep behaviors may occur with zolpidem alone at recommended dosages, with or without the concomitant use of alcohol or other central nervous system (CNS) depressants [see Drug Interactions (7.1)] and may occur on first use of zolpidem. Patients who have experienced complex sleep behaviors after taking INTERMEZZO may experience a complex sleep behavior resulting in serious injuries or death after taking a subsequent dose of INTERMEZZO [see Contraindications (4)].Discontinue INTERMEZZO immediately if a patient experiences a complex sleep behavior.

5.2 CNS Depressant Effects and Next-Day Impairment

INTERMEZZO, like other sedative-hypnotic drugs, has central nervous system (CNS) depressant effects. Co-administration with other CNS depressants (e.g., benzodiazepines, opioids, tricyclic antidepressants, alcohol) increases the risk of CNS depression. Dosage adjustments of INTERMEZZO and of other concomitant CNS depressants may be necessary when INTERMEZZO is administered with such agents because of the potentially additive effects. The use of INTERMEZZO with other sedative-hypnotics (including other zolpidem products) at bedtime or the middle of the night is not recommended [see Dosage and Administration (2.3)] .
In a driving study, healthy subjects who received INTERMEZZO with fewer than four hours of bedtime remaining had evidence of impaired driving compared to subjects who received placebo [see Clinical Studies (14.2)] . The risk of next-day driving impairment (and psychomotor impairment) is increased if INTERMEZZO is taken with less than 4 hours of bedtime remaining, if higher than recommended dose is taken, if co-administered with other CNS depressants, or co-administered with other drugs that increase the blood levels of zolpidem.
Because INTERMEZZO can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at a higher risk of falls.

5.3 Need to Evaluate for Co-morbid Diagnoses

Because sleep disturbances may be the presenting manifestation of a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs, including zolpidem.

5.4 Severe Anaphylactic and Anaphylactoid Reactions

Cases of angioedema involving the tongue, glottis, or larynx have been reported in patients after taking the first or subsequent doses of zolpidem. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema or anaphylaxis after treatment with zolpidem should not be rechallenged with INTERMEZZO.

5.5 Abnormal Thinking and Behavioral Changes

Abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including zolpidem. Some of these changes included decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, agitation, and depersonalization. Visual and auditory hallucinations have also been reported.
In controlled trials of zolpidem tartrate 10 mg taken at bedtime, < 1% of adults with insomnia who received zolpidem reported hallucinations. In a clinical trial, 7% of pediatric patients treated with zolpidem tartrate 0.25 mg/kg taken at bedtime, reported hallucinations, versus 0% treated with placebo [see Use in Specific Populations (8.4)] .
The emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.6 Use in Patients with Depression

In primarily depressed patients treated with sedative-hypnotics, worsening of depression, and suicidal thoughts and actions (including completed suicides), have been reported. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional overdosage is more common in this group of patients; therefore, the lowest number of tablets that is feasible should be prescribed for the patient at any one time.

5.7 Respiratory Depression

Although studies with 10 mg zolpidem tartrate did not reveal respiratory depressant effects at hypnotic doses in healthy subjects or in patients with mild-to-moderate chronic obstructive pulmonary disease (COPD), a reduction in the Total Arousal Index, together with a reduction in lowest oxygen saturation and increase in the times of oxygen desaturation below 80% and 90%, was observed in patients with mild-to-moderate sleep apnea when treated with zolpidem compared to placebo. Since sedative-hypnotics have the capacity to depress respiratory drive, precautions should be taken if INTERMEZZO is prescribed to patients with compromised respiratory function. Post-marketing reports of respiratory insufficiency in patients receiving 10 mg of zolpidem tartrate, most of whom had pre-existing respiratory impairment, have been reported. The risks of respiratory depression should be considered prior to prescribing INTERMEZZO in patients with respiratory impairment including sleep apnea and myasthenia gravis.

5.8 Withdrawal Effects

There have been reports of withdrawal signs and symptoms following the rapid dose decrease or abrupt discontinuation of zolpidem. Monitor patients for tolerance, abuse, and dependence [see Drug Abuse and Dependence (9.2) and (9.3)] .

6adverse Reactions

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

• Complex Sleep Behaviors [See Warnings and Precautions (5.1)]
• CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.2)]
• Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)]
• Abnormal Thinking and Behavioral Changes [see Warnings and Precautions (5.5)]
• Withdrawal effects [see Warnings and Precautions (5.8)]

Most commonly observed adverse reactions (> 1% in adult patients) are headache, nausea, and fatigue. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Purdue Pharma at 1-888-726-7535 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 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 (14.1)] . 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 3-way 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 Preferred Term	3.5 mg INTERMEZZO (n=150)	Placebo (n=145)
Gastrointestinal Disorders	4%	2%
Nausea	1%	1%
General Disorders and Administration Site Conditions	3%	0%
Fatigue	1%	0%
Nervous System Disorders	5%	3%
Headache	3%	1%

• CNS depressants, including alcohol: Possible adverse additive CNS depressant effects (5.1, 7.1)
• Imipramine: Decreased alertness observed (7.1)
• Chlorpromazine: Impaired alertness and psychomotor performance observed (7.1)
• Rifampin: Combination use may decrease effects (7.2)
• Ketoconazole: Combination use may increase effects (7.2)

7.1 CNS-active Drugs

Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.1, 5.2)] . 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 [see Warnings and Precautions (5.1, 5.2)] .
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 [see Clinical Pharmacology (12.3)] .

