EDLUAR- zolpidem tartrate tablet
For Healthcare Providers >

1. Edluar May Cause Serious Side Effects, Including:
2. Do Not Take Edluar If You:
3. What Is Edluar?
4. Edluar May Not Be Right For You. Before Starting Edluar, Tell Your Healthcare Provider About All Of Your Health Conditions, Including If You:
5. How Should I Take Edluar?
6. The Most Common Side Effects Of Edluar Are:
7. How Should I Store Edluar?
8. Active Ingredient:
9. Patient Information
10. Edluar Is A Sedative-hypnotic (sleep) Medicine. Edluar Is Used In Adults For The Short-term Treatment Of A Sleep Problem Called Insomnia. A Symptom Of Insomnia Includes:
11. Who Should Not Take Edluar?
12. Serious Side Effects Of Edluar Include:
13. Inactive Ingredients:
14. Revised: 3/2009document Id:

Edluar May Cause Serious Side Effects, Including: ⮝

Complex sleep behaviors that have caused serious injury and death.After taking Edluar, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing (complex sleep behaviors). The next morning, you may not remember that you did anything during the night. These activities may occur with Edluar whether or not you drink alcohol or take other medicines that make you sleepy.

Reported activities include:

o

driving a car ( sleep-driving )

o

making and eating food

o

talking on the phone

o

having sex

o

sleep-walking

Stop taking Edluar and call your healthcare provider right away if you find out that you have done any of the above activities after taking Edluar.

Do Not Take Edluar If You: ⮝

have ever experienced a complex sleep behavior (such as driving a car, making or eating food, talking on the phone, or having sex) while not being fully awake after taking Edluar

drank alcohol that evening or before bed

took another medicine to help you sleep

What Is Edluar? ⮝

Edluar is a sedative-hypnotic (sleep) medicine. Edluar is used in adults for the short-term treatment of a sleep problem called insomnia (trouble falling asleep).

It is not known if Edluar is safe and effective in children under the age of 18 years.

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

Edluar May Not Be Right For You. Before Starting Edluar, Tell Your Healthcare Provider 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 lung disease or breathing problems

are pregnant or planning to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take Edluar.

using Edluar in the last trimester of pregnancy may cause breathing difficulties or excess sleepiness in your newborn. Monitor for signs of sleepiness (more than usual), trouble breathing, or limpness in the newborn if Edluar is taken late in pregnancy.

are breastfeeding or plan to breastfeed. Edluar passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you take Edluar.

Tell your healthcare provider about all of 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 Edluar with other medicines that can make you sleepy, unless directed by your healthcare provider.

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

How Should I Take Edluar? ⮝

Take Edluar exactly as prescribed. Only take 1 Edluar tablet a night and only if needed.

Do not take Edluar if you drank alcohol that evening or before bed.

You should not take Edluar with or right after a meal. Edluar may help you fall asleep faster if you take it on an empty stomach.

Do not use the tablet if the seal on the childproof blister pack is broken, or if the blister holding the tablet is broken.

To open the blister pack, separate the individual blisters at the perforations. Peel off the top layer of paper, and push the tablet through the foil. Alternatively, use scissors to open the blister.

Place the tablet under the tongue, where it will disintegrate. Do not swallow or take with water.

Call your healthcare provider 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 Edluar or overdose, get emergency treatment.

The Most Common Side Effects Of Edluar Are: ⮝

drowsiness

dizziness

diarrhea

grogginess or feeling as if you have been drugged

fatigue

headache

You may still feel drowsy the next day after taking Edluar.

After you stop taking a sleep medicine, you may have symptoms for 1 to 2 days such as:

trouble sleeping

nausea

flushing

lightheadedness

uncontrolled crying

vomiting

stomach cramps

panic attack

nervousness

stomach area pain

These are not all the side effects of Edluar. Ask your doctor or pharmacist for more information.

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

How Should I Store Edluar? ⮝

Store Edluar at room temperature, between 68 F and 77 F (20 to 25 C).

Protect from light and moisture.

Keep Edluar and all medicines out of reach of children.

General information about the safe and effective use of Edluar

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.

Do not use Edluar for a condition for which it was not prescribed.

Do not share Edluar with other people, even if you think they 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 Edluar.

If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about Edluar that is written for healthcare professionals.

For more information about Edluar, go towww.meda.usor call Meda Pharmaceuticals Inc. at 1-866-444-7799.

Active Ingredient: ⮝

zolpidem tartrate

Patient Information ⮝

Prescribers or other healthcare professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with sedative-hypnotics, should counsel them in its appropriate use, and should instruct them to read the accompanying Medication Guide[

After taking Edluar, 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 Edluar. 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 Edluar.

Important

Take Edluar exactly as prescribed

• Do not take more Edluar than prescribed.
• Take Edluar right before you get in bed, not sooner.

Edluar Is A Sedative-hypnotic (sleep) Medicine. Edluar Is Used In Adults For The Short-term Treatment Of A Sleep Problem Called Insomnia. A Symptom Of Insomnia Includes: ⮝

• trouble falling asleep

Edluar is not for children.

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

Who Should Not Take Edluar? ⮝

Do not take Edluar if you have had an allergic reaction to zolpidem (Ambien , Ambien CR, ZolpiMist, Edluar).

Some signs of allergic reaction may be swelling of the face, a feeling of the throat closing, or difficulty breathing shortly after taking Zolpidem.

Do not take Edluar if you are allergic to anything in it.

• Take Edluar exactly as prescribed. Do not take more Edluar than prescribed for you.
• Take Edluar right before you get into bed.
• Do not take Edluar unless you are able to stay in bed a full night (7-8 hours) before you must be active again.
• For faster sleep onset, Edluar should NOT be taken with or right after a meal.
• Do not use the tablet if the seal on the childproof blister pack is broken, or if the blister holding the tablet is broken.
• To open the blister pack, separate the individual blisters at the perforations. Peel off the top layer of paper, and push the tablet through the foil.
• Place the tablet under the tongue, where it will disintegrate. Do not swallow or take with water.
• 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 Edluar or overdose, call your doctor or poison control center right away, or get emergency treatment.

Serious Side Effects Of Edluar Include: ⮝

• getting out of bed while not being fully awake and do an activity that you do not know you are doing.(
  • Store Edluar between 68 and 77 F (20 to 25 C). Protect from light and moisture.
  • Keep Edluar and all medicines out of reach of children.

  General Information about Edluar

  • Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide.
  • Do not use Edluar for a condition for which it was not prescribed.
  • Do not share Edluar with other people, even if you think they 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 Edluar.

  If you would like more information, talk with your doctor. You can ask your doctor or pharmacist for information about Edluar that is written for healthcare professionals.

  For more information about Edluar, call Meda Pharmaceuticals at 1-800-526-3840.

Inactive Ingredients: ⮝

mannitol, colloidal silicon dioxide, silicified microcrystalline cellulose, croscarmellose sodium, saccharin sodium, and magnesium stearate.

Rx Only

This Medication Guide has been approved

by U.S. Food and Drug Administration.

Orexo AB, Sweden

March 2009

EDLUAR zolpidem tartrate tablet

Product Information Product Type Item Code (Source) NDC:42447-112 Route of Administration SUBLINGUAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength zolpidem tartrate(UNII: WY6W63843K) (zolpidem - UNII:7K383OQI23) 5 mg

Inactive Ingredients Ingredient Name Strength mannitol(UNII: 3OWL53L36A) silicified microcrystalline cellulose() silicon dioxide, colloidal(UNII: ETJ7Z6XBU4) croscarmellose sodium(UNII: M28OL1HH48) saccharin sodium(UNII: SB8ZUX40TY) magnesium stearate(UNII: 70097M6I30)

Product Characteristics Color white Score no score Shape ROUND Size 8mm Flavor Imprint Code Contains Coating false Symbol true

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42447-112-01 10 in 1 BLISTER PACK 2 NDC:42447-112-03 30 in 1 BLISTER PACK 3 NDC:42447-112-10 100 in 1 BLISTER PACK

EDLUAR zolpidem tartrate tablet

Product Information Product Type Item Code (Source) NDC:42447-122 Route of Administration SUBLINGUAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength zolpidem tartrate(UNII: WY6W63843K) (zolpidem - UNII:7K383OQI23) 10 mg

