Intermezzo

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.

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.

Pharmacokinetics

Intermezzo disintegrates in the sublingual cavity after administration. On average, Intermezzo is rapidly absorbed in both genders, with a mean Tmax 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 Cmax and AUC were 77 ng/mL and 296 ng·h/mL, respectively in women. The average Cmax and AUC were 53 ng/mL and 198 ng·h/mL, respectively in men. In women, the average Cmax and AUC of the 1.75 mg Intermezzo dose were 37 ng/mL and 151 ng·h/mL, respectively.

Food decreased the overall Cmax and AUC of Intermezzo 3.5 mg by 42% and 19%, respectively, and increased the time to peak exposure (Tmax) to nearly 3 hours. For optimal effect, Intermezzo should not be administered with or immediately after a meal.

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.

Based on data obtained with oral zolpidem, zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion.

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 Cmax and AUC0-4 hr in elderly subjects following the 3.5 mg dose was higher by 34% and 30%, respectively, than the non-elderly subjects. The Cmax 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 Cmax 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. 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 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].

Renal Impairment: 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 renallyimpaired patients. No dosage adjustment is necessary in patients with renal impairment.

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 T½ (-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 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. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

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

Middle-Of-The-Night Awakening Trials

Intermezzo was evaluated in two randomized, double-blind, placebo-controlled studies (Studies 1 and 2) in patients with insomnia characterized by difficulty returning to sleep after a middle-ofthe-night (MOTN) awakening. In these studies, patients met the diagnosis for primary insomnia as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and had at least three prolonged MOTN awakenings per week that were at least 30 minutes in duration.

Adult patients aged 19 to 64 years (N=82; 58 female, 24 male) with a history of difficulty returning to sleep after middle-of-the-night awakenings were evaluated in a double-blind, placebo-controlled, 3-period cross-over sleep laboratory study (Study 1). The primary outcome measure was latency to persistent sleep (LPS).

Doses of 3.5 mg and 1.75 mg of Intermezzo significantly decreased both objective (by polysomnography) and subjective (patient-estimated) sleep latency after a scheduled middle-ofthe-night awakening as compared to placebo. The effect on sleep latency was similar for females receiving 1.75 mg of Intermezzo and males receiving 3.5 mg of Intermezzo.

Adult patients aged 18 to 64 years (N=295; 201 women, 94 men) with difficulty returning to sleep after middle-of-the-night awakenings were evaluated in a double-blind, placebo-controlled 4-week outpatient study of Intermezzo. Patients took study drug (3.5 mg of Intermezzo or placebo) on an as-needed (prn) basis, when they had difficulty returning to sleep after waking in the middle of the night, provided they had at least 4 hours time remaining in bed. Subjective (patient-estimated) time to fall back to sleep after middle-of-the-night awakening was significantly shorter for Intermezzo 3.5 mg compared to placebo.

Special Safety Studies

A randomized, double-blind, placebo-controlled, active-control, single-center, four-period, crossover study in 40 healthy subjects was conducted to evaluate the effects of middle-of-thenight administration of Intermezzo on next-morning driving performance. The four randomized treatments included Intermezzo 3.5 mg four hours before driving, Intermezzo 3.5 mg three hours before driving, placebo, and a positive control (an unapproved sedative-hypnotic) given nine hours before driving.

The primary outcome measure was the change in the standard deviation of lateral position (SDLP), a measure of driving impairment. The results were analyzed using a symmetry analysis, which determined the proportion of subjects whose change from their own SDLP in the placebo condition was statistically significantly above a threshold thought to reflect clinically meaningful driving impairment.

When driving began 3 hours after taking Intermezzo, testing had to be terminated for one subject (a 23-year old woman) due to somnolence. Overall, the symmetry analysis showed a statistically significant impairing effect at 3 hours. When driving began 4 hours after taking Intermezzo, statistically significant impairment was not found, but numerically Intermezzo was worse than placebo. Zolpidem blood levels were not measured in the driving study, and the study was not designed to correlate specific blood level with degree of impairment. However, the estimated blood level of zolpidem in patients whose SDLP worsened according to the symmetry analysis is considered to present a risk for driving impairment. In some women, the 3.5 mg dose of Intermezzo results in zolpidem blood levels that remain at or sometimes considerably above this level 4 or more hours after dosing. Therefore, the recommended dose for women is 1.75 mg. A small negative effect on SDLP may remain in some patients 4 hours after the 1.75 mg dose in women, and after the 3.5 mg dose in men, such that a potential negative effect on driving cannot be completely excluded.