7.2 Drugs that AffectDrug 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.

8use In Specific Populations

• Pregnancy: Based on animal data, zolpidem may cause fetal harm. (8.1)
• Pediatric use: Safety and effectiveness of INTERMEZZO not established. With bedtime dosing of zolpidem, hallucinations observed (incidence 7%) (8.4)

8.1 Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies of zolpidem in pregnant women. Studies in children to assess the effects of prenatal exposure to zolpidem have not been conducted; however, cases of severe neonatal respiratory depression have been reported when zolpidem was used at the end of pregnancy, especially when taken with other CNS-depressants. Children born to mothers taking sedative-hypnotic drugs may be at risk for withdrawal symptoms during the postnatal period. Neonatal flaccidity has also been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy. INTERMEZZO should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring at doses greater than the recommended human dose (RHD) of 3.5 mg/day (approximately 2.8 mg/day zolpidem base); however, teratogenicity was not observed.
When zolpidem was administered at oral doses of 4, 20, and 100 mg base/kg/day to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification were observed at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg/day, increased embryo-fetal death and incomplete fetal skull ossification were seen at the highest dose tested. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 30 times the RHD on a mg/m² basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg/day during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 15 times the RHD on a mg/m² basis.

8.3 Nursing Mothers

Zolpidem is excreted in human milk. The effect of zolpidem on the nursing infant is not known.

8.4 Pediatric Use

INTERMEZZO is not recommended for use in children. Safety and effectiveness of INTERMEZZO have not been established in pediatric patients below the age of 18.
In an 8-week study in pediatric patients (aged 6 to 17 years) with insomnia associated with ADHD, an oral solution of zolpidem tartrate dosed at 0.25 mg/kg at bedtime did not decrease sleep latency compared to placebo. Hallucinations were reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations.

8.5 Geriatric Use

INTERMEZZO dosage adjustment is necessary in geriatric patients. Sedating drugs may cause confusion and over-sedation in the elderly; elderly patients generally should be started on low doses of INTERMEZZO and observed closely [see Dosage and Administration (2.4), and Clinical Pharmacology (12.3)] .
Clinical trial experience with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime:
A total of 154 patients in U.S.-controlled clinical trials and 897 patients in non-U.S. clinical trials who received oral zolpidem were ≥ 60 years of age. For a pool of U.S. patients receiving oral zolpidem tartrate at doses of ≤ 10 mg or placebo, there were three adverse reactions occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (see Table 2).

Table 2: Adverse Reactions in Geriatric Patients in Pooled Trials of 5 mg to 10 mg of Oral Zolpidem Tartrate Given at Bedtime

Adverse Reaction	5 to 10 mg OralZolpidem tartrate	Placebo
Dizziness	3%	0%
Drowsiness	5%	2%
Diarrhea	3%	1%

Falls in geriatric patients: A total of 30/1,959 (2%) non-U.S. patients receiving other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) reported falls, including 28/30 (93%) who were ≥ 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem tartrate doses > 10 mg. A total of 24/1,959 (1%) non-U.S. patients receiving zolpidem reported confusion, including 18/24 (75%) who were ≥70 years of age. Of these 18 patients, 14 (78%) were receiving zolpidem tartrate doses >10 mg.
The dose of INTERMEZZO in elderly patients is 1.75 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative-hypnotic drugs.

8.6 Gender Differencesin Pharmacokinetics

Women cleared zolpidem tartrate from the body after sublingual administration of a 3.5 mg dose of INTERMEZZO at a lower rate than men (2.7 mL/min/kg vs. 4.0 mL/min/kg). C_max and AUC parameters of zolpidem were approximately 45% higher at the same dose in female subjects compared with male subjects. Given the higher blood levels of zolpidem tartrate in women compared to men at a given dose, the recommended dose of INTERMEZZO for women is 1.75 mg, and the recommended dose for adult men is 3.5 mg.

9drug Abuse And Dependence

9.1 Controlled Substance

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

9.2 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.

9.3 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 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.

10overdosage

10.1 Signs and Symptoms

In post-marketing experience of overdose with oral zolpidem tartrate alone, or in combination with CNS-depressant agents, impairment of consciousness ranging from somnolence to coma, cardiovascular and/or respiratory compromise, and fatal outcomes have been reported.

