DORAL (Page 3 of 4)

11 DESCRIPTION

DORAL contains quazepam, a trifluoroethyl benzodiazepine hypnotic agent, having the chemical name 7-chloro-5- (o-fluoro-phenyl)-1,3-dihydro-1-(2,2,2- trifluoroethyl)-2H-1,4-benzodiazepine-2-thione and the following structural

structural formula

Quazepam has the empirical formula C 17 H 11 ClF 4 N 2 S, and a molecular weight of 386.8. It is a white crystalline compound, soluble in ethanol and insoluble in water.

Each DORAL Tablet contains 15 mg of quazepam. The inactive ingredients for DORAL Tablets include cellulose, corn starch, FD&C Yellow No. 6, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

DORAL, like other central nervous system agents of the 14-benzodiazepine class, presumably exerts its effects by binding to stereo-specific receptors at several sites within the central nervous system (CNS). The exact mechanism of action is unknown.

12.3 Pharmacokinetics

Absorption

DORAL is rapidly (absorption half-life of about 30 minutes) and well absorbed from the gastrointestinal tract. The peak plasma concentration of quazepam is approximately 20 ng/mL after a 15 mg dose and occurs at about 2 hours.

Metabolism

Quazepam, the active parent compound, is extensively metabolized in the liver; two of the plasma metabolites are 2-oxoquazepam and N-desalkyl-2-oxoquazepam. All three compounds show CNS depressant activity.

Distribution

The degree of plasma protein binding for quazepam and its two major metabolites is greater than 95%.

Elimination

Following administration of 14C-quazepam, 31% of the dose appeared in the urine and 23% in the feces over five days; only trace amounts of unchanged drug were present in the urine.

The mean elimination half-life of quazepam and 2-oxoquazepam is 39 hours and that of N-desalkyl-2-oxoquazepam is 73 hours. Steady-state levels of quazepam and 2-oxoquazepam are attained by the seventh daily dose and that of N-desalkyl-2-oxoquazepam by the thirteenth daily dose.

Special Populations

Geriatrics: The pharmacokinetics of quazepam and 2-oxoquazepam in geriatric subjects are comparable to those seen in young adults; as with desalkyl metabolites of other benzodiazepines, the elimination half-life of N-desalkyl-2-oxoquazepam in geriatric patients is about twice that of young adults.

Drug Interactions

Bupropion (a CYP2B6 substrate): Co-administration of a single dose of 150 mg Bupropion Hydrochloride XL with steady state quazepam did not significantly affect the AUC and Cmax of bupropion or its primary metabolite, hydroxybupropion.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

DORAL showed no evidence of carcinogenicity in oral carcinogenicity studies in mice and hamsters.

Mutagenesis

DORAL was negative in the bacterial reverse mutation (Ames) assay and equivocal in the mouse lymphoma tk assay.

Impairment of Fertility

Reproduction studies in mice conducted with DORAL at doses equal to 60 and

180 times the human dose of 15 mg produced slight reductions in fertility rate. Similar reductions in fertility rate have been reported in mice dosed with other benzodiazepines, and is believed to be related to the sedative effects of these drugs at high doses

14 CLINICAL STUDIES

The effectiveness of DORAL was established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL was established in chronic insomnia in a sleep laboratory (polysomnographic) study of 28 nights duration. In the sleep laboratory study, DORAL significantly decreased sleep latency and total wake time, and significantly increased total sleep time and percent sleep time, for one or more nights.

DORAL 15 mg was effective on the first night of administration. Sleep latency, total wake time and wake time after sleep onset were still decreased and percent sleep time was still increased for several nights after the drug was discontinued. Percent slow wave sleep was decreased, and REM sleep was essentially unchanged. No transient sleep disturbance, such as “rebound insomnia,” was observed after withdrawal of the drug in sleep laboratory studies in 12 patients using 15 mg doses.

A double-blind, controlled sleep laboratory study (N=30) in elderly patients compared the effects of DORAL 7.5 mg and 15 mg to that of placebo over a period of 7 days. Both the 7.5 mg and 15 mg doses appeared to be effective. Caution must be used in interpreting this data due to the small size of the study.

16 HOW SUPPLIED / STORAGE AND HANDLING

DORAL Tablets, 15 mg: A capsule shaped light orange, slightly white-speckled bisected tablet debossed “15″ on one side & “DORAL” on the other side.

15 mg Bottles of 30 NDC 61825-165-30
15 mg Bottles of 100 NDC 61825-165-10

Store DORAL Tablets at controlled room temperature 20°-25°C (68°-77°F).

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling ( Medication Guide).

Inform patients and caregivers that potentially fatal additive effects may occur if DORAL is used with opioids and not to use such drugs concomitantly unless supervised by a healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7)]

Inform patients about the benefits and risks of DORAL, stressing the importance of use as directed. Assist patients in understanding the Medication Guide and instruct them to read it with each prescription refill.

CNS depressant Effects and Next-Day Impairment

Tell patients that DORAL can cause next-day impairment, even in the absence of symptoms. Caution patients against driving or engaging in other hazardous activities or activities requiring complete mental alertness when using DORAL. Tell patients that daytime impairment may persist for several days following discontinuation of DORAL. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients.

Withdrawal

Instruct patients to contact you before stopping or decreasing the dose of DORAL, because withdrawal symptoms can occur.

Abnormal thinking and behavior change

Instruct patients 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.

