Zolpidem Tartrate Oral Spray

Signs and symptoms

In postmarketing experience of overdose with 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.

Recommended treatment

General symptomatic and supportive measures should be used along with immediate gastric lavage where appropriate. Intravenous fluids should be administered as needed. sedative-hypnotic effect was shown to be reduced by flumazenil and therefore 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 monitored and 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 the management of all overdosage, the possibility of multiple drug ingestion should be considered. The physician may wish to consider contacting a poison control center for up-to­date information on the management of hypnotic drug product overdosage.

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 α1/α5 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

Zolpimist (zolpidem tartrate) Oral Spray is bioequivalent to Ambien® tablets (Sanofi-Aventis). The pharmacokinetic profile of Zolpimist (zolpidem tartrate oral spray) is characterized by rapid absorption from the oral mucosa and gastrointestinal tract, and a short t½ in healthy subjects.

In a single-dose crossover study in 10 healthy young (18-40 years of age) male subjects administered 2.5, 5, and 10 mg Zolpimist (zolpidem tartrate oral spray) , the results demonstrated a linear relationship to dose for mean Cmax and AUC0-∞ over the range of doses administered in the study.

In a single-dose crossover study in 43 healthy young (18-45 years of age) subjects administered 5 and 10 mg Zolpimist (zolpidem tartrate oral spray) , the means for Cmax were 114 (range: 19 to 197) and 210 ng/mL (range: 77 to 401), respectively, occurring at a mean Tmax of approximately 0.9 hours for both. The mean zolpidem t½ was 2.7 (range: 1.7 to 5.0) and 3.0 hours (range: 1.7 to 8.4), for 5 and 10 mg Zolpimist (zolpidem tartrate oral spray) , respectively. In the same study, the means for Cmax were 123 (range: 53 to 221) and 219 ng/mL (range: 101 to 446) for 5 and 10 mg Ambien® tablets, respectively, occurring at a mean Tmax of 0.9 and 1.0 hours, respectively. The mean zolpidem t½ was 2.8 (range: 1.5 to 6.0) and 3.1 hours (range: 1.1 to 8.6) for the 5 and 10 mg Ambien® tablets, respectively.

Zolpidem is converted to inactive metabolites that are eliminated primarily by renal excretion. Total protein binding for zolpidem 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 for 2 weeks.

A food-effect crossover study in 14 healthy young (18-45 years of age) male subjects compared the pharmacokinetics of Zolpimist (zolpidem tartrate oral spray) 10 mg when administered while fasting at least 8 hours or 5 minutes after eating a standard high-fat meal. Results demonstrated that with food, mean AUC0-∞ and Cmax were decreased by 27% and 58%, respectively, while mean Tmax was prolonged by 225% (from 0.8 to 2.6 hours). These results suggest that, for faster sleep onset, as with all zolpidem products, Zolpimist (zolpidem tartrate oral spray) should not be administered with or immediately after a meal.

Elderly: In the elderly, the dose for zolpidem tartrate should be 5 mg [see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION]. This recommendation is based on several studies in which the mean Cmax, t½, and AUC were significantly increased when compared to results in young adults administered zolpidem tartrate. In a pharmacokinetic study of 24 elderly ( ≥ 65 years of age) subjects administered 5 mg Zolpimist (zolpidem tartrate oral spray) , the means for Cmax and AUC were 134 ng/mL and 493 ng*hr/mL respectively, following administration of a single 5 mg oral dose of Zolpimist. Zolpidem tartrate did not accumulate in elderly subjects following nightly oral dosing of 10 mg for 1 week.

Hepatic Impairment: The pharmacokinetics of zolpidem 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 t½ in cirrhotic patients of 9.9 hours (range: 4.1 to 25.8 hours) was greater than that observed in normal subjects of 2.2 hours (range: 1.6 to 2.4 hours). Dosing should be modified accordingly in patients with hepatic insufficiency [see DOSAGE AND ADMINISTRATION and WARNINGS AND PRECAUTIONS].

