sult in profound sedation, respiratory depression, coma, and death. because of these risks, reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioids alone. if a decision is made to prescribe doral concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use, and follow patients closely for signs and symptoms of respiratory depression and sedation. in patients already receiving an opioid analgesic, prescribe a lower initial dose of doral than indicated in the absence of an opioid and titrate based on clinical response. if an opioid is initiated in a patient already taking doral, prescribe a lower initial dose of the opioid and titrate based upon clinical response. advise both patients and caregivers about the risks of respiratory depression and sedation when doral is used with opioids. advise patients not to drive or operate heavy machinery until the effects of concomitant use with the opioid have been determined. [see drug interactions ( 7 )] . 5.2 abuse, misuse, and addiction the use of benzodiazepines, including doral, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see drug abuse and dependence ( 9.2 )] . before prescribing doral and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction (e.g., using a standardized screening tool). use of doral, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of doral along with monitoring for signs and symptoms of abuse, misuse, and addiction. prescribe the lowest effective dosage; avoid or minimize concomitant use of cns depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. if a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 dependence and withdrawal reactions to reduce the risk of withdrawal reactions, use a gradual taper to discontinue doral or reduce the dosage (a patient-specific plan should be used to taper the dose) [see dosage and administration ( 2.3 )] . patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. acute withdrawal reactions the continued use of benzodiazepines, including doral, may lead to clinically significant physical dependence. abrupt discontinuation or rapid dosage reduction of doral after continued use, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see drug abuse and dependence ( 9.3 )] . protracted withdrawal syndrome in some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see drug abuse and dependence ( 9.3 )] . 5.4 cns-depressant effects and daytime impairment doral is a central nervous system (cns) depressant and can impair daytime function in some patients even when used as prescribed. prescribers should monitor for excess depressant effects, but impairment can occur in the absence of subjective symptoms, and may not be reliably detected by ordinary clinical exam (i.e. less than formal psychomotor testing). while pharmacodynamics tolerance or adaptation to some adverse depressant effects of doral may develop, patients using doral should be cautioned against driving or engaging in other hazardous activities or activities requiring complete mental alertness. additive effects occur with concomitant use of other cns depressants (e.g., other benzodiazepines, opioids, tricyclic antidepressants, alcohol), including daytime use. downward dose adjustment of doral and concomitant cns depressants should be considered. the potential for adverse drug interactions continues for several days following discontinuation of doral, until serum levels of both active parent drug and psychoactive metabolites decline. use of doral with other sedative-hypnotics is not recommended. alcohol generally should not be used during treatment with doral. the risk of next-day psychomotor impairment is increased if doral is taken with less than a full night of sleep remaining (7 to 8 hours); if higher than the recommended dose is taken; if co-administered with other cns depressants [see dosage and administration ( 2.1 )] . because doral can cause drowsiness and a decreased level of consciousness, patients particularly the elderly, are at higher risk of falls. 5.5 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. 5.6 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 doral. 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 tongue, glottis or larynx, airway obstruction may occur and be fatal. patients who develop angioedema after treatment with doral should not be rechallenged with the drug. 5.7 abnormal thinking and behavior changes abnormal thinking and behavior changes have been reported in patients treated with sedative-hypnotics including doral. some of these changes include decreased inhibition (e.g., aggressiveness and extroversion that seemed out of character), bizarre behavior, and depersonalization. visual and auditory hallucinations have also been reported. amnesia, and other neuro-psychiatric symptoms may occur. paradoxical reactions such as stimulation, agitation, increased muscle spasticity, and sleep disturbances may occur unpredictably. complex behaviors such as "sleep-driving" (i.e., driving while not fully awake, with amnesia for the event) have been reported with use of sedative-hypnotics. these behaviors can occur with initial treatment or in patients previously tolerant of doral or other sedative-hypnotics. although these behaviors can occur with use at therapeutic doses, risk is increased by higher doses or concomitant use of alcohol or other cns depressants. due to risk to the patient and community, doral should be discontinued if "sleep-driving" occurs. 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. 5.8 worsening of depression benzodiazepines may worsen depression. consequently, appropriate precautions (e.g., limiting the total prescription size and increased monitoring for suicidal ideation) should be considered. 5.9 neonatal sedation and withdrawal syndrome use of doral late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate [see use in specific populations ( 8.1 )] . monitor neonates exposed to doral during pregnancy or labor for signs of sedation and monitor neonates exposed to doral during pregnancy for signs of withdrawal; manage these infants accordingly.