In studies performed with other zolpidem formulations (5 mg to 10 mg oral zolpidem tartrate) given at bedtime, there was no objective (polysomnographic) evidence of rebound insomnia at recommended doses seen in studies evaluating sleep on the nights following discontinuation. 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 oral zolpidem tartrate.

Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration at bedtime of 5 mg to 10 mg oral zolpidem tartrate. However, in one study involving zolpidem tartrate doses of 10 mg 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 oral zolpidem tartrate, predominantly at doses above 10 mg.

Intermezzo is a prescription medication used in adults for the treatment of insomnia. Intermezzo helps those patients that have difficulty returning to sleep after awakening in the middle of the night. Intermezzo belongs to a group of drugs called hypnotics. It works by slowing down brain activity so you can fall asleep.

Intermezzo comes as a sublingual tablet and is taken by mouth at night, if needed, without food. While in bed, place the tablet under your tongue and allow it to break apart completely. Do not swallow it whole.

Intermezzo is taken only if you have at least 4 hours of bedtime left.

Common side effects of Intermezzo include headache, nausea, and fatigue.

Intermezzo can cause daytime drowsiness and dizziness, and diarrhea. Do not drive or operate heavy machinery until you know how Intermezzo affects you.

• Purdue Pharma LP

Warning: Impairment from sleep drugs can be present despite feeling fully awake.

You may still feel drowsy the next day after taking Intermezzo. Do not drive or operate heavy machinery or take part in anything that requires alertness after taking Intermezzo until you are certain you are alert.

Serious side effects of Intermezzo may include:

• getting out of bed while not being fully awake and taking part in an activity that you do not know you are doing
• abnormal thoughts and behavior including:
  • more outgoing or aggressive behavior than normal
  • confusion 
  • agitation
  • hallucinations (seeing or hearing things that aren't there)
  • worsening of depression
  • suicidal thoughts or actions
• memory loss
• anxiety
• severe allergic reactions including:
• swelling of the tongue or throat
• trouble breathing
• nausea and vomiting

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using Intermezzo.

The most common side effects of Intermezzo are:

• Headache
• Nausea
• Fatigue

Some people experience symptoms such as trouble sleeping, nausea, flushing, lightheadedness, uncontrolled crying, vomiting, stomach cramps, panic attack, nervousness, and stomach area pain after stopping sleep medicine. This may last a couple days. 

This is not a complete list of Intermezzo side effects. Ask your doctor or pharmacist for more information.

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

Intermezzo Sublingual Tablet

The recommended dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime.

For geriatric patients and patients with liver impairment, the recommended dose is 5 mg for men and women.

In the U.S.

• Edluar
• Intermezzo
• Zolpimist

Available Dosage Forms:

• Tablet
• Spray

Therapeutic Class: Nonbarbiturate Hypnotic

Use this medicine as ordered by your doctor. Read all information given to you. Follow all instructions closely.

• Use Intermezzo (zolpidem sublingual tablets (intermezzo)) only for short periods of time (7 to 10 days).
• If you still have trouble sleeping after 7 to 10 days, call your doctor.
• Take this medicine at bedtime.
• Take Intermezzo only 1 time per night.
• Take on an empty stomach.
• Be sure your hands are dry before you touch this medicine.
• Place under tongue and let melt all the way. Do not chew, suck or swallow tablet.
• Do not eat, drink, or smoke while the tablet is melting.
• Take only as needed if you wake up in the middle of the night and have trouble going back to sleep. Only take a dose if you have 4 or more hours of bedtime left. Do not take more than 1 dose per night.
• Only keep 1 pouch with Intermezzo in it at your bedside. Store all other pouches away from your bedside. Do not remove the drug from the pouch until you are ready to take a dose. After you take this medicine, leave the empty pouch where you can see it. This will help remind you that you have taken your dose.

What do I do if I miss a dose?