Renal Impairment: The pharmacokinetics of zolpidem were studied in 11 patients with endstage 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, t½, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. On Day 1, Cmax was 172 ± 29 ng/mL (range: 46 to 344 ng/mL). After repeated dosing for 14 or 21 days, Cmax was 203 ± 32 ng/mL (range: 28 to 316 ng/mL). On Day 1, Tmax was 1.7 ± 0.3 hours (range: 0.5 to 3.0 hours); after repeated dosing Tmax was 0.8 ± 0.2 hour (range: 0.5 to 2.0 hours). This variation is accounted for by noting that last-day serum sampling began 10 hours after the previous dose, rather than after 24 hours. This resulted in residual drug concentration and a shorter period to reach maximal serum concentration. On Day 1, t½ was 2.4 ± 0.4 hours (range: 0.4 to 5.1 hours). After repeated dosing, t½ was 2.5 ± 0.4 hours (range: 0.7 to 4.2 hours). AUC was 796 ± 159 ng*hr/mL after the first dose and 818 ± 170 ng*hr/mL after repeated dosing. 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. However, as a general precaution, these patients should be closely monitored.

Clinical Studies

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).

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 zolpidem.

Next-day residual effects: Next-day residual effects of zolpidem tartrate 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 zolpidem tartrate 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 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 zolpidem tartrate. 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 zolpidem tartrate, predominantly at doses above 10 mg.

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

MEDICATION GUIDE

Zolpimist Oral Spray
(zolpidem tartrate) Spray, Metered for Oral Use

Read the Medication Guide that comes with Zolpimist (zolpidem tartrate oral spray) before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or treatment.

What is the most important information I should know about Zolpimist (zolpidem tartrate oral spray) ?

After taking Zolpimist (zolpidem tartrate oral spray) , 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 have a higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with Zolpimist (zolpidem tartrate oral spray) . 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 Zolpimist (zolpidem tartrate oral spray) .

Important:

1. Take Zolpimist (zolpidem tartrate oral spray) exactly as prescribed
   • Do not take more Zolpimist (zolpidem tartrate oral spray) than prescribed.
   • Take Zolpimist (zolpidem tartrate oral spray) right before you get in bed, not sooner.
2. Do not take Zolpimist (zolpidem tartrate oral spray) if you:
   • drink alcohol
   • take other medicines that can make you sleepy. Talk to your doctor about all of your medicines. Your doctor will tell you if you can take Zolpimist (zolpidem tartrate oral spray) with your other medicines.
   • cannot get a full night sleep

What is Zolpimist (zolpidem tartrate oral spray) ?

Zolpimist (zolpidem tartrate oral spray) is a sedative-hypnotic (sleep) medicine. Zolpimist (zolpidem tartrate oral spray) is used in adults for the short-term treatment of a sleep problem called insomnia. Symptoms of insomnia include:

• trouble falling asleep

Zolpimist (zolpidem tartrate oral spray) is not for children.

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

Who should not take Zolpimist (zolpidem tartrate oral spray) ?

Do not take Zolpimist (zolpidem tartrate oral spray) if you have had an allergic reaction to zolpidem (Ambien, Ambien CR, Zolpimist (zolpidem tartrate oral spray) ). Some signs of allergic reaction may be swelling of the face, a feeling of the throat closing, or difficulty breathing shortly after taking Zolpidem.

See the end of this Medication Guide for a complete list of ingredients in Zolpimist (zolpidem tartrate oral spray) .

Zolpimist (zolpidem tartrate oral spray) may not be right for you. Before starting Zolpimist (zolpidem tartrate oral spray) , tell your doctor about all of your health 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 the medicines you take including prescription and nonprescription medicines, vitamins, and herbal supplements. Medicines can interact with each other, sometimes causing serious side effects. Do not take Zolpimist (zolpidem tartrate oral spray) with other medicines that can make you sleepy.

Know the medicines you take. Keep a list of your medicines with you to show your doctor and pharmacist each time you get a new medicine.

How should I take Zolpimist (zolpidem tartrate oral spray) ?

