FDA label 72d1f4e7-4c1a-430e-ad24-f2daf0fd4721

WARNINGS 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. Because some of the important adverse effects of sedative-hypnotics appear to be dose related (see Precautions and Dosage and Administration), it is important to use the smallest possible effective dose, especially in the elderly. Complex behaviors such as "sleep-driving" (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported. These events can occur in sedative-hypnotic-naive as well as in sedative-hypnotic-experienced persons. Although behaviors such as sleep-driving may occur with sedative-hypnotics alone at therapeutic doses, the use of alcohol and other CNS depressants with sedative-hypnotics appears to increase the risk of such behaviors, as does the use of sedative-hypnotics at doses exceeding the maximum recommended dose. Due to the risk to the patient and the community, discontinuation of sedative-hypnotics should be strongly considered for patients who report a "sleep-driving" episode. 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. 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. Patients receiving benzodiazepines should be cautioned about possible combined effects with alcohol and other CNS depressants. Also, caution patients that an additive effect may occur if alcoholic beverages are consumed during the day following the use of benzodiazepines for nighttime sedation. The potential for this interaction continues for several days following their discontinuance until serum levels of psychoactive metabolites have declined. Patients should also be cautioned about engaging in hazardous occupations requiring complete mental alertness, such as operating machinery or driving a motor vehicle, after ingesting benzodiazepines, including potential impairment of the performance of such activities which may occur the day following ingestion. Withdrawal symptoms of the type associated with sedatives/hypnotics (e.g., barbiturates, bromides, etc.) and alcohol have been reported after the discontinuation of benzodiazepines. While these symptoms have been more frequently reported after the discontinuation of excessive benzodiazepine doses, there have also been controlled studies demonstrating the occurrence of such symptoms after discontinuation of therapeutic doses of benzodiazepines, generally following prolonged use (but in some instances after periods as brief as 6 weeks). It is generally believed that the gradual reduction of dosage will diminish the occurrence of such symptoms (see DRUG ABUSE AND DEPENDENCE).

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Questcor Pharmaceuticals, Inc. at 1-800-465-9217 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Adverse events most frequently encountered in patients treated with quazepam are drowsiness and headache. Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. Consequently, the table below is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of quazepam. The figures cited cannot be used to predict precisely the incidence of such events in the course of usual medical practice. These figures, also, cannot be compared with those obtained from other clinical studies involving related drug products and placebo. The figures cited below are estimates of untoward clinical event incidences of 1% or greater among subjects who participated in the relatively short-duration, placebo-controlled clinical trials of quazepam. DORAL * PLACEBO NUMBER OF PATIENTS 267 268 % OF PATIENTS REPORTING Central Nervous System Daytime Drowsiness 12.0 3.3 Headache 4.5 2.2 Fatigue 1.9 0 Dizziness 1.5 <1 Autonomic neervous System Dry Mouth 1.5 <1 Gastrointestinal System Dyspepsia 1.1 <1 * DORAL 15 mg The following incidences of laboratory abnormalities occurred at a rate of 1% or greater in patients receiving quazepam and the corresponding placebo group. None of these changes were considered to be of physiological significance. DORAL PLACEBO NUMBER OF PATIENTS 234 244 % OF PATIENTS REPORTING Low High Low High Hematology Hemoglobin 1.4 0. 1.2 0 Hematocrit 1.5 0 1.7 0 Lymphocyte 1.3 1.6 1.2 1.9 Eosinophil * 1.5 * 1.3 SEG 1.1 * 1.6 * Monocyte * 1.1 * * Blood Chemistry Glucose * * * 1.2 SGOT * 1.3 * 1.1 Urinalysis Specific Gravity * * * 1.1 WBC 0 2.6 0 3.0 RBC 0 * 0 1.1 Epithelial Cells 0 2.5 0 3.2 Crystals 0 * 0 1.0 * These laboratory abnormalities occured in less than 1% of patients. In addition abnormalities in the following laboratory tests were observed in less than 1% of the patients evaluated: WBC count, total protein, albumin, BUN, creatinine, total bilirubin, alkaline phosphatase, and SGPT. The following additional events occurred among individuals receiving quazepam at doses equivalent to or greater than those recommended during its clinical testing and development. There is no way to establish whether or not the administration of DORAL® caused these events. Hypokinesia, ataxia, confusion, incoordination, hyperkinesia, speech disorder, and tremor were reported. Also, depression, nervousness, agitation, amnesia, anorexia, anxiety, apathy, euphoria, impotence, decreased libido, paranoid reaction, nightmares, abnormal thinking, abnormal taste perception, abnormal vision, and cataract were reported. Also reported were urinary incontinence, palpitations, nausea, constipation, diarrhea, abdominal pain, pruritus, rash, asthenia, and malaise. The following list provides an overview of adverse experiences that have been reported and are considered to be reasonably related to the administration of benzodiazepines: incontinence, slurred speech, urinary retention, jaundice, dysarthria, dystonia, changes in libido, irritability, and menstrual irregularities. As with all benzodiazepines, paradoxical reactions such as stimulation, agitation, increased muscle spasticity, sleep disturbances, hallucinations, and other adverse behavioral effects may occur in rare instances and in a random fashion. Should these occur, use of the drug should be discontinued. There have been reports of withdrawal signs and symptoms of the type associated with withdrawal from CNS depressant drugs following the rapid decrease or the abrupt discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE). DRUG ABUSE AND DEPENDENCE Controlled Substance: DORAL® is a controlled substance under the Controlled Substances Act and has been assigned by the Drug Enforcement Administration to Schedule IV. Abuse and Dependence: Abuse and addiction are separate and distinct from physical dependence and tolerance. Abuse is characterized by misuse of the drug for non-medical purposes, often in combination with other psychoactive substances. Physical dependence is a state of adaptation that is manifested by a specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug and/or administration of an antagonist. Tolerance is a state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time. Tolerance may occur to both the desired and undesired effects of drugs and may develop at different rates for different effects. Addiction is a primary, chronic, neurobiological disease with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Drug addiction is a treatable disease, utilizing a multidisciplinary approach, but relapse is common. Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (e.g., convulsions, tremor, abdominal and muscle cramps, vomiting, and sweating), have occurred following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. Addiction-prone individuals (such as drug addicts or alcoholics) should be under careful surveillance when receiving quazepam or other psychotropic agents because of the predisposition of such patients to habituation and dependence.