Inactive Ingredients Ingredient Name Strength mannitol(UNII: 3OWL53L36A) silicified microcrystalline cellulose() silicon dioxide, colloidal(UNII: ETJ7Z6XBU4) croscarmellose sodium(UNII: M28OL1HH48) saccharin sodium(UNII: SB8ZUX40TY) magnesium stearate(UNII: 70097M6I30)

Product Characteristics Color white Score no score Shape ROUND Size 8mm Flavor Imprint Code Contains Coating false Symbol true

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:42447-122-01 10 in 1 BLISTER PACK 2 NDC:42447-122-03 30 in 1 BLISTER PACK 3 NDC:42447-122-10 100 in 1 BLISTER PACK

Labeler -Meda Pharmaceuticals

Revised: 3/2009document Id: ⮝

219CB7C9-7CBF-BF5D-8532-0EBC5D34562745129-4Set id: de965605-268a-4479-86f7-84de949cf36fVersion: 1Effective Time: 20090327Meda Pharmaceuticals

1. Highlights Of Prescribing Information
2. Warning: Complex Sleep Behaviors
3. See Full Prescribing Information For Complete Boxed Warning.
4. Recent Major Changes
5. Indications And Usage
6. Dosage And Administration
7. Dosage Forms And Strengths
8. Contraindications
9. Warnings And Precautions
10. Adverse Reactions
11. Drug Interactions
12. Use In Specific Populations
13. 1 Indications And Usage
14. 2 Dosage And Administration
15. 3 Dosage Forms And Strengths
16. 4 Contraindications
17. 5 Warnings And Precautions
18. 6 Adverse Reactions
19. 7 Drug Interactions
20. 8 Use In Specific Populations
21. 9 Drug Abuse And Dependence
22. 10 Overdosage
23. 11 Description
24. 12 Clinical Pharmacology
25. 13 Nonclinical Toxicology
26. 14 Clinical Studies
27. 16 How Supplied/storage And Handling
28. Principal Display Panel 5 Mg
29. Principal Display Panel 10 Mg
30. 1 Indications And Usage
31. 2 Dosage And Administration
32. 3 Dosage Forms And Strengths
33. 4 Contraindications
34. 5 Warnings And Precautions
35. 6 Adverse Reactions
36. 7 Drug Interactions
37. 8 Use In Specific Populations
38. 9 Drug Abuse And Dependence
39. 10 Overdosage
40. 11 Description
41. 12 Clinical Pharmacology
42. 13 Nonclinical Toxicology
43. 14 Clinical Studies
44. 16 How Supplied/storage And Handling

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use EDLUAR safely and effectively. See full prescribing information for EDLUAR.

EDLUAR (zolpidem tartrate) sublingual tablets, for oral use, CIV
Initial U.S. Approval: 1992

Warning: 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 Edluar. Some of these events may result in serious injuries, including death. Discontinue Edluar immediately if a patient experiences a complex sleep behavior [see Contraindications (4) and Warnings and Precautions (5.1)].

See Full Prescribing Information For Complete Boxed Warning. ⮝

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

Recent Major Changes ⮝

Boxed Warning XX/2019
Contraindications (4) XX/2019
Warnings and Precautions, Complex Sleep Behaviors (5.1) XX/2019
Warnings and Precautions, CNS Depressant Effects and Next-Day
Impairment (5.2) 12/2018

Indications And Usage ⮝

Edluar, a gamma-aminobutyric acid (GABA) A receptor positive modulator, is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation. Zolpidem tartrate has been shown to decrease sleep latency for up to 35 days in controlled clinical studies. (1)

Dosage And Administration ⮝

Use the lowest dose effective for the patient (2.1)

Recommended dose is 5 mg for women and 5 or 10 mg for men, immediately before bedtime. (2.1)

Geriatric patients and patients with hepatic impairment: Recommended dose is 5 mg for men and women. (2.2)

Lower doses of CNS depressants may be necessary when taken concomitantly with Edluar. (2.3)

Co-administration with CNS depressants: Recommended dose is 5 mg for men and women. (2.3)

The effect of Edluar may be slowed if taken with or immediately after a meal. (2.4)

Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. (2.4)

The tablet should not be swallowed and the tablet should not be taken with water. (2.4)

Dosage Forms And Strengths ⮝

Sublingual tablets: 5 mg and 10 mg. Tablets not scored. (3)

Contraindications ⮝

Patients who have experienced complex sleep behaviors after taking Edluar. (4, 5.1)

Known hypersensitivity to zolpidem. (4)

Warnings 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)

Need to Evaluate for Co-morbid Diagnosis: Reevaluate if insomnia persists after 7 to 10 days of use. (5.3)

Severe Anaphylactic and Anaphylactoid Reactions: angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4)

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 amount of tablets feasible to avoid intentional overdose. (5.6)

Respiratory Depression: Consider this risk before prescribing in patients with compromised respiratory function. (5.7)

Withdrawal Effects: Symptoms may occur with rapid dose reduction or discontinuation. (5.8, 9.3)

Adverse Reactions ⮝

Most commonly observed adverse reactions were:

Short term (< 10 nights): Drowsiness, dizziness, and diarrhea

Long term (28-35 nights): Dizziness and drugged feelings (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-866-444-7799 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

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 effect (7.2)

Use In Specific Populations ⮝

Pregnancy: May cause respiratory depression and sedation in neonates with exposure late in third trimester. (8.1)

Lactation: A lactating woman may pump and discard breast milk during treatment and for 23 hours after Edluar administration. (8.2)

Pediatric use: Safety and effectiveness not established. Hallucinations (incidence rate 7%) and other psychiatric and/or nervous system adverse reactions were observed frequently in a study of pediatric patients with Attention-Deficit/Hyperactivity Disorder. (5.4, 8.4)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 8/2019

1 Indications And Usage ⮝

Edluar (zolpidem tartrate) sublingual tablets are indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation [see Clinical Studies (14)].

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

2 Dosage And Administration ⮝

2.1 Dosage in Adults

Use the lowest effective dose for the patient. The recommended initial dose is 5 mg for women and either 5 or 10 mg for men, taken only once per night immediately before bedtime with at least 7-8 hours remaining before the planned time of awakening. If the 5 mg dose is not effective, the dose can be increased to 10 mg. In some patients, the higher morning blood levels following use of the 10 mg dose increase the risk of next day impairment of driving and other activities that require full alertness [see Warnings and Precautions (5.1)]. The total dose of Edluar should not exceed 10 mg once daily immediately before bedtime.

The recommended initial doses for women and men are different because zolpidem clearance is lower in women.

2.2 Special Populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Edluar in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.1); Use in Specific Populations (8.5)].

2.3 Use with CNS Depressants

Dosage adjustment may be necessary when Edluar is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.1)].

2.4 Administration

The effect of Edluar may be slowed by ingestion with or immediately after a meal.

Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.

3 Dosage Forms And Strengths ⮝

Edluar is available in 5 mg and 10 mg strength tablets for sublingual administration. Tablets are not scored.

Edluar 5 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed V on one side.

Edluar 10 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed X on one side.

4 Contraindications ⮝

Edluar is contraindicated in patients:

who have experienced complex sleep behaviors after taking Edluar [see Warnings and Precautions (5.1)].

with known hypersensitivity to zolpidem. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.4)].

5 Warnings And Precautions ⮝

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. Patients can be seriously injured or injure others during complex sleep behaviors. Such injuries may result in a fatal outcome. 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)]. Discontinue Edluar immediately if a patient experiences a complex sleep behavior.

5.2 CNS Depressant Effects and Next-Day Impairment

Edluar, like other sedative-hypnotic drugs, 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 Edluar and of other concomitant CNS depressants may be necessary when Edluar is administered with such agents because of the potentially additive effects. The use of Edluar 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)].

The risk of next-day psychomotor impairment, including impaired driving, is increased if Edluar is taken with less than a full night of sleep remaining (7 to 8 hours); if a higher than the recommended dose is taken; if co-administered with other CNS depressants; or if co-administered with other drugs that increase the blood level of zolpidem. Patients should be cautioned against driving and other activities requiring complete mental alertness if Edluar is taken in these circumstances.