• Take Zolpimist (zolpidem tartrate oral spray) exactly as prescribed. Do not take more Zolpimist (zolpidem tartrate oral spray) than prescribed for you.
• Take Zolpimist (zolpidem tartrate oral spray) right before you get into bed.
• Do not take Zolpimist (zolpidem tartrate oral spray) unless you are able to stay in bed a full night (7-8 hours) before you must be active again.
• For faster sleep onset, Zolpimist (zolpidem tartrate oral spray) should NOT be taken with or immediately after a meal.
• Call your doctor if your insomnia worsens or is not better within 7 to 10 days. This may mean that there is another condition causing your sleep problem.
• If you take too much Zolpimist (zolpidem tartrate oral spray) or overdose, call your doctor or poison control center right away, or get emergency treatment.

What are the possible side effects of Zolpimist (zolpidem tartrate oral spray) ?

Serious side effects of Zolpimist (zolpidem tartrate oral spray) include:

• getting out of bed while not being fully awake and doing an activity that you do not know you are doing. (See “What is the most important information I should know about Zolpimist (zolpidem tartrate oral spray) ?”)
• abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts or actions.
• memory loss
• anxiety
• severe allergic reactions. Symptoms include swelling of the tongue or throat, trouble breathing, and nausea and vomiting. Get emergency medical help if you get these symptoms after takingZolpimist (zolpidem tartrate oral spray) .

Call your doctor right away if you have any of the above side effects or any other side effects that worry you while using Zolpimist (zolpidem tartrate oral spray) .

The most common side effects of Zolpimist (zolpidem tartrate oral spray) are:

• drowsiness
• dizziness
• diarrhea
• “drugged feelings”
• You may still feel drowsy the next day after taking Zolpimist (zolpidem tartrate oral spray) . Do not drive or do other dangerous activities after taking Zolpimist (zolpidem tartrate oral spray) until you feel fully awake.

After you stop taking a sleep medicine, you may have symptoms for 1 or 2 days such as: tiredness, trouble sleeping, nausea, flushing, lightheadedness, uncontrolled crying, vomiting, stomach cramps, panic attack, nervousness, and stomach area pain.

These are not all the side effects of Zolpimist (zolpidem tartrate oral spray) . Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Zolpimist (zolpidem tartrate oral spray) ?

• Store Zolpimist (zolpidem tartrate oral spray) in an upright position at 59 °F to 86 °F (15 °C to 30 °C).
• Do not freeze.
• Avoid prolonged product exposure above 86 °F (30 °C).
• The child-resistant container should be thrown away when the 60 sprays have been used.

Keep Zolpimist (zolpidem tartrate oral spray) and all medicines out of reach of children.

General Information about Zolpimist (zolpidem tartrate oral spray)

• Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
• Do not use Zolpimist (zolpidem tartrate oral spray) for a condition for which it was not prescribed.
• Do not share Zolpimist (zolpidem tartrate oral spray) with other people, even if you think they may have the same symptoms that you have. It may harm them and it is against the law.

This Medication Guide summarizes the most important information about Zolpimist (zolpidem tartrate oral spray) . If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zolpimist (zolpidem tartrate oral spray) that is written for healthcare professionals. For more information about Zolpimist (zolpidem tartrate oral spray) , call 1-800-XXX-XXXX.

What are the ingredients in Zolpimist?

Active Ingredient: Zolpidem tartrate

Inactive Ingredients: artificial cherry flavor, benzoic acid, citric acid monohydrate, hydrochloric acid, neotame, propylene glycol, and purified water.

This Medication Guide has been approved by U.S. Food and Drug Administration.

Patient Instructions for Use

Zolpimist
(zolpidem tartrate) Spray, Metered for Oral Use

Be sure to carefully read, understand, and follow these instructions so that you use Zolpimist (zolpidem tartrate oral spray) the right way. Ask your doctor or pharmacist if you have any questions about how to use Zolpimist (zolpidem tartrate oral spray) .