<table width="60%" ID="i93891b67-6b6e-42ed-8797-8a7fe3d9dde5"> <tbody> <tr> <td> </td> <td>DORAL * </td> <td>PLACEBO </td> </tr> <tr> <td>NUMBER OF PATIENTS </td> <td>267 </td> <td>268 </td> </tr> <tr> <td>% OF PATIENTS REPORTING </td> <td> </td> <td> </td> </tr> <tr> <td>Central Nervous System </td> <td> </td> <td> </td> </tr> <tr> <td> Daytime Drowsiness </td> <td>12.0 </td> <td>3.3 </td> </tr> <tr> <td> Headache </td> <td>4.5 </td> <td>2.2 </td> </tr> <tr> <td> Fatigue </td> <td>1.9 </td> <td>0 </td> </tr> <tr> <td> Dizziness </td> <td>1.5 </td> <td>&lt;1 </td> </tr> <tr> <td>Autonomic neervous System </td> <td> </td> <td> </td> </tr> <tr> <td> Dry Mouth </td> <td>1.5 </td> <td>&lt;1 </td> </tr> <tr> <td>Gastrointestinal System </td> <td> </td> <td> </td> </tr> <tr> <td> Dyspepsia </td> <td>1.1 </td> <td>&lt;1 </td> </tr> </tbody> </table>

<table width="60%" ID="ib5b050c8-a351-43b4-87bd-b3a49d4e0672"> <tbody> <tr> <td> </td> <td> </td> <td>DORAL </td> <td> </td> <td>PLACEBO </td> </tr> <tr> <td>NUMBER OF PATIENTS </td> <td> </td> <td> 234 </td> <td> </td> <td> 244 </td> </tr> <tr> <td>% OF PATIENTS REPORTING </td> <td>Low </td> <td>High </td> <td>Low </td> <td>High </td> </tr> <tr> <td> <content styleCode="underline">Hematology</content> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td> Hemoglobin </td> <td>1.4 </td> <td>0. </td> <td>1.2 </td> <td>0 </td> </tr> <tr> <td> Hematocrit </td> <td>1.5 </td> <td>0 </td> <td>1.7 </td> <td>0 </td> </tr> <tr> <td> Lymphocyte </td> <td>1.3 </td> <td>1.6 </td> <td>1.2 </td> <td>1.9 </td> </tr> <tr> <td> Eosinophil </td> <td>* </td> <td>1.5 </td> <td>* </td> <td>1.3 </td> </tr> <tr> <td> SEG </td> <td>1.1 </td> <td>* </td> <td>1.6 </td> <td>* </td> </tr> <tr> <td> Monocyte </td> <td>* </td> <td>1.1 </td> <td>* </td> <td>* </td> </tr> <tr> <td> <content styleCode="underline">Blood Chemistry</content> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td> Glucose </td> <td>* </td> <td>* </td> <td>* </td> <td>1.2 </td> </tr> <tr> <td> SGOT </td> <td>* </td> <td>1.3 </td> <td>* </td> <td>1.1 </td> </tr> <tr> <td> <content styleCode="underline">Urinalysis</content> </td> <td> </td> <td> </td> <td> </td> <td> </td> </tr> <tr> <td> Specific Gravity </td> <td>* </td> <td>* </td> <td>* </td> <td>1.1 </td> </tr> <tr> <td> WBC </td> <td>0 </td> <td>2.6 </td> <td>0 </td> <td>3.0 </td> </tr> <tr> <td> RBC </td> <td>0 </td> <td>* </td> <td>0 </td> <td>1.1 </td> </tr> <tr> <td> Epithelial Cells </td> <td>0 </td> <td>2.5 </td> <td>0 </td> <td>3.2 </td> </tr> <tr> <td> Crystals </td> <td>0 </td> <td>* </td> <td>0 </td> <td>1.0 </td> </tr> </tbody> </table>