Because Edluar can cause drowsiness and a decreased level of consciousness, patients, particularly the elderly, are at 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 sedative-hypnotics, including zolpidem tartrate. 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 after treatment with Edluar should not be rechallenged with the drug.

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 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)].

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, 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 least amount of drug 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 time 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 Edluar 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 Edluar 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)].

6 Adverse Reactions ⮝

The following serious adverse reactions 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 Warning and Precautions (5.4)]

Abnormal Thinking and Behavioral Changes [see Warning and Precautions (5.5)]

Withdrawal Effects [see Warning and Precautions (5.8)]

6.1 Clinical Trials Experience

Associated with discontinuation of treatment:

Approximately 4% of 1,701 patients who received zolpidem tartrate at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem tartrate at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem tartrate revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.

Most commonly observed adverse reactions in controlled trials:

During short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

Adverse reactions observed at an incidence of 1% in controlled trials:

The following tables enumerate treatment-emergent adverse event frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following table was derived from a pool of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

TABLE 1: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 10 nights (Percentage of patients reporting)

*Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo.
Body System/ Adverse Event*	Zolipidem tartrate ( 10 mg) (N=685)	Placebo (N=473)
Central and Peripheral Nervous System
Headache	7	6
Drowsiness	2	-
Dizziness	1	-
Gastrointestinal System
Diarrhea	1	-

The following table was derived from a pool of three placebo-controlled long-term efficacy trials involving oral zolpidem. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.

TABLE 2: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 35 nights (Percentage of patients reporting)

*Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo.
Body System/ Adverse Event*	Zolpidem tartrate ( 10 mg) (N=152)	Placebo (N=161)
Autonomic Nervous System	3	1
Dry mouth
Body as a Whole
Allergy	4	1
Back Pain	3	2
Influenza-like symptoms	2	-
Chest pain	1	-
Cardiovascular System
Palpitation	2	-
Central and Peripheral Nervous System
Drowsiness	8	5
Dizziness	5	1
Lethargy	3	1
Drugged feeling	3	-
Lightheadedness	2	1
Depression	2	1
Abnormal dreams	1	-
Amnesia	1	-
Sleep disorder	1	-
Gastrointestinal System
Diarrhea	3	2
Abdominal pain	2	2
Constipation	2	1
Respiratory System
Sinusitis	4	2
Pharyngitis	3	1
Skin and Appendages
Rash	2	1

Dose relationship for adverse reactions associated with oral zolpidem:

There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with oral zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Oral tissue-related adverse reactions to Edluar:

The effect of chronic daily administration of Edluar on oral tissue was evaluated in a 60-day open-label study in 60 insomniac patients. One patient developed transient sublingual erythema, and another transient paresthesia of the tongue.

Adverse event incidence across the entire preapproval oral zolpidem database:

Zolpidem was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zolpidem, they were not necessarily caused by it.

Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension, syncope.
Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fever, malaise, trauma.
Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.

Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.
Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo.
Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor.
Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea.
Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting.
Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system: Infrequent: infection.
Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.

Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT.
Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional: Infrequent: hyperglycemia, thirst.
Rare: gout, hypercholesterolemia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.

Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis.
Rare: arthrosis, muscle weakness, sciatica, tendinitis.

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

Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis.
Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: Infrequent: pruritus.
Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus.
Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system: Frequent: urinary tract infection. Infrequent: cystitis, urinary incontinence.
Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

7 Drug Interactions ⮝

7.1 CNS-active Drugs

CNS Depressants

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, Chlorpromazine

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 [see Clinical Pharmacology (12.3)].

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 [see Clinical Pharmacology (12.3)].

Alcohol

An additive adverse effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions (5.1)].

Sertraline

Concomitant administration of zolpidem and sertraline increases exposure to zolpidem and may increase the pharmacodynamics effect of zolpidem [see Clinical Pharmacology (12.3)].

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 Affect Drug 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 pharmacodynamics effects of zolpidem. Use of Rifampin in combination with zolpidem may decrease the efficacy of zolpidem.

Ketoconazole

Ketoconazole, a potent CYP3A4 inhibitor, increased the pharmacodynamics effects of zolpidem. Consideration should be given to using a lower dose of zolpidem when ketoconazole and zolpidem are given together.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

Neonates born to mothers using zolpidem late in the third trimester of pregnancy have been reported to experience symptoms of respiratory depression and sedation (see Clinical Considerations and Data). Published data on the use of zolpidem during pregnancy have not identified a drug-associated risk of and major birth defects (see Data). Oral administration of zolpidem to pregnant rats and rabbits did not indicate a risk for adverse effects on fetal development at clinically relevant doses (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Fetal/neonatal adverse reactions

Zolpidem crosses the placenta and may produce respiratory depression and sedation in neonates. Monitor neonates exposed to Edluar during pregnancy and labor for signs of excess sedation, hypotonia, and respiratory depression and manage accordingly.

Data

Human Data

Published data from observational studies, birth registries and case reports on the use of zolpidem during pregnancy have not identified a drug-associated risk of major birth defects.

There are limited postmarketing reports of severe to moderate cases of respiratory depression that occurred after birth in neonates whose mothers had taken zolpidem during pregnancy. These cases required artificial ventilation or intra-tracheal intubation. The majority of neonates recovered within hours to a few weeks after birth once treated.

Zolpidem has been shown to cross the placenta.

Animal Data

Oral administration of zolpidem to pregnant rats during the period of organogenesis at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, caused delayed fetal development (incomplete fetal skeletal ossification) at maternally toxic (ataxia) doses 25 and 120 times the MRHD based on mg/m2 body surface area.

Oral administration of zolpidem to pregnant rabbits during the period of organogenesis at 1, 4, and 16 mg base/kg/day, which are approximately 2.5, 10, and 40 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area caused embryo-fetal death and delayed fetal development (incomplete fetal skeletal ossification) at a maternally toxic (decreased body weight gain) dose 40 times the MRHD based on mg/m2 body surface area.

Oral administration of zolpidem to pregnant rats from day 15 of gestation through lactation at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, delayed offspring growth and decreased survival at doses 25 and 120 times, respectively, the MRHD based on mg/m2 body surface area.

8.2 Lactation

Risk Summary

Limited data from published literature reports the presence of zolpidem in human milk. There are reports of excess sedation in infants exposed to zolpidem through breastmilk (see Clinical Considerations). There is no information on the effects of zolpidem on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for Edluar and any potential adverse effects on the breastfed infant from Edluar or from the underlying maternal condition.

Clinical Considerations

Infants exposed to Edluar through breastmilk should be monitored for excess sedation, hypotonia, and respiratory depression. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment and for 23 hours (approximately 5 elimination half-lives) after Edluar administration in order to minimize drug exposure to a breast fed infant.

8.4 Pediatric Use

Edluar is not recommended for use in children. Safety and effectiveness in pediatric patients have not been established in pediatric patients below the age of 18.

In an 8-week controlled study in 201 pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), an oral solution of zolpidem tartrate dosed at 0.25mg/kg at bedtime did not decrease sleep latency compared to placebo. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations reported in 7% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Warnings and Precautions (5.4)].

8.5 Geriatric Use

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 zolpidem tartrate at doses of 10 mg or placebo, there were three adverse events occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug-related).

Adverse Event	Zolpidem	Placebo
Dizziness	3%	0%
Drowsiness	5%	2%
Diarrhea	3%	1%

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem tartrate reported falls, including 28/30 (93%) who were 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) 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 doses >10 mg.

The dose of Edluar in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Dosage and Administration (2), Warnings and Precautions (5)Clinical Pharmacology (12) and Clinical Studies (14)].

8.6 Gender Difference in Pharmacokinetics

Women clear zolpidem tartrate from the body at a lower rate than men, Cmax 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 Edluar for adult women is 5 mg, and the recommended dose for adult men is 5 or 10 mg.

In geriatric patients, clearance of zolpidem is similar in men and women. The recommended dose of Edluar in geriatric patients is 5 mg regardless of gender.

9 Drug Abuse And Dependence ⮝

9.1 Controlled Substance

Edluar contains the same active substance, zolpidem tartrate, as zolpidem tartrate oral tablets and 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 a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

Because persons with a history of addiction to or abuse of, drugs or alcohol are at increased risk for misuse, abuse, and addiction of Edluar, they should be monitored carefully when receiving Edluar or any other hypnotic.