Severe Allergic Reactions

Inform patients that severe allergic reactions can occur from DORAL. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if these occur.

Suicide

Tell patients that DORAL can worsen depression, and to immediately report any suicidal thoughts.

Alcohol and other drugs

Ask patients about alcohol consumption, medicines they are taking now, and drugs they may be taking without a prescription. Advise patients that alcohol generally should not be used during treatment with DORAL.

Pregnancy

Instruct patients to inform you if they are nursing or pregnant, or may become pregnant while taking DORAL.

Tolerance, Abuse, and Dependence

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

Manufactured for:
Galt Pharmaceuticals, LLC.
Atlanta, GA 30339

Printed in USA. 500494-07 Rev. 10/2019

Medication Guide
DORAL (DOOR-al)
(quazepam) Tablets, C-IV

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

  • DORAL is a benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death.
  • DORAL may cause serious side effects that you may not know are happening to you. These side effects include:
    • sleepiness during the day
    • not thinking clearly
    • acting strangely, confused, or upset
    • “sleep-walking” or doing other activities when you are asleep like:
      • eating
      • talking
      • having sex
      • driving a car

Call your healthcare provider right away if you find out that you have done any of the above activities after taking DORAL.

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

What is DORAL?

  • DORAL is a prescription medicine used to treat certain types of insomnia including difficulty falling asleep, waking up often during the night, or waking up early in the morning.
  • DORAL is a federal controlled substance (C-IV) because it can be abused or lead to dependence. Keep DORAL in a safe place to prevent misuse and abuse. Selling or giving away DORAL may harm others, and is against the law. Tell your healthcare provider if you have ever abused or been dependent on alcohol, prescription medicines or street drugs.
  • It is not known if DORAL is safe and effective in children.

Do not take DORAL if you:

  • are allergic to quazepam or any of the ingredients in DORAL. See the end of this Medication Guide for a complete list of ingredients in DORAL.
  • have had an allergic reaction to other sleep medicines or sedatives such as benzodiazepines. Symptoms of a serious allergic reaction can include:
    • swelling of your face, lips, and throat that may cause difficulty breathing or swallowing
    • nausea and vomiting
  • have sleep apnea, breathing or lung problems

Before you take DORAL, tell your healthcare provider about all of your medical 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 lung disease or breathing problems
  • are pregnant or plan to become pregnant. It is not known if DORAL can harm your unborn baby.
  • are breastfeeding, or plan to breastfeed. DORAL can pass through your breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take DORAL.

Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.

Taking DORAL with certain other medicines can cause side effects or affect how well DORAL or the other medicines work.

Do not start or stop other medicines without talking to your healthcare provider.

Do not take DORAL with other medicines that can make you sleepy unless your healthcare provider tells you to.

How should I take DORAL?

  • See “What is the most important information I should know about DORAL?”
  • Take DORAL exactly as your healthcare providers tell you to take it.
  • DORAL comes in 15 mg tablets. Your healthcare provider may start your DORAL dose at 7.5 mg which is half a tablet. Talk to your healthcare provider or pharmacist about your dose schedule.
  • If you take too much DORAL or overdose, get emergency treatment right away.

What should I avoid while taking DORAL?

  • Do not drive, operate machinery, do other dangerous activities or do anything that needs you to be alert until you know how DORAL affects you. You may still feel drowsy the next day after taking DORAL.
  • You should not drink alcohol while you are taking DORAL.

What are the possible side effects of DORAL?

DORAL may cause serious side effects, including:

  • See “What is the most important information I should know about DORAL?”
  • Withdrawal symptoms. You may have withdrawal symptoms if you stop taking DORAL suddenly. Withdrawal symptoms can be serious and include seizures. Mild withdrawal symptoms include a depressed mood and trouble sleeping. Talk to your healthcare provider about slowly stopping DORAL to avoid withdrawal symptoms.
  • Other conditions. 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.
  • Severe allergic reactions. Symptoms include swelling of the tongue or throat, and trouble breathing. Other symptoms may include nausea and vomiting. Get emergency medical help right away if you have these symptoms after taking DORAL.
  • Abnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts.
  • Depression. Pre-existing depression may emerge or worsen during use of benzodiazepines including DORAL.
  • Abuse and dependence. Taking DORAL can cause physical and psychological dependence. Physical and psychological dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical and psychological dependence and drug addiction.

Call your healthcare provider right away if you have any of the above side effects while taking DORAL. The most common side effects of DORAL include:

  • drowsiness
  • headache
  • feeling very tired
  • dizziness
  • dry mouth
  • upset stomach

After you stop taking a sleep medicine, you may have symptoms for the next 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 possible side effects of DORAL. 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 DORAL?

  • Store at room temperature between 68°F to 77°F (20°C to 25°C).
  • Keep DORAL and all medicines out of the reach of children.

General information about the safe and effective use of Doral.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use DORAL for a condition for which it was not prescribed. Do not give DORAL to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about DORAL that is written for healthcare professionals.

What are the ingredients in DORAL?

Active Ingredient: quazepam

Inactive Ingredients: cellulose, corn starch, FD&C Yellow No.6, lactose, magnesium stearate, silicon dioxide, and sodium lauryl sulfate

Distributed by Galt Pharmaceuticals, Atlanta, GA 30339 USA. If you would like more information, call Galt Pharmaceuticals at 1-855-965-2783 or visit www.doralrx.com.

This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: 04/2019

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