1. Line up the arrows on the child-resistant cap and base (see Figure 1).
2. Squeeze the cap at arrows (see Figure 2).
3. Pull the cap and base to separate (see Figure 3).
4. Remove the clear protective cap from the pump (see Figure 4).
5. Hold the container upright. Point the black spray opening in a safe direction away from your face and other people. Fully press down on the pump with your forefinger. Release the pump and let the pump return to the starting position.
6. Follow step 5 and press down on the pump 4 more times. You should see a fine spray. Zolpimist (zolpidem tartrate oral spray) is now ready to use. Now go directly to Step 11.
   Taking a dose of Zolpimist (zolpidem tartrate oral spray) :
   • If you are using Zolpimist (zolpidem tartrate oral spray) for the first time or you have not used Zolpimist (zolpidem tartrate oral spray) for 14 days, you will need to prime the pump (Steps 1-6). Otherwise, there is no need to prime the pump.
   • Take Zolpimist (zolpidem tartrate oral spray) exactly as prescribed. Do not take more Zolpimist (zolpidem tartrate oral spray) than prescribed for you. Your doctor will tell you whether to take 1 or 2 sprays of Zolpimist (zolpidem tartrate oral spray) .
   • Take Zolpimist (zolpidem tartrate oral spray) right before you get into bed.
   • Do not take Zolpimist (zolpidem tartrate oral spray) unless you are able to stay in bed a full night (7-8 hours) before you must be active again.
7. Line up the arrows on the child-resistant cap and base (see Figure 1).
8. Squeeze the cap at arrows (see Figure 2).
9. Pull the cap and base to separate (see Figure 3).
10. Remove the clear protective cap from the pump (see Figure 4).
11. Hold the container upright with the black spray opening pointed directly into your mouth. Fully press down on the pump to make sure that a full dose of Zolpimist (zolpidem tartrate oral spray) is sprayed directly into your open mouth over your tongue (see Figure 5).
12. Let the pump return to the starting position. If your doctor prescribed only one spray of Zolpimist (zolpidem tartrate oral spray) (5 mg dose), go directly to Step 14.
13. If your doctor prescribes a second spray of Zolpimist (zolpidem tartrate oral spray) (10 mg dose), repeat Step 11.
14. Put the clear protective cap back over the pump at the top of the child-resistant base after each use (see Figure 6).
15. Snap the child-resistant cap back onto the base and rotate the child-resistant cap and the child-resistant base so that the arrows are not lined up (see Figure 7).
16. The child-resistant container should be thrown away when the 60 sprays have been used.

There are no special requirements for cleaning and maintaining Zolpimist (zolpidem tartrate oral spray) . Professional assistance regarding questions about product performance or use can be obtained by calling 1800-XXX-XXXX.

See Medication Guide section “How should I store Zolpimist (zolpidem tartrate oral spray) ?” for instructions about how to store Zolpimist (zolpidem tartrate oral spray) .

Zolpidem is a sedative, also called a hypnotic. It affects chemicals in your brain that may become unbalanced and cause sleep problems (insomnia).

Zolpidem is used to treat insomnia. The immediate-release forms of zolpidem are Ambien, Intermezzo,Edluar, and Zolpimist, which are used to help you fall asleep. The extended-release form of zolpidem is Ambien CR, which has a first layer that dissolves quickly to help you fall asleep, and a second layer that dissolves slowly to help you stay asleep.

Ambien, Edluar, and Zolpimist are used to help you fall asleep when you first go to bed. Intermezzo, is used to help you fall back to sleep if you wake up in the middle of the night and then have trouble sleeping.

Your doctor will determine which form of zolpidem is best for you.

Zolpidem may also be used for purposes not listed in this medication guide.

In January 2013, the Food and Drug Administration (FDA) lowered the recommended dose for zolpidem. If you have taken zolpidem in the past, your doctor may direct you to take a lower dose of this medicine than you did before.

Do not share this medication with another person, even if they have the same symptoms you have. The recommended doses of zolpidem 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.

Zolpidem may impair your thinking or reactions. You may still feel sleepy the morning after taking zolpidem, especially if you take the extended-release tablet, or if you are a woman. Wait at least 4 hours or until you are fully awake before you do anything that requires you to be awake and alert.

Some people using this medicine have engaged in activity such as driving, eating, or making phone calls and later having no memory of the activity. If this happens to you, stop taking zolpidem and talk with your doctor about another treatment for your sleep disorder.

Do not take this medicine if you have consumed alcohol during the day or just before bed.

Zolpidem may be habit forming. Keep the medication in a place where others cannot get to it.

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

• Insomnia (Symptoms, Causes, Remedies, and Cures)
• Insomnia Treatment (Sleep Aids and Stimulants)
• Sleep Disorders (How to Get a Good Night's Sleep)