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 following placebo substitution occurring within 48 hours following last zolpidem tartrate treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence and withdrawal have been received.

10 Overdosage ⮝

10.1 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.

10.2 Recommended Treatment

Based on data obtained for zolpidem tartrate, general symptomatic and supportive measures for overdose with Edluar 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 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-to-date information on the management of hypnotic drug product overdosage.

11 Description ⮝

Edluar contains zolpidem tartrate, a gamma-aminobutyric acid (GABA) A receptor positive modulator of the imidazopyridine class. Edluar is available in 5 mg and 10 mg strength tablets for sublingual administration.

Chemically, zolpidem tartrate is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

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 Edluar tablet includes the following inactive ingredients: mannitol, colloidal silicon dioxide, silicified microcrystalline cellulose, croscarmellose sodium, saccharin sodium, and magnesium stearate.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Zolpidem is a GABA A receptor positive modulator presumed to exert its therapeutic effects in the short-term treatment of insomnia through binding to the benzodiazepine site of 1 subunit containing GABA A receptors, increasing the frequency of chloride channel opening resulting in the inhibition of neuronal excitation.

12.2 Pharmacodynamics

Zolpidem binds to GABAA receptors with a greater affinity for 1 subunit relative to 2 and 3 subunit containing receptors. Zolpidem has no appreciable binding affinity for 5 subunit containing GABAA receptors. This binding profile may explain the relative absence of myorelaxant effects in animal studies. Zolpidem has no appreciable binding affinity for dopaminergic D2, serotonergic 5HT2, adrenergic, histaminergic or muscarinic receptors.

12.3 Pharmacokinetics

Absorption:

Edluar (zolpidem tartrate) sublingual tablets are bioequivalent to Ambien tablets (Sanofi-Aventis) with respect to Cmax and AUC. Similar to zolpidem tartrate oral tablets, Edluar sublingual tablets result in a pharmacokinetic profile characterized by rapid absorption.

Following administration of single 10 mg Edluar, in 18 healthy adult subjects (18-65 years of age), the mean peak concentration (Cmax) of zolpidem was 106 ng/mL (range: 52 to 205 ng/ml) occurring at a median time (Tmax) of 82 minutes (range: 30-180 min).

A food-effect study in 18 healthy volunteers compared the pharmacokinetics of Edluar 10 mg when administered while fasting or within 20 minutes after a high fat meal. The mean AUC and Cmax were decreased by 20% and 31%, respectively, while median Tmax was prolonged by 28% (from 82 to 105 min). The half-life remained unchanged. These results suggest that, for faster sleep onset, Edluar 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 92.5 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.

Metabolism:

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

Elimination:

When Edluar administered as a single 5 or 10 mg dose in healthy adult subjects, the mean zolpidem elimination half-life was 2.85 hours (range: 1.57-6.73 hr) and 2.65 hours (range: 1.75 to 3.77 hr) respectively.

Special Populations

Elderly:

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

Hepatic Impairment:

The pharmacokinetics of zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20-mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs. 499 ng/mL) and five times (788 vs. 4,203 ng hr/mL) higher, respectively, in hepatically-compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing with Edluar should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2)].

Renal Impairment:

The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage 4 renal failure (mean ClCr = 6.5 1.5 mL/min) undergoing hemodialysis three times a week, who were dosed with zolpidem tartrate 10 mg orally each day for 14 or 21 days. No statistically significant differences were observed for Cmax, Tmax, half-life, and AUC between the first and last day of drug administration when baseline concentration adjustments were made. Zolpidem was not hemodialyzable. No accumulation of unchanged drug appeared after 14 or 21 days. Zolpidem pharmacokinetics were not significantly different in renally-impaired patients. No dosage adjustment is necessary in patients with compromised renal function.

Drug Interactions

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 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 pharmacodynamics 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 AUC0- of zolpidem tartrate. There were no pharmacodynamics 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 T (-36 %) of zolpidem together with significant reductions in the pharmacodynamics effects of zolpidem tartrate. Rifampin, a CYP3A4 inducer, significantly reduced the exposure to and the pharmacodynamics effects of zolpidem.

A single-dose interaction study with zolpidem 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 pharmacodynamics 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.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis:

Zolpidem was administered to mice and rats for 2 years at oral doses of 4, 18, and 80 mg base/kg/day. In mice, these doses are approximately 2.5, 10, and 50 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area and in rats, these doses are approximately 5, 20, and 100 times the MRHD based on mg/m2 body surface area. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid and high doses.

Mutagenesis:

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment of Fertility:

Zolpidem was administered to rats at 4, 20, and 100 mg base/kg/day, which are approximately 5, 25, and 120 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) based on mg/m2 body surface area, prior to and during mating, and continuing in females through postpartum day 25. Zolpidem caused irregular estrus cycles and prolonged precoital intervals at the highest dose tested, which is approximately 120 times the MRHD based on mg/m2 body surface area. The NOAEL for these effects is 25 times the MRHD based on a mg/m2 body surface area. There was no impairment of fertility at any dose tested.

14 Clinical Studies ⮝

14.1 Transient Insomnia

Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single night trial comparing two doses of zolpidem tartrate oral tablets (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).

14.2 Chronic Insomnia

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV ). Adult outpatients with chronic insomnia (n = 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.

14.3 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

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 of zolpidem tartrate 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.

16 How Supplied/storage And Handling ⮝

Edluar is supplied as sublingual tablets in two dosage strengths: Tablets are not scored.

Edluar 5 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed V on one side and supplied as:

NDC Number Size
0037-6050-30 blister pack of 30

The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.

Edluar 10 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed X on one side and supplied as:

NDC Number Size
0037-6010-30 blister pack of 30

The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.

Store at controlled room temperature 20-25 C (68-77 F). Protect from light and moisture.

Principal Display Panel 5 Mg  ⮝

Rx Only NDC 0037-6050-30

EDLUAR 5 mg CIV
Zolpidem Tartrate Sublingual Tablets

Federal Law
required dispensing
of EDLUAR with
the Medication
Guide enclosed

Each sublingual tablet (to be placed under the tongue) contains 5 mg
of zolpidem tartrate. See prescribing information for dosage information.

30 Sublingual Tablets

Store at controlled room temperature 20-25 C (68-77 F). Protect from light
and moisture. Do not use if blisters are torn, or seal is broken.

UC-605030-03 Rev. 5/2017

Manufactured by:
Recipharm Stockholm AB, Sweden for
Meda Pharmaceuticals Inc.
Made in Sweden

Distributed by:
Meda Pharmaceuticals Inc.
Somerset, New Jersey

08873-4120

U.S. Patents 6,761,910; 8,512,747

MEDA and EDLUAR are registered trademarks of
Meda AB or a related entity.

Principal Display Panel 10 Mg  ⮝

Rx Only NDC 0037-6010-30

EDLUAR 10 mg CIV
Zolpidem Tartrate Sublingual Tablets

Federal Law
required dispensing
of EDLUAR with
the Medication
Guide enclosed

Each sublingual tablet (to be placed under the tongue) contains 10 mg
of zolpidem tartrate. See prescribing information for dosage information.

30 Sublingual Tablets

Store at controlled room temperature 20-25 C (68-77 F). Protect from light
and moisture. Do not use if blisters are torn, or seal is broken.

UC-601030-03 Rev. 5/2017

Manufactured by:
Recipharm Stockholm AB, Sweden for
Meda Pharmaceuticals Inc.
Made in Sweden

Distributed by:
Meda Pharmaceuticals Inc.
Somerset, New Jersey

08873-4120

U.S. Patents 6,761,910; 8,512,747

MEDA and EDLUAR are registered trademarks of
Meda AB or a related entity.

