Edluar (Page 5 of 5)

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. 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) on mg/m2 basis. In rats, these doses are approximately 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) to rats prior to and during mating, and continuing in females through postpartum day 25, resulted in irregular estrus cycles and prolonged precoital intervals at the highest dose tested. The no-effect dose for these findings is approximately 24 times the MRHD on a mg/m2 basis. 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.

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Medication Guide).

Inform patients and their families about the benefits and risks of treatment with Edluar. Inform patients of the availability of a Medication Guide and instruct them to read the Medication Guide prior to initiating treatment with Edluar and with each prescription refill. Review the Edluar Medication Guide with every patient prior to initiation of treatment. Instruct patients or caregivers that Edluar should be taken only as prescribed.

CNS-depressant Effects and Next-Day Impairment

Tell patients that Edluar has the potential to cause next-day impairment, and that this risk is increased if dosing instructions are not carefully followed. Tell patients to wait for at least 8 hours after dosing before driving or engaging in other activities requiring full mental alertness. Inform patients that impairment can be present despite feeling fully awake.

Severe Anaphylactic and Anaphylactoid Reactions

Inform patients that severe anaphylactic and anaphylactoid reactions have occurred with zolpidem. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if any of them occur.

Sleep-Driving and Other Complex Behaviors

Instruct patients and their families that sedative hypnotics can cause abnormal thinking and behavior change, including “sleep-driving” and other complex behaviors while not being fully awake (preparing and eating food, making phone calls, or having sex). Tell patients to call you immediately if they develop any of these symptoms.

Suicide

Tell patients to immediately report any suicidal thoughts.

Alcohol and Other Drugs

Ask patients about alcohol consumption, medicines they are taking, and drugs they may be taking without a prescription. Advise patients not to use Edluar if they drank alcohol that evening or before bed.

Tolerance, Abuse, and Dependence

Tell patients not to increase the dose of Edluar on their own, and to inform you if they believe the drug “does not work”.

Administration Instructions

Patients should be counseled to take Edluar right before they get into bed and only when they are able to stay in bed a full night (7-8 hours) before being active again. Edluar tablets should not be taken with or immediately after a meal. Advise patients NOT to take Edluar when drinking alcohol that evening or before bed. 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.

Medication Guide
Edluar® [ED’ – loo-ahr]
(zolpidem tartrate)
sublingual tablets C-IV

Read this Medication Guide that comes with Edluar before you start taking it and each time you get a refill. There may be new information. This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about Edluar?

  • Do not take more Edluar than prescribed.
  • Do not take Edluar unless you are able to stay in bed a full night (7 to 8 hours) before you must be active again.
  • Take Edluar right before you get in bed, not sooner

Edluar may cause serious side effects, including:

  • 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 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:

  • 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.

Who should not take Edluar?

  • Do not take Edluar if you are allergic to zolpidem or any other ingredients in Edluar. See the end of this Medication Guide for a complete list of ingredients in Edluar.
  • Do not take Edluar if you have had an allergic reaction to drugs containing zolpidem, such as Ambien, Ambien CR, Zolpimist, or Intermezzo.

Symptoms of a serious allergic reaction to zolpidem can include:

  • swelling of your face, lips, and throat that may cause difficulty breathing or swallowing
  • nausea and vomiting

What should I tell my healthcare provider before taking Edluar?

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. It is not known if Edluar will harm your unborn baby.
  • are breastfeeding or plan to breastfeed. Edluar can pass into your breast milk. It is not known if Edluar will harm your baby. 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?

  • See “What is the most important information I should know about 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.

What are the possible side effects of Edluar?

Edluar may cause serious side effects, including:

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

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

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 to www.meda.us or call Meda Pharmaceuticals Inc. at 1-866-444-7799

What are the ingredients in Edluar?

Active Ingredient: zolpidem tartrate

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

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

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

Distributed by:
Meda Pharmaceuticals
Meda Pharmaceuticals Inc.
Somerset, NJ 08873-4120

©2014 Meda Pharmaceuticals Inc. U.S. Patents 6,761,910; 8,512,747;

MEDA PHARMACEUTICALS is a registered trademark of Meda AB. EDLUAR is a registered trademark of Meda Pharmaceuticals Inc.

IG-6010-05 Rev. 10/2014

Package Label — Principal Display Panel – 30-Count Trade Carton for 5 mg Tablet

Rx Only NDC 0037-6050-30
EDLUAR™ 5 mg CIV
Zolpidem Tartrate Sublingual Tablets
Each sublingual tablet (to be placed under the tongue) contains 5 mg
of zolpidem tartrate. See prescribing information for dosage information.
30 Sublingual Tablets
Federal Law requires dispensing of EDLUAR with the Medication Guide enclosed
MEDA Pharmaceuticals®

30-Count Trade Carton for 5 mg Tablet
(click image for full-size original)

Package Label — Principal Display Panel – 30-Count Trade Carton for 10 mg Tablet

Rx Only NDC 0037-6010-30
EDLUAR™ 10 mg CIV
Zolpidem Tartrate Sublingual Tablets
Each sublingual tablet (to be placed under the tongue) contains 10 mg
of zolpidem tartrate. See prescribing information for dosage information.
30 Sublingual Tablets
Federal Law requires dispensing of EDLUAR with the Medication Guide enclosed
MEDA Pharmaceuticals®

30-Count Trade Carton for 10 mg Tablet
(click image for full-size original)
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 (ZOLPIDEM) ZOLPIDEM TARTRATE 5 mg
Product Characteristics
Color WHITE Score no score
Shape ROUND Size 8mm
Flavor Imprint Code V
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0037-6050-30 3 BLISTER PACK in 1 CARTON contains a BLISTER PACK
1 10 TABLET in 1 BLISTER PACK This package is contained within the CARTON (0037-6050-30)
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 (ZOLPIDEM) ZOLPIDEM TARTRATE 10 mg
Product Characteristics
Color WHITE Score no score
Shape ROUND Size 8mm
Flavor Imprint Code X
Contains
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:0037-6010-30 3 BLISTER PACK in 1 CARTON contains a BLISTER PACK
1 10 TABLET in 1 BLISTER PACK This package is contained within the CARTON (0037-6010-30)
2 NDC:0037-6010-02 20 BLISTER PACK in 1 BOX, UNIT-DOSE contains a BLISTER PACK
2 2 TABLET in 1 BLISTER PACK This package is contained within the BOX, UNIT-DOSE (0037-6010-02)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA021997 07/24/2009
Labeler — Meda Pharmaceuticals Inc. (051229602)

Revised: 10/2014 Meda Pharmaceuticals Inc.

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