10.2 Recommended Treatment

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. Zolpidem’s sedative-hypnotic effect was shown to be reduced by flumazenil and therefore flumazenil may be useful; however, flumazenil administration may contribute to the appearance of neurological symptoms (convulsions). As in all cases of drug overdose, respiration, pulse, blood pressure, and other appropriate signs should be monitored and general supportive measures employed. Hypotension and CNS depression should be treated by appropriate medical intervention. Sedating drugs should be withheld following zolpidem overdosage, even if excitation occurs. The value of dialysis in the treatment of overdosage has not been determined, although hemodialysis studies in patients with renal failure receiving therapeutic doses have demonstrated that zolpidem is not dialyzable.
As with management of all overdosage, the possibility of multiple drug ingestion should be considered. The healthcare provider may wish to consider contacting a poison control center for up-to-date information on the management of hypnotic drug overdosage.

11description

INTERMEZZO contains zolpidem tartrate, a non-benzodiazepine hypnotic of the imidazopyridine class. INTERMEZZO is available in 1.75 mg and 3.5 mg strength tablets for sublingual administration. INTERMEZZO sublingual tablets are intended to be placed under the tongue where they will disintegrate.
INTERMEZZO sublingual tablets contain a bicarbonate-carbonate buffer.
Chemically, zolpidem tartrate is N,N-6-trimethyl-2-p-tolylimidazo[1,2-α]pyridine-3-acetamide L-(+)-tartrate (2:1).
Zolpidem tartrate is a white to off-white crystalline powder that is sparingly soluble in water, alcohol, and propylene glycol. It has a molecular weight of 764.88.
Each INTERMEZZO tablet includes the following inactive ingredients: mannitol, sorbitol, crospovidone, silicon dioxide, sodium carbonate, sodium bicarbonate, croscarmellose sodium, sodium stearyl fumarate, silicon dioxide, natural and artificial spearmint flavor, silicon dioxide-colloidal, and sucralose. The 1.75 mg tablet also contains yellow iron oxide, and the 3.5 mg tablet contains beige iron oxide.

12clinical Pharmacology

12.1 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 complex and shares some of the pharmacological properties of the benzodiazepines. In contrast to the benzodiazepines, which nonselectively bind to and activate all BZ receptor subtypes, zolpidem in vitro binds the BZ₁ receptor preferentially with a high affinity ratio of the alpha₁/alpha₅ 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 at hypnotic doses.

12.3 Pharmacokinetics

INTERMEZZO disintegrates in the sublingual cavity after administration. On average, INTERMEZZO is rapidly absorbed in both genders, with a mean T_max across studies of about 35 minutes to about 75 minutes.
In healthy normal volunteers (age 21 to 45 years) dosed with 3.5 mg INTERMEZZO, the average C_max and AUC were 77 ng/mL and 296 ng•h/mL, respectively in women. The average C_max and AUC were 53 ng/mL and 198 ng•h/mL, respectively in men. In women, the average C_max and AUC of the 1.75 mg INTERMEZZO dose were 37 ng/mL and 151 ng•h/mL, respectively.
Food decreased the overall C_max and AUC of INTERMEZZO 3.5 mg by 42% and 19%, respectively, and increased the time to peak exposure (T_max) to nearly 3 hours. For optimal effect, INTERMEZZO should not be administered with or immediately after a meal.
Distribution Based on data obtained with oral zolpidem, the total protein binding was found to be 93% ± 0.1% and remained constant independent of concentration between 40 ng/mL and 790 ng/mL.
Metabolism Based on data obtained with oral zolpidem, zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion.
Elimination The elimination half-life of a single dose of a 3.5 mg INTERMEZZO sublingual tablet is approximately 2.5 hours (range 1.4 to 3.6 hours).
Special Populations
Elderly : The recommended dose for INTERMEZZO is 1.75 mg. A pharmacokinetic study of 1.75 mg and 3.5 mg doses of INTERMEZZO showed that the plasma C_max and AUC_{0-4 hr} in elderly subjects following the 3.5 mg dose was higher by 34% and 30%, respectively, than the non-elderly subjects. The C_max and AUC of 1.75 mg in elderly subjects were consistently lower than those observed for the 3.5 mg dose in non-elderly subjects but consistently higher than the 1.75 mg dose in non-elderly subjects. The elimination half-life remained unchanged.
Hepatic Impairment : The pharmacokinetics of oral zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in subjects with normal hepatic function. Following a single 20 mg oral zolpidem tartrate dose, mean C_max and AUC were found to be two times (250 ng/mL vs. 499 ng/mL) and five times (788 ng•hr/mL vs. 4203 ng•hr/mL) higher, respectively, in hepatically compromised patients compared to subjects with normal hepatic function. T_max 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 subjects with normal hepatic function of 2.2 hr (range: 1.6 to 2.4 hr). Dosing should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.5)] .
Renal Impairment : The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage renal failure (mean Cl_Cr= 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 C_max, T_max, 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 renal impairment.
Drug Interactions
CNS-depressants Co-administration of zolpidem with other CNS depressants increases the risk of CNS depression [see Warnings and Precautions (5.1)] . 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 (5.1)] .
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 C_max was significantly higher (43%) and T_max 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.
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 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 AUC_0-∞ 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%), C_max (-58%), and T_1/2 (-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.
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 C_max 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. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.
Other Drugs with No Interactions with Zolpidem 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.