EDLUAR zolpidem tartrate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0037-6050 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ZOLPIDEM TARTRATE (UNII: WY6W63843K) (ZOLPIDEM - UNII:7K383OQI23) ZOLPIDEM TARTRATE 5 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SACCHARIN SODIUM (UNII: SB8ZUX40TY) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 8mm Flavor Imprint Code V Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0037-6050-30 3 in 1 CARTON 07/24/2009 1 10 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021997 07/24/2009

EDLUAR zolpidem tartrate tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0037-6010 Route of Administration ORAL DEA Schedule CIV

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength ZOLPIDEM TARTRATE (UNII: WY6W63843K) (ZOLPIDEM - UNII:7K383OQI23) ZOLPIDEM TARTRATE 10 mg

Inactive Ingredients Ingredient Name Strength MANNITOL (UNII: 3OWL53L36A) SILICON DIOXIDE (UNII: ETJ7Z6XBU4) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) SACCHARIN SODIUM (UNII: SB8ZUX40TY) MAGNESIUM STEARATE (UNII: 70097M6I30)

Product Characteristics Color WHITE Score no score Shape ROUND Size 8mm Flavor Imprint Code X Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0037-6010-30 3 in 1 CARTON 07/24/2009 1 10 in 1 BLISTER PACK; Type 0: Not a Combination Product 2 NDC:0037-6010-02 20 in 1 BOX, UNIT-DOSE 07/24/2009 2 2 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021997 07/24/2009

Labeler - Meda Pharmaceuticals (051229602)

Revised: 8/2019 Document Id: 5f57f9b8-4244-4999-ae38-8edf6f920298 34391-3 Set id: a32884d0-85b5-11de-8a39-0800200c9a66 Version: 14 Effective Time: 20190815 Meda Pharmaceuticals

1 Indications And Usage ⮝

Edluar (zolpidem tartrate) sublingual tablet is indicated for the short-term treatment of insomnia characterized by difficulties with sleep initiation.

The clinical trials performed with Zolpidem tartrate in support of efficacy were 4-5 weeks in duration with the final formal assessments of sleep latency performed at the end of treatment [see Clinical Studies (14)].

2 Dosage And Administration ⮝

The dose of Edluar should be individualized.

2.1 Dosage in adults

The recommended dose for Edluar for adults is 10 mg once daily immediately before bedtime. The total Edluar daily dose should not exceed 10 mg.

2.2 Special populations

Elderly or debilitated patients may be especially sensitive to the effects of zolpidem tartrate. Patients with hepatic insufficiency do not clear the drug as rapidly as normal subjects. The recommended dose of Edluar in both of these patient populations is 5 mg once daily immediately before bedtime [see Warnings and Precautions (5.6)].

2.3 Use with CNS depressants

Dosage adjustment may be necessary when Edluar is combined with other CNS-depressant drugs because of the potentially additive effects [see Warnings and Precautions (5.5)].

2.4 Administration

The effect of Edluar may be slowed by ingestion with or immediately after a meal. Edluar should not be given with or immediately after a meal.

Edluar sublingual tablet should be placed under the tongue, where it will disintegrate. The tablet should not be swallowed and the tablet should not be taken with water.

3 Dosage Forms And Strengths ⮝

Edluar is available in 5 mg and 10 mg strength tablets for sublingual administration. Tablets are not scored.

Edluar 5 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed on one side.

Edluar 10 mg sublingual tablets are round white, flat-faced, bevel-edged, with debossed on one side.

4 Contraindications ⮝

Edluar is contraindicated in patients with known hypersensitivity to zolpidem tartrate or to any of the inactive ingredients in the formulation. Observed reactions include anaphylaxis and angioedema [see Warnings and Precautions (5.2) and Description (11)].

5 Warnings And Precautions ⮝

5.1 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 tartrate.

5.2 Severe anaphylactic and anaphylactoid reactions

Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including zolpidem tartrate. 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 after treatment with Edluar should not be rechallenged with the drug.

5.3 Abnormal thinking and behavioral changes

A variety of abnormal thinking and behavior changes have been reported to occur in association with the use of sedative/hypnotics. Some of these changes may be characterized by decreased inhibition (e.g. aggressiveness and extroversion that seemed out of character), similar to effects produced by alcohol and other CNS depressants. Visual and auditory hallucinations have been reported as well as behavioral changes such as bizarre behavior, agitation and depersonalization. In controlled trials, <1% of adults with insomnia who received zolpidem tartrate reported hallucinations. In a clinical trial, 7.4% of pediatric patients with insomnia associated with attention-deficit/hyperactivity disorder (ADHD), who received zolpidem reported hallucinations [see Use in Specific Populations (8.4)].

Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported with sedative-hypnotics, including zolpidem tartrate. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as "sleep-driving" may occur with Edluar alone at therapeutic doses, the use of alcohol and other CNS depressants with Edluar appears to increase the risk of such behaviors, as does the use of Edluar at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of Edluar should be strongly considered for patients who report a "sleep-driving" episode. Other complex behaviors (e.g., preparing and eating food, making phone calls, or having sex) have been reported in patients who are not fully awake after taking a sedative-hypnotic. As with "sleep-driving", patients usually do not remember these events. Amnesia, anxiety and other neuro-psychiatric symptoms may occur unpredictably.

In primarily depressed patients, worsening of depression, including suicidal thoughts and actions (including completed suicides), has been reported in association with the use of sedative/hypnotics.

It can rarely be determined with certainty whether a particular instance of the abnormal behaviors listed above is drug-induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

5.4 Withdrawal effects

Following rapid dose decrease or abrupt discontinuation of sedative/hypnotics, there have been reports of signs and symptoms similar to those associated with withdrawal from other CNS-depressant drugs [see Drug Abuse and Dependence (9)].

5.5 CNS depressant effects

Edluar, like other sedative/hypnotic drugs, has CNS-depressant effects. Due to the rapid onset of action, Edluar should be ingested immediately prior to going to bed. Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness or motor coordination such as operating machinery or driving a motor vehicle after ingesting the drug, including potential impairment of the performance of such activities that may occur the day following ingestion of Edluar. Zolpidem tartrate showed additive effects when combined with alcohol and should not be taken with alcohol. Patients should also be cautioned about possible combined effects with other CNS-depressant drugs. Dosage adjustments of Edluar may be necessary when Edluar is administered with such agents because of the potentially additive effects.

5.6 Special populations

Use in the elderly and/or debilitated patients:

Impaired motor and/or cognitive performance after repeated exposure or unusual sensitivity to sedative/hypnotic drugs is a concern in the treatment of elderly and/or debilitated patients. Therefore, the recommended Edluar dosage is 5 mg in the elderly and/or debilitated patients [see Dosage and Administration (2.2) and Geriatric Use (8.5)] to decrease the possibility of side effects. These patients should be closely monitored.

Use in patients with concomitant illness:

Clinical experience with zolpidem tartrate in patients with concomitant systemic illness is limited. Caution is advisable in using Edluar in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Although studies did not reveal respiratory depressant effects at hypnotic doses of zolpidem tartrate in normal 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 tartrate (10 mg) when compared to placebo. Since sedative/hypnotics have the capacity to depress respiratory drive, precautions should be taken if Edluar is prescribed to patients with compromised respiratory function. Edluar should be used with caution in patients with sleep apnea syndrome or myasthenia gravis. Post-marketing reports of respiratory insufficiency following treatment with zolpidem tartrate, most of which involved patients with pre-existing respiratory impairment, have been received.

Data in end-stage renal failure patients repeatedly treated with zolpidem tartrate did not demonstrate drug accumulation or alterations in pharmacokinetic parameters. No dosage adjustment of Edluar in renally impaired patients is required; however, these patients should be closely monitored [see Clinical Pharmacology (12.3)].

A study in subjects with hepatic impairment treated with zolpidem tartrate did reveal prolonged elimination in this group; therefore, treatment with Edluar should be initiated with 5 mg in patients with hepatic compromise, and they should be closely monitored [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

Use in patients with depression:

As with other sedative/hypnotic drugs, Edluar should be administered with caution to patients exhibiting signs or symptoms of depression. Suicidal tendencies may be present in such patients and protective measures may be required. Intentional over-dosage is more common in this group of patients; therefore, the least amount of drug that is feasible should be prescribed for the patient at any one time.

Pediatric patients:

Edluar is not recommended for use in children. Safety and effectiveness of Edluar have not been established in pediatric patients below the age of 18. In an 8-week study in pediatric patients (aged 6-17 years) with insomnia associated with ADHD, an oral solution of zolpidem did not decrease sleep latency compared to placebo. Hallucinations were reported in 7.4% of the pediatric patients who received zolpidem; none of the pediatric patients who received placebo reported hallucinations [see Use in Specific Populations (8.4)].