e dosage more slowly [see warnings and precautions ( 5.3 ) and drug abuse and dependence ( 9.3 )] .

er 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 table shows adverse reactions occurring at an incidence of 1% or greater in relatively short-duration, placebo-controlled clinical trials of doral. doral 15 mg placebo number of patients 267 268 % of patients reporting central nervous system daytime drowsiness 12 3 headache 5 2 fatigue 2 0 dizziness 2 <1 autonomic nervous system dry mouth 2 <1 gastrointestinal system dyspepsia 1 <1 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 well tolerated. caution must be used in interpreting this data due to the small size of the study.

defect, loss, or other adverse outcomes. in the u.s. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. monitor neonates exposed to doral during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. monitor neonates exposed to doral during pregnancy for signs of withdrawal. manage these neonates accordingly [see warnings and precautions ( 5.9 )] . data human data published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. in addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. animal data developmental toxicity studies of doral in mice at doses up to 400 times the human dose (15 mg) revealed no major drug-related malformations. minor fetal skeletal variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses approximately 70 and 400 times the human dose. a developmental toxicity study of doral in new zealand rabbits at doses up to approximately 130 times the human dose demonstrated no effect on fetal morphology or development of offspring. 8.3 nursing mothers risk summary quazepam and its metabolites are present in breast milk. there are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. the effects of quazepam on milk production are unknown. the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for doral and any potential adverse effects on the breastfed infant from doral or from the underlying maternal condition. clinical considerations infants exposed to doral through breast milk should be monitored for sedation, poor feeding and poor weight gain. 8.4 pediatric use safety and effectiveness in pediatric patients have not been established. 8.5 geriatric use doral may cause confusion and over-sedation in the elderly. elderly patients generally should be started on a low dose of doral and observed closely. elderly and debilitated patients may be more sensitive to benzodiazepines, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. a double-blind controlled sleep laboratory study (n=30) 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 well tolerated. caution must be used in interpreting this data due to the small size of the study.

outcomes. in the u.s. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. clinical considerations fetal/neonatal adverse reactions benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. monitor neonates exposed to doral during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. monitor neonates exposed to doral during pregnancy for signs of withdrawal. manage these neonates accordingly [see warnings and precautions ( 5.9 )] . data human data published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. in addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. animal data developmental toxicity studies of doral in mice at doses up to 400 times the human dose (15 mg) revealed no major drug-related malformations. minor fetal skeletal variations that occurred were delayed ossification of the sternum, vertebrae, distal phalanges and supraoccipital bones, at doses approximately 70 and 400 times the human dose. a developmental toxicity study of doral in new zealand rabbits at doses up to approximately 130 times the human dose demonstrated no effect on fetal morphology or development of offspring.

eces 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.

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.

ontrolled 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.

2 )] . withdrawal reactions inform patients that the continued use of doral may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of doral may precipitate acute withdrawal reactions, which can be life-threatening. inform patients that in some cases, patients have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. instruct patients that discontinuation or dosage reduction of doral may require a slow taper [see warnings and precautions ( 5.3 ) and drug abuse and dependence ( 9.3 )] . 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 [see warnings and precautions ( 5.4 )] 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 [see warnings and precautions ( 5.6 )] . 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 [see warnings and precautions ( 5.7 )] . suicide tell patients that doral can worsen depression, and to immediately report any suicidal thoughts [see warnings and precautions ( 5.8 )] . 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 advise pregnant females that use of doral late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in newborns [see warnings and precautions ( 5.9 ), use in specific populations ( 8.1 )] . instruct patients to inform their healthcare provider if they are pregnant. advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to doral during pregnancy [see use in specific populations ( 8.1 )] . nursing instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. instruct breastfeeding patients using doral to monitor infants for excessive sedation, poor feeding and poor weight gain, and to seek medical attention if they notice these signs [see use in specific populations ( 8.3 )] . galt pharmaceuticals, llc. atlanta, ga 30339 printed in usa. 500494-12 rev. 01/2023