• If you take Intermezzo on a regular basis, take a missed dose as soon as you think about it.
• If you will not be able to get 4 or more hours of sleep after taking the missed dose, skip the missed dose and go back to your normal time.
• Do not take 2 doses at the same time or extra doses.
• Do not take more than 1 dose of this medicine in the same day.
• Many times Intermezzo is taken on an as needed basis. Do not take more often than told by the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Dizziness.
• Feeling sleepy the next day.
• Headache.
• Upset stomach.
• Loose stools (diarrhea).
• Feeling tired or weak.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to the FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• This medicine comes with an extra patient fact sheet called a Medication Guide. Read it with care. Read it again each time this medicine is refilled. If you have any questions about Intermezzo, please talk with the doctor, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Intermezzo. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Intermezzo (zolpidem sublingual tablets (intermezzo)).

Review Date: October 4, 2017

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.

Intermezzo is contraindicated in patients with known hypersensitivity to zolpidem. Observed reactions with zolpidem include anaphylaxis and angioedema [see Warnings and Precautions (5.3)].

  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.

  Pharmacokinetics

Intermezzo disintegrates in the sublingual cavity after administration. On average, Intermezzo is rapidly absorbed in both genders, with a mean Tmax 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 Cmax and AUC were 77 ng/mL and 296 ng•h/mL, respectively in women. The average Cmax and AUC were 53 ng/mL and 198 ng•h/mL, respectively in men. In women, the average Cmax and AUC of the 1.75 mg Intermezzo dose were 37 ng/mL and 151 ng•h/mL, respectively.

Food decreased the overall Cmax and AUC of Intermezzo 3.5 mg by 42% and 19%, respectively, and increased the time to peak exposure (Tmax) to nearly 3 hours. For optimal effect, Intermezzo should not be administered with or immediately after a meal.

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.

Based on data obtained with oral zolpidem, zolpidem tartrate is converted to inactive metabolites that are eliminated primarily by renal excretion.

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 Cmax and AUC0-4 hr in elderly subjects following the 3.5 mg dose was higher by 34% and 30%, respectively, than the non-elderly subjects. The Cmax 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 Cmax 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. 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 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 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 renal impairment.

Drug Interactions

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 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.

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. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

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.

Take Intermezzo exactly as prescribed by your doctor. Follow all directions on your prescription label. Read all patient information, medication guides, and instruction sheets provided to you. Ask your doctor or pharmacist if you have any questions. Never take this medicine in larger amounts, or for longer than prescribed.

Do not share this medication with another person, even if they have the same symptoms you have. The recommended doses of Intermezzo are not the same in men and women, and this drug is not approved for use in children. Misuse of this medication can result in dangerous side effects.

Do not take Intermezzo for middle-of-the-night insomnia unless you have 4 hours of sleep time left before being active.

Intermezzo is for short-term use only. Tell your doctor if your insomnia symptoms do not improve, or if they get worse after using this medication for 7 to 10 nights in a row. Do not take Intermezzo for longer than 4 or 5 weeks without your doctor's advice.

Do not stop using Intermezzo suddenly after long-term use, or you could have unpleasant withdrawal symptoms. Ask your doctor how to avoid withdrawal symptoms when you stop using the medicine.

Insomnia symptoms may also return after you stop taking this medicine. These symptoms may seem to be even worse than before you started taking the medication. Call your doctor if you still have worsened insomnia after the first few nights without taking zolpidem.

Do not swallow an Intermezzo tablet whole. Place the tablet under your tongue and allow it to dissolve in your mouth without water.

Store at room temperature away from moisture and heat.

Taking Intermezzo with other drugs that make you sleepy or slow your breathing can cause dangerous or life-threatening side effects. Ask your doctor before taking a sleeping pill, narcotic pain medicine, prescription cough medicine, a muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Intermezzo, especially:

• chlorpromazine;

• itraconazole or ketoconazole;

• rifampin; or

• an antidepressant - imipramine, sertraline.

Many drugs can interact with zolpidem, making it less effective or increasing side effects. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide. Tell your doctor about all medicines you use, and those you start or stop using during your treatment with Intermezzo. Give a list of all your medicines to any healthcare provider who treats you.