6 Adverse Reactions ⮝

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

• Serious anaphylactic and anaphylactoid reactions [see Warnings and Precautions (5.2)].
• Abnormal thinking and behavior, complex behaviors [see Warnings and Precautions (5.3)].
• Withdrawal effects [see Warnings and Precautions (5.4)].
• CNS-depressant effects [see Warnings and Precautions (5.5)].

6.1 Clinical trials experience

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 practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating incidence rates.

Associated with discontinuation of treatment:

Approximately 4% of 1,701 patients who received zolpidem tartrate at all doses (1.25 to 90 mg) in U.S. premarketing clinical trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from U.S. trials were daytime drowsiness (0.5%), dizziness (0.4%), headache (0.5%), nausea (0.6%), and vomiting (0.5%).

Approximately 4% of 1,959 patients who received zolpidem tartrate at all doses (1 to 50 mg) in similar foreign trials discontinued treatment because of an adverse reaction. Reactions most commonly associated with discontinuation from these trials were daytime drowsiness (1.1%), dizziness/vertigo (0.8%), amnesia (0.5%), nausea (0.5%), headache (0.4%), and falls (0.4%).

Data from a clinical study in which selective serotonin reuptake inhibitor (SSRI)-treated patients were given zolpidem tartrate revealed that four of the seven discontinuations during double-blind treatment with zolpidem (n=95) were associated with impaired concentration, continuing or aggravated depression, and manic reaction; one patient treated with placebo (n=97) was discontinued after an attempted suicide.

Most commonly observed adverse reactions in controlled trials:

During short-term treatment (up to 10 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were drowsiness (reported by 2% of zolpidem patients), dizziness (1%), and diarrhea (1%). During longer-term treatment (28 to 35 nights) with zolpidem tartrate at doses up to 10 mg, the most commonly observed adverse reactions associated with the use of zolpidem and seen at statistically significant differences from placebo-treated patients were dizziness (5%) and drugged feelings (3%).

Adverse reactions observed at an incidence of 1% in controlled trials:

The following tables enumerate treatment-emergent adverse event frequencies that were observed at an incidence equal to 1% or greater among patients with insomnia who received zolpidem tartrate and at a greater incidence than placebo in U.S. placebo-controlled trials. Events reported by investigators were classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms for the purpose of establishing event frequencies. The prescriber should be aware that these figures cannot be used to predict the incidence of side effects in the course of usual medical practice, in which patient characteristics and other factors differ from those that prevailed in these clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigators involving related drug products and uses, since each group of drug trials is conducted under a different set of conditions. However, the cited figures provide the physician with a basis for estimating the relative contribution of drug and nondrug factors to the incidence of side effects in the population studied.

The following table was derived from a pool of 11 placebo-controlled short-term U.S. efficacy trials involving zolpidem in doses ranging from 1.25 to 20 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use.

TABLE 1: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 10 nights (Percentage of patients reporting)

Body System/ Adverse Event*	Zolpidem tartrate ( 10 mg) (n=685)	Placebo (n=473)
*Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo.
Central and Peripheral Nervous System
Headache	7	6
Drowsiness	2	-
Dizziness	1	-
Gastrointestinal System
Diarrhea	1	-

The following table was derived from a pool of three placebo-controlled long-term efficacy trials involving oral zolpidem. These trials involved patients with chronic insomnia who were treated for 28 to 35 nights with zolpidem at doses of 5, 10, or 15 mg. The table is limited to data from doses up to and including 10 mg, the highest dose recommended for use. The table includes only adverse events occurring at an incidence of at least 1% for zolpidem patients.

TABLE 2: Incidence of Treatment-Emergent Adverse Experiences in Placebo-Controlled Clinical Trials with zolpidem tartrate lasting up to 35 nights (Percentage of patients reporting)

Body System/ Adverse Event*	Zolpidem tartrate ( 10 mg) (n=152)	Placebo (n=161)
*Reactions reported by at least 1% of patients treated with oral zolpidem and at a greater frequency than placebo.
Autonomic Nervous System
Dry mouth	3	1
Body as a Whole
Allergy	4	1
Back pain	3	2
Influenza-like symptoms	2	-
Chest pain	1	-
Cardiovascular System
Palpitation	2	-
Central and Peripheral Nervous System
Drowsiness	8	5
Dizziness	5	1
Lethargy	3	1
Drugged feeling	3	-
Lightheadedness	2	1
Depression	2	1
Abnormal dreams	1	-
Amnesia	1	-
Sleep disorder	1	-
Gastrointestinal System
Diarrhea	3	2
Abdominal pain	2	2
Constipation	2	1
Respiratory System
Sinusitis	4	2
Pharyngitis	3	1
Skin and Appendages
Rash	2	1

Dose relationship for adverse reactions associated with oral zolpidem:

There is evidence from dose comparison trials suggesting a dose relationship for many of the adverse reactions associated with oral zolpidem use, particularly for certain CNS and gastrointestinal adverse events.

Oral tissue-related adverse reactions to Edluar:

The effect of chronic daily administration of Edluar on oral tissue was evaluated in a 60-day open-label study in 60 insomniac patients. One patient developed transient sublingual erythema, and another transient paresthesia of the tongue.

Adverse event incidence across the entire preapproval oral zolpidem database: Zolpidem was administered to 3,660 subjects in clinical trials throughout the U.S., Canada, and Europe. Treatment-emergent adverse events associated with clinical trial participation were recorded by clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals experiencing treatment-emergent adverse events, similar types of untoward events were grouped into a smaller number of standardized event categories and classified utilizing a modified World Health Organization (WHO) dictionary of preferred terms.

The frequencies presented, therefore, represent the proportions of the 3,660 individuals exposed to zolpidem, at all doses, who experienced an event of the type cited on at least one occasion while receiving zolpidem. All reported treatment-emergent adverse events are included, except those already listed in the table above of adverse events in placebo-controlled studies, those coding terms that are so general as to be uninformative, and those events where a drug cause was remote. It is important to emphasize that, although the events reported did occur during treatment with zolpidem, they were not necessarily caused by it.

Adverse events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in greater than 1/100 subjects; infrequent adverse events are those occurring in 1/100 to 1/1,000 patients; rare events are those occurring in less than 1/1,000 patients.

Autonomic nervous system: Infrequent: increased sweating, pallor, postural hypotension, syncope. Rare: abnormal accommodation, altered saliva, flushing, glaucoma, hypotension, impotence, increased saliva, tenesmus.

Body as a whole: Frequent: asthenia. Infrequent: edema, falling, fever, malaise, trauma.

Rare: allergic reaction, allergy aggravated, anaphylactic shock, face edema, hot flashes, increased ESR, pain, restless legs, rigors, tolerance increased, weight decrease.

Cardiovascular system: Infrequent: cerebrovascular disorder, hypertension, tachycardia.

Rare: angina pectoris, arrhythmia, arteritis, circulatory failure, extrasystoles, hypertension aggravated, myocardial infarction, phlebitis, pulmonary embolism, pulmonary edema, varicose veins, ventricular tachycardia.

Central and peripheral nervous system: Frequent: ataxia, confusion, euphoria, headache, insomnia, vertigo. Infrequent: agitation, anxiety, decreased cognition, detached, difficulty concentrating, dysarthria, emotional lability, hallucination, hypoesthesia, illusion, leg cramps, migraine, nervousness, paresthesia, sleeping (after daytime dosing), speech disorder, stupor, tremor. Rare: abnormal gait, abnormal thinking, aggressive reaction, apathy, appetite increased, decreased libido, delusion, dementia, depersonalization, dysphasia, feeling strange, hypokinesia, hypotonia, hysteria, intoxicated feeling, manic reaction, neuralgia, neuritis, neuropathy, neurosis, panic attacks, paresis, personality disorder, somnambulism, suicide attempts, tetany, yawning.

Gastrointestinal system: Frequent: dyspepsia, hiccup, nausea. Infrequent: anorexia, constipation, dysphagia, flatulence, gastroenteritis, vomiting. Rare: enteritis, eructation, esophagospasm, gastritis, hemorrhoids, intestinal obstruction, rectal hemorrhage, tooth caries.

Hematologic and lymphatic system: Rare: anemia, hyperhemoglobinemia, leukopenia, lymphadenopathy, macrocytic anemia, purpura, thrombosis.

