ZOLPIDEM TARTRATE (Page 6 of 7)

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 MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m 2 body surface area and in rats, these doses are approximately 5, 20, and 100 times the MRHD based on a mg/m 2 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 MRHD of 10 mg/day (8 mg zolpidem base) based on mg/m 2 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/m 2 body surface area. The NOAEL for these effects is 25 times the MRHD based on a mg/m 2 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 (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 tablets.

14.3 Studies Pertinent to Safety Concerns for Sedative/Hypnotic Drugs

Next-Day Residual Effects

Next-day residual effects of zolpidem tartrate tablets 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 tablets 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 tablets. There was subjective evidence of impaired sleep in the elderly on the first post-treatment night at doses above the recommended elderly dose of 5 mg.

Memory Impairment

Controlled studies in adults utilizing objective measures of memory yielded no consistent evidence of next-day memory impairment following the administration of zolpidem tartrate tablets. 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 tablets, 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 tablets have 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

Zolpidem tartrate 5 mg tablets, USP are red colored, capsule shaped tablets with the Torrent logo debossed on one side and ’5 MG’ debossed on the other side and supplied as:

Carton of 100 Tablets (10 per blister pack x 10), NDC 0904-6082-61

Zolpidem tartrate 10 mg tablets, USP are peach-yellow colored, capsule shaped tablets with the Torrent logo debossed on one side and ’10 MG’ debossed on the other side and supplied as:

Carton of 100 tablets (10 per blister pack x 10), NDC 0904-6083-61

Store at 20º to 25°C (68º to 77°F); excursions permitted to 15° to 30°C (59º to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise the patients to read the FDA-approved patient labeling (Medication Guide).

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

Complex Sleep Behaviors

Instruct patients and their families that zolpidem may cause complex sleep behaviors, including sleep-walking, sleep-driving, preparing and eating food, making phone calls, or having sex while not being fully awake. Serious injuries and death have occurred during complex sleep behavior episodes. Tell patients to discontinue zolpidem and notify their healthcare provider immediately if they develop any of these symptoms [see Boxed Warning, Warnings and Precautions ( 5.1)] .

CNS-Depressant Effects and Next-Day Impairment

Tell patients that zolpidem 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. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions ( 5.2)] .

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 [see Warnings and Precautions ( 5.4)] .

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 zolpidem if they drank alcohol that evening or before bed.

Tolerance, Abuse, and Dependence

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

Administration Instructions

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

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with zolpidem tartrate tablets. Advise patients that use of zolpidem tartrate tablets late in the third trimester may cause respiratory depression and sedation in neonates. Advise mothers who used zolpidem tartrate tablets during the late third trimester of pregnancy to monitor neonates for signs of sleepiness (more than usual), breathing difficulties, or limpness [see Use in Specific Populations ( 8.1)].

Lactation

Advise breastfeeding mothers using zolpidem tartrate tablets to monitor infants for increased sleepiness, breathing difficulties, or limpness. Instruct breastfeeding mothers to seek immediate medical care if they notice these signs. A lactating woman may consider pumping and discarding breastmilk during treatment and for 23 hours after zolpidem tartrate tablets administration to minimize drug exposure to a breastfed infant [see Use in Specific Populations ( 8.2)] .

image

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured for:

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

Distributed By:

MAJOR® PHARMACEUTICALS

17177 N Laurel Park Dr., Suite 233

Livonia, MI 48152

8076676 Revised September 2019

MEDICATION GUIDE

Zolpidem Tartrate (zole-PI-dem TAR-trate) Tablets, USP C-IV

Read the Medication Guide that comes with zolpidem tartrate tablets 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 zolpidem tartrate tablets?

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

Zolpidem tartrate tablets may cause serious side effects, including:

complex sleep behaviors that have caused serious injury and death. After taking zolpidem tartrate tablets, 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 zolpidem tartrate tablets 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 zolpidem tartrate tablets and call your healthcare provider right away if you find out that you have done any of the above activities after taking zolpidem tartrate tablets.

Do not take zolpidem tartrate tablets if you:

have ever experienced a complex sleep behavior (such as driving a car, making and eating food, talking on the phone , or having sex while not being fully awake) after taking zolpidem tartrate tablets.
drank alcohol that evening or before bed
took another medicine to help you sleep

What are zolpidem tartrate tablets?

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

Zolpidem tartrate tablets are not recommended for use in children under the age of 18 years.

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

Who should not take zolpidem tartrate tablets?

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

What should I tell my healthcare provider before taking zolpidem tartrate tablets?

Zolpidem tartrate tablets may not be right for you. Before starting zolpidem tartrate tablets, 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 a lung disease or breathing problems
are pregnant, planning to become pregnant. Talk to your healthcare provider about the risk to your unborn baby if you take zolpidem tartrate tablets.
Using zolpidem tartrate tablets in the last trimester of pregnancy may cause breathing difficulties or excess sleepiness in your newborn. Monitor for signs of sleepiness (more than usual), troublebreathing, or limpness in the newborn if zolpidem tartrate tablets is taken late in pregnancy.
are breastfeeding or plan to breastfeed.

Zolpidem tartrate tablets passes into your breast milk. Talk to your healthcare provider about the best way to feed your baby while you take zolpidem tartrate tablets.

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 zolpidem tartrate tablets with other medicines that can make you sleepy unless your healthcare provider tells you to.

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 zolpidem tartrate tablets?

See “What is the most important information I should know about zolpidem tartrate tablets?”
Take zolpidem tartrate tablets exactly as prescribed. Only take 1 zolpidem tartrate tablet a night if needed.
Do not take zolpidem tartrate tablets if you drank alcohol that evening or before bed.
You should not take zolpidem tartrate tablets with or right after a meal. Zolpidem tartrate tablets may help you fall asleep faster if you take it on an empty stomach.
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 zolpidem tartrate tablets or overdose, get emergency treatment.

What are the possible side effects of zolpidem tartrate tablets?

Zolpidem tartrate tablets may cause serious side effects, including:

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

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 zolpidem tartrate tablets.

The most common side effects of zolpidem tartrate tablets are:

drowsiness
dizziness
diarrhea
grogginess or feeling as if you have been drugged

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 zolpidem tartrate tablets. Ask your healthcare provider or pharmacist for more information.

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

How should I store zolpidem tartrate tablets?

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Keep zolpidem tartrate tablets and all medicines out of reach of children.

General Information about the safe and effective use of zolpidem tartrate tablets

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use zolpidem tartrate tablets for a condition for which it was not prescribed. Do not share zolpidem tartrate tablets with other people, even if 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 zolpidem tartrate tablets. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about zolpidem tartrate tablets that are written for healthcare professionals.

For more information, call 1-800-912-9561.

What are the ingredients in zolpidem tartrate tablets?

Active Ingredient: Zolpidem tartrate, USP

Inactive Ingredients: hypromellose, lactose monohydrate, microcrystalline cellulose, magnesium stearate, polyethylene glycol, sodium starch glycolate, titanium dioxide and ferric oxide red; the 10 mg tablet also contains ferric oxide yellow.

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

Trademarks are the property of their respective owners.

Logo

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured for

TORRENT PHARMA INC., Basking Ridge, NJ 07920.

Distributed By:

MAJOR® PHARMACEUTICALS

17177 N Laurel Park Dr., Suite 233

Livonia, MI 48152

8076677 Revised September 2019

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