1 INDICATIONS AND USAGE DORAL® (quazepam) is indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. The effectiveness of DORAL has been established in placebo-controlled clinical studies of 5 nights duration in acute and chronic insomnia. The sustained effectiveness of DORAL has been established in chronic insomnia in a sleep lab (polysomnographic) study of 28 nights duration. Because insomnia is often transient and intermittent, the prolonged administration of DORAL Tablets is generally not necessary or recommended. Since insomnia may be a symptom of several other disorders, the possibility that the complaint may be related to a condition for which there is a more specific treatment should be considered. DORAL, a gamma-aminobutyric (GABAA) agonist, is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. (1)
3 D OSAGE FORMS AND STRENGTHS Tablets, 15 mg, functionally scored, capsule-shaped, light orange, slightly white speckled tablets, impressed with the product identification number 15 on one side of the tablet, and the product name (DORAL) on the other. 15 mg functionally scored tablet, oral (3)
4 CONTRA INDICATIONS DORAL is contraindicated in patients with known hypersensitivity to quazepam or other benzodiazepines. Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of DORAL. Some patients have had additional symptoms such as dyspnea, throat closing, or nausea and vomiting that suggest anaphylaxis. Patients who develop such reactions should not be rechallenged with DORAL. Contraindicated in patients with established or suspected sleep apnea, or with pulmonary insufficiency. Hypersensitivity to quazepam or other benzodiazepines (4) Established or suspected sleep apnea, or chronic pulmonary insufficiency (4)
5 WARNINGS AND PRECAUTIONS CNS depressant effects: Impaired alertness and motor coordination, including risk of daytime impairment. Caution patients against driving and other activities requiring complete mental alertness (5.1) Benzodiazepine withdrawal syndrome: avoid abrupt discontinuation in at-risk patients (5.2) 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. (5.3) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.4) Sleep driving and other complex behaviors while not fully awake. Risk increases with dose and concomitant CNS depressants and alcohol. Immediately evaluate any new onset behavioral changes (5.5) Worsening of depression or suicidal thinking may occur: Prescribe the least number of tablets feasible to avoid intentional overdose (5.6) 5.1 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 pharmacodynamic 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)]. 5.2 Ben zodiazepine Withdrawal Syndrome A withdrawal syndrome similar to that from alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating) can occur following abrupt discontinuation of DORAL. The more severe withdrawal effects are usually limited to patients taking higher than recommended doses over an extended time. Abrupt discontinuation should be avoided in such patients, and the dose gradually tapered. Prescribers should monitor patients for tolerance, abuse, and dependence. Milder withdrawal symptoms (e.g., dysphoria and insomnia) can occur following abrupt discontinuation of benzodiazepines taken at therapeutic levels for short periods [See Drug Abuse and Dependence (9)]. 5.3 Need to E valuate 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. 5.4 Severe Anaphylac tic 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. 5.5 Abnorma l 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. 5.6 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.
6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: CNS-depressant effects and next-day impairment [see Warnings and Precautions (5.1)] Benzodiazepine withdrawal syndrome [see Warnings and Precautions (5.2)] Abnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions (5.5)] Worsening of depression [see Warnings and Precautions (5.6)] Most common adverse reactions (>1%): drowsiness, headache, fatigue, dizziness, dry mouth, dyspepsia (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Cutis Health at 1-855-965-2783 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 clinical practice. The table shows adverse reactions occurring at an incidence of 1% or greater in relatively short-duration, placebo-controlled clinical trials of DORAL. 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 actual practice. 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 quazepam 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.
7 DRUG INTERACTIONS Benzodiazepines, including DORAL, produce additive CNS depressant effects when co-administered with ethanol or other CNS depressants (e.g. psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of DORAL and/or concomitant CNS depressants may be necessary because of additive effects. CNS Depressants: downward dose adjustment may be necessary due to additive effects (7)
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1) Nursing Mothers: Administration of DORAL Tablets to nursing mothers is not recommended as quazepam and its metabolites are excreted in human milk. (8.3) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Administration of benzodiazepines immediately prior to or during childbirth can result in a syndrome of hypothermia, hypotonia, respiratory depression, and difficulty feeding. In addition, infants born to mothers who have taken benzodiazepines during the later stages of pregnancy can develop dependence, and subsequently withdrawal, during the postnatal period. Although administration of quazepam to pregnant animals did not indicate a risk for adverse effects on morphological development at clinically relevant doses, data for other benzodiazepines suggest the possibility of adverse developmental effects (long-term effects on neurobehavioral and immunological function) in animals following prenatal exposure to benzodiazepines. DORAL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Developmental toxicity studies of quazepam 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 quazepam 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 Quazepam and its metabolites are excreted in human milk. Caution should be exercised when administering DORAL to a nursing woman. 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 quazepam 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.