Immunologic system: Infrequent: infection. Rare: abscess herpes simplex herpes zoster, otitis externa, otitis media.

Liver and biliary system: Infrequent: abnormal hepatic function, increased SGPT. Rare: bilirubinemia, increased SGOT.

Metabolic and nutritional: Infrequent: hyperglycemia, thirst. Rare: gout, hypercholesteremia, hyperlipidemia, increased alkaline phosphatase, increased BUN, periorbital edema.

Musculoskeletal system: Frequent: arthralgia, myalgia. Infrequent: arthritis. Rare: arthrosis, muscle weakness, sciatica, tendinitis.

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

Respiratory system: Frequent: upper respiratory infection. Infrequent: bronchitis, coughing, dyspnea, rhinitis. Rare: bronchospasm, epistaxis, hypoxia, laryngitis, pneumonia.

Skin and appendages: Infrequent: pruritus. Rare: acne, bullous eruption, dermatitis, furunculosis, injection-site inflammation, photosensitivity reaction, urticaria.

Special senses: Frequent: diplopia, vision abnormal. Infrequent: eye irritation, eye pain, scleritis, taste perversion, tinnitus. Rare: conjunctivitis, corneal ulceration, lacrimation abnormal, parosmia, photopsia.

Urogenital system: Infrequent: urinary tract infection. Infrequent: cystitis, urinary incontinence. Rare: acute renal failure, dysuria, micturition frequency, nocturia, polyuria, pyelonephritis, renal pain, urinary retention.

7 Drug Interactions ⮝

For details of drug interactions, please refer to Clinical Pharmacology (12.3).

7.1 CNS-active drugs

Any drug with CNS-depressant effects could potentially enhance the CNS-depressant effects of zolpidem.

Imipramine in combination with zolpidem produced an additive effect of decreased alertness. Similarly, chlorpromazine in combination with zolpidem produced an additive effect of decreased alertness and psychomotor performance. These drugs did not show any significant pharmacokinetic interaction.

A study involving haloperidol and zolpidem revealed no effect of haloperidol on the pharmacokinetics or pharmacodynamics of zolpidem. The lack of a drug interaction following single-dose administration does not predict a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)]. Concomitant administration of zolpidem and sertraline increased zolpidem Cmax (43%) and decreased Tmax (53%), whether or not these changes alter the pharmacodynamic effect of zolpidem is unknown.

7.2 Drugs that affect drug metabolism via cytochrome P450

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

Co-administration of multiple doses of rifampin and a single dose of zolpidem tartrate (20 mg) given 17 hours after the last dose of rifampin showed significant reductions of the AUC (73%), Cmax (58%), and T1/2 (36%) of zolpidem together with significant reductions in the pharmacodynamic effects of zolpidem tartrate.

Co-administration of a single dose of zolpidem tartrate with 4 doses of ketoconazole, a potent CYP3A4 inhibitor 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. Patients should be advised that use of Edluar with ketoconazole may enhance the sedative effects.

7.3 Drug-laboratory test interactions

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

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category C:

There are no adequate and well-controlled studies of Edluar in pregnant women. Edluar should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Studies to assess the effects on children whose mothers took zolpidem during pregnancy have not been conducted. There is a published case report documenting the presence of zolpidem in human umbilical cord blood. Children born to mothers taking sedative-hypnotic drugs may be at some risk for withdrawal symptoms from the drug during the postnatal period. In addition, neonatal flaccidity has been reported in infants born to mothers who received sedative-hypnotic drugs during pregnancy.

Administration of zolpidem to pregnant rats and rabbits resulted in adverse effects on offspring development at doses greater than the maximum recommended human dose (MRHD) of 10 mg/day (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 (approximately 5, 24, and 120 times the MRHD on a mg/m2 basis) to pregnant rats during the period of organogenesis, dose-related decreases in fetal skull ossification occurred at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis. In rabbits treated during organogenesis with zolpidem at oral doses of 1, 4, and 16 mg base/kg (approximately 2.5, 10, and 40 times the MRHD on a mg/m2 basis), increased embryo-fetal death and incomplete fetal skeletal ossification occurred at the highest dose. The no-effect dose for embryo-fetal toxicity in rabbits is approximately 10 times the MRHD on a mg/m2 basis. Administration of zolpidem to rats at oral doses of 4, 20, and 100 mg base/kg (approximately 5, 24, and 120 times the MRHD on a mg/m2 basis) during the latter part of pregnancy and throughout lactation produced decreased offspring growth and survival at all but the lowest dose, which is approximately 5 times the MRHD on a mg/m2 basis.

8.2 Labor and delivery

Edluar has no established use in labor and delivery [see Pregnancy (8.1)].

8.3 Nursing mothers

Zolpidem is excreted into human milk. Studies in lactating mothers indicate that the t1/2 of zolpidem is similar to that in non-lactating women (2.6 0.3 hours). The effect of zolpidem on the nursing infant is not known. Caution should be exercised when Edluar is administered to a nursing mother.

8.4 Pediatric use

Safety and effectiveness of Edluar have not been established in pediatric patients below the age of 18.

In an 8-week controlled study, 201 pediatric patients (aged 6-17 years) with insomnia associated with attention-deficit/hyperactivity disorder (90% of the patients were using psychoanaleptics) were treated with an oral solution of zolpidem (n=136), or placebo (n=65). Zolpidem did not significantly decrease latency to persistent sleep, compared to placebo, as measured by polysomnography after 4 weeks of treatment. Psychiatric and nervous system disorders comprised the most frequent (>5%) treatment-emergent adverse reactions observed with zolpidem versus placebo and included dizziness (23.5% vs. 1.5%), headache (12.5% vs. 9.2%), and hallucinations (7.4% vs. 0%) [see Warnings and Precautions (5.6)]. Ten patients on zolpidem (7.4%) discontinued treatment due to an adverse reaction.

8.5 Geriatric use

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 zolpidem tartrate at doses of 10 mg or placebo, there were three adverse events occurring at an incidence of at least 3% for zolpidem and for which the zolpidem incidence was at least twice the placebo incidence (i.e., they could be considered drug-related).

Adverse Event	Zolpidem	Placebo
Dizziness	3%	0%
Drowsiness	5%	2%
Diarrhea	3%	1%

A total of 30/1,959 (1.5%) non-U.S. patients receiving zolpidem tartrate reported falls, including 28/30 (93%) who were 70 years of age. Of these 28 patients, 23 (82%) were receiving zolpidem doses >10 mg. A total of 24/1,959 (1.2%) 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 doses >10 mg.

The dose of Edluar in elderly patients is 5 mg to minimize adverse effects related to impaired motor and/or cognitive performance and unusual sensitivity to sedative/hypnotic drugs [see Dosage and Administration (2), Warnings and Precautions (5), Clinical Pharmacology (12) and Clinical Studies (14)].

9 Drug Abuse And Dependence ⮝

9.1 Controlled substance

Edluar contains the same active substance, zolpidem tartrate, as zolpidem tartrate oral tablets and 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 a diminution of one or more of the drug effects over time. Tolerance may occur to both desired and undesired effects of drugs and may develop at different rates for different effects.

Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, using a multidisciplinary approach, but relapse is common.

Studies of abuse potential in former drug abusers found that the effects of single doses of zolpidem tartrate 40 mg were similar, but not identical, to diazepam 20 mg, while zolpidem tartrate 10 mg was difficult to distinguish from placebo.

Because persons with a history of addiction to, or abuse of, drugs or alcohol are at increased risk for misuse, abuse, and addiction of Edluar, they should be monitored carefully when receiving Edluar or any other hypnotic.

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 following placebo substitution occurring within 48 hours following last zolpidem tartrate treatment: fatigue, nausea, flushing, lightheadedness, uncontrolled crying, emesis, stomach cramps, panic attack, nervousness, and abdominal discomfort. These reported adverse events occurred at an incidence of 1% or less. However, available data cannot provide a reliable estimate of the incidence, if any, of dependence during treatment at recommended doses. Post-marketing reports of abuse, dependence and withdrawal have been received.

10 Overdosage ⮝

10.1 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.

10.2 Recommended treatment

Based on data obtained for zolpidem tartrate, general symptomatic and supportive measures for overdose with Edluar 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 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-to-date information on the management of hypnotic drug product overdosage.

11 Description ⮝

Edluar (zolpidem tartrate) sublingual tablet is a non-benzodiazepine hypnotic of the imidazopyridine class and is available in 5 mg and 10 mg strength tablets for sublingual administration.

Chemically, zolpidem tartrate is N,N,6-trimethyl-2-p-tolylimidazo[1,2-a] pyridine-3-acetamide L-(+)-tartrate (2:1). It has the following structure:

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 Edluar tablet includes the following inactive ingredients: mannitol, colloidal silicon dioxide, silicified microcrystalline cellulose, croscarmellose sodium, saccharin sodium, and magnesium stearate.

12 Clinical 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 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 1/ 5 subunits. This selective binding of zolpidem on the BZ1 receptor is not absolute, but it may explain the relative absence of myorelaxant and anticonvulsant effects in animal studies as well as the preservation of deep sleep (stages 3 and 4) in human studies of zolpidem tartrate at hypnotic doses.

12.3 Pharmacokinetics

Absorption:

Edluar (zolpidem tartrate) sublingual tablet is bioequivalent to Ambien tablets (Sanofi-Aventis) with respect to Cmax and AUC. Similar to zolpidem tartrate oral tablets, Edluar sublingual tablet results in a pharmacokinetic profile characterized by rapid absorption.

Following administration of single 10 mg Edluar, in 18 (18-65 years of age) healthy adult subjects, the mean peak concentration (Cmax) of zolpidem was 106 ng/mL (range: 52 to 205 ng/ml) occurring at a median time (Tmax) of 82 minutes (range: 30-180 min).

A food-effect study in 18 healthy volunteers compared the pharmacokinetics of Edluar 10 mg when administered while fasting or within 20 minutes after a high fat meal. The mean AUC and Cmax were decreased by 20% and 31%, respectively, while median Tmax was prolonged by 28% (from 82 to 105 min). The half-life remained unchanged. These results suggest that, for faster sleep onset, Edluar 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 92.5 0.1% and remained constant, independent of concentration between 40 and 790 ng/mL.

Metabolism:

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

Elimination:

When Edluar was administered as a single 5 or 10 mg dose in healthy adult subjects, the mean zolpidem elimination half-life was 2.85 hours (range: 1.57-6.73 hr) and 2.65 hours (range: 1.75 to 3.77 hr) respectively.

Special populations

Elderly:

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

Hepatic impairment:

The pharmacokinetics of zolpidem tartrate in eight patients with chronic hepatic insufficiency were compared to results in healthy subjects. Following a single 20-mg oral zolpidem tartrate dose, mean Cmax and AUC were found to be two times (250 vs 499 ng/mL) and five times (788 vs 4,203 ng hr/mL) higher, respectively, in hepatically-compromised patients. Tmax did not change. The mean half-life in cirrhotic patients of 9.9 hr (range: 4.1 to 25.8 hr) was greater than that observed in normals of 2.2 hr (range: 1.6 to 2.4 hr). Dosing with Edluar should be modified accordingly in patients with hepatic insufficiency [see Dosage and Administration (2.2) and Warnings andPrecautions (5.6)].

Renal impairment:

The pharmacokinetics of zolpidem tartrate were studied in 11 patients with end-stage 4 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. 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 hr (range: 0.5 to 3.0 hr); after repeated dosing Tmax was 0.8 0.2 hr (range: 0.5 to 2.0 hr). 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, T1/2 was 2.4 0.4 hr (range: 0.4 to 5.1 hr). After repeated dosing, T1/2 was 2.5 0.4 hr (range: 0.7 to 4.2 hr). 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 of Edluar is necessary in patients with compromised renal function.

Drug interactions

CNS-active drugs:

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

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 a lack following chronic administration.

An additive effect on psychomotor performance between alcohol and oral zolpidem was demonstrated [see Warnings and Precautions: CNS depressant effects (5.5)].

A single-dose interaction study with zolpidem tartrate10 mg and fluoxetine 20 mg at steady-state levels in male volunteers did not demonstrate any clinically significant pharmacokinetic or pharmacodynamic interactions. When multiple doses of zolpidem and fluoxetine at steady state the concentrations were evaluated in healthy females, increase in the zolpidem half-life (17%) was observed. There was no evidence of an additive effect in psychomotor performance.

Following five consecutive nightly doses of oral zolpidem tartrate10 mg in the presence of sertraline 50 mg (17 consecutive daily doses, at 7:00 am, in healthy female volunteers), zolpidem Cmax was significantly higher (43%) and Tmax was significantly decreased (53%). Pharmacokinetics of sertraline and N-desmethylsertraline were unaffected by zolpidem.

Drugs that affect drug metabolism via cytochrome P450:

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

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

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

A randomized double-blind crossover interaction study in twelve healthy subjects showed that co-administration of a single 5 mg dose of zolpidem tartrate with 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. Patients should be advised that use of Edluar with ketoconazole may enhance the sedative effects.

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 normal subjects.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, mutagenesis, impairment of fertility

Carcinogenesis:

Zolpidem was administered to mice and rats for 2 years at dietary dosages of 4, 18, and 80 mg base/kg. In mice, these doses are 2.5, 10, and 50 times the maximum recommended human dose (MRHD) of 10 mg/day (8 mg zolpidem base) on mg/m2 basis. In rats, these doses are 5, 20, and 100 times the MRHD on a mg/m2 basis. No evidence of carcinogenic potential was observed in mice. In rats, renal tumors (lipoma, liposarcoma) were seen at the mid- and high doses.

Mutagenesis:

Zolpidem was negative in in vitro (bacterial reverse mutation, mouse lymphoma, and chromosomal aberration) and in vivo (mouse micronucleus) genetic toxicology assays.

Impairment of fertility:

Oral administration of zolpidem (doses of 4, 20, and 100 mg base/kg or 5, 24, and 120 times the MRHD on a mg/m2 basis) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals. The no-effect dose for these findings is 24 times the MRHD on a mg/m2 basis. There was no impairment of fertility at any dose tested.

14 Clinical Studies ⮝

14.1 Chronic insomnia

Zolpidem was evaluated in two controlled studies for the treatment of patients with chronic insomnia (most closely resembling primary insomnia, as defined in the APA Diagnostic and Statistical Manual of Mental Disorders, DSM-IV ). Adult outpatients with chronic insomnia (n = 75) were evaluated in a double-blind, parallel group, 5-week trial comparing two doses of zolpidem tartrate and placebo. On objective (polysomnographic) measures of sleep latency and sleep efficiency, zolpidem 10 mg was superior to placebo on sleep latency for the first 4 weeks and on sleep efficiency for weeks 2 and 4. Zolpidem was comparable to placebo on number of awakenings at both doses studied.

Adult outpatients (n=141) with chronic insomnia were also evaluated, in a double-blind, parallel group, 4-week trial comparing two doses of zolpidem and placebo. Zolpidem 10 mg was superior to placebo on a subjective measure of sleep latency for all 4 weeks, and on subjective measures of total sleep time, number of awakenings, and sleep quality for the first treatment week.

Increased wakefulness during the last third of the night as measured by polysomnography has not been observed in clinical trials with zolpidem tartrate.

14.2 Transient insomnia

Normal adults experiencing transient insomnia (n = 462) during the first night in a sleep laboratory were evaluated in a double-blind, parallel group, single-night trial comparing two doses of zolpidem tartrate oral tablets (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).

14.3 Studies pertinent to safety concerns for sedative/hypnotic drugs

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 of zolpidem tartrate 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.

16 How Supplied/storage And Handling ⮝

16.1 How supplied

Edluar is supplied as sublingual tablets in two dosage strengths. Tablets are not scored.

Edluar 5 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed on one side and supplied as:

NDC Number Size

42447-112-01 blister pack of 10

42447-112-03 blister pack of 30

42447-112-10 blister pack of 100

The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.

Edluar 10 mg sublingual tablets are round white tablets, flat-faced, bevel-edged with debossed on one side and supplied as:

NDC Number Size

42447-122-01 blister pack of 10

42447-122-03 blister pack of 30

42447-122-10 blister pack of 100

The blister packs consist of aluminum/aluminum Child Resistant Control (CRC) blisters.

16.2 Storage and handling

Store at controlled room temperature 20-25 C (68-77 F). Protect from light and moisture.