ABUSE SECTION.

9.2 Abuse Flurazepam hydrochloride capsules are benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse may lead to addiction.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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label:oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]oCNS-depressant effects and next-day impairment [see Warnings and Precautions (5.4)]oSevere Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.6)]oAbnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions (5.7)]oWorsening of depression [see Warnings and Precautions (5.8)]. oRisks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)]. oAbuse, Misuse, and Addiction [see Warnings and Precautions (5.2)]. oDependence and Withdrawal Reactions [see Warnings and Precautions (5.3)]. oCNS-depressant effects and next-day impairment [see Warnings and Precautions (5.4)]. oSevere Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions (5.6)]. oAbnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions (5.7)]. oWorsening of depression [see Warnings and Precautions (5.8)]. Adverse reactions: dizziness, drowsiness, light-headedness, staggering, ataxia, falling. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Reported were headache, heartburn, upset stomach, nausea, vomiting, diarrhea, constipation, gastrointestinal pain, nervousness, talkativeness, apprehension, irritability, weakness, palpitations, chest pains, body and joint pains, and genitourinary complaints. There have also been rare occurrences of leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, burning eyes, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations and elevated SGOT, SGPT, total and direct bilirubin elevations, and elevated alkaline phosphatase.

BOXED WARNING SECTION.

WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. oReserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. oLimit dosages and durations to the minimum required. oFollow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].oThe use of benzodiazepines, including flurazepam hydrochloride capsules, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing flurazepam hydrochloride capsules, and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].oThe continued use of benzodiazepines, including flurazepam hydrochloride capsules, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. oReserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. oLimit dosages and durations to the minimum required. oFollow patients for signs and symptoms of respiratory depression and sedation [see Warnings and Precautions (5.1) and Drug Interactions (7.1)].. oThe use of benzodiazepines, including flurazepam hydrochloride capsules, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing flurazepam hydrochloride capsules, and throughout treatment, assess each patients risk for abuse, misuse, and addiction [see Warnings and Precautions (5.2)].. oThe continued use of benzodiazepines, including flurazepam hydrochloride capsules, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)].. WARNING: RISKS FROM CONCOMITANT USE WITH OPIOIDS; ABUSE, MISUSE, AND ADDICTION; and DEPENDENCE AND WITHDRAWAL REACTIONS See full prescribing information for complete boxed warning.oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. oReserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. oLimit dosages and durations to the minimum required. oFollow patients for signs and symptoms of respiratory depression and sedation (5.1, 7.1).oThe use of benzodiazepines, including flurazepam hydrochloride capsules, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing flurazepam hydrochloride capsules, and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2).oThe continued use of benzodiazepines, including flurazepam hydrochloride capsules, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage (2.3, 5.3).. oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. oReserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. oLimit dosages and durations to the minimum required. oFollow patients for signs and symptoms of respiratory depression and sedation (5.1, 7.1).. oThe use of benzodiazepines, including flurazepam hydrochloride capsules, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes. Before prescribing flurazepam hydrochloride capsules, and throughout treatment, assess each patients risk for abuse, misuse, and addiction (5.2).. oThe continued use of benzodiazepines, including flurazepam hydrochloride capsules, may lead to clinically significant physical dependence. The risks of dependence and withdrawal increase with longer treatment duration and higher daily dose. Abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage (2.3, 5.3).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS Flurazepam Hydrochloride Capsules, USP are available containing either 15 mg or 30 mg of flurazepam hydrochloride, USP.oThe 15 mg capsule is hard-shell gelatin capsule with white opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4415 in black ink on both the cap and body.oThe 30 mg capsule is hard-shell gelatin capsule with powder blue opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4430 in black ink on both the cap and body.. oThe 15 mg capsule is hard-shell gelatin capsule with white opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4415 in black ink on both the cap and body.. oThe 30 mg capsule is hard-shell gelatin capsule with powder blue opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4430 in black ink on both the cap and body.. o15 mg and 30 mg capsules. (3). o15 mg and 30 mg capsules. (3).

DRUG ABUSE AND DEPENDENCE SECTION.

9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance Flurazepam is Schedule IV controlled substance.. 9.2 Abuse Flurazepam hydrochloride capsules are benzodiazepine and CNS depressant with potential for abuse and addiction. Abuse is the intentional, non-therapeutic use of drug, even once, for its desirable psychological or physiological effects. Misuse is the intentional use, for therapeutic purposes, of drug by an individual in way other than prescribed by health care provider or for whom it was not prescribed. Drug addiction is cluster of behavioral, cognitive, and physiological phenomena that may include strong desire to take the drug, difficulties in controlling drug use (e.g., continuing drug use despite harmful consequences, giving higher priority to drug use than other activities and obligations), and possible tolerance or physical dependence. Even taking benzodiazepines as prescribed may put patients at risk for abuse and misuse of their medication. Abuse and misuse may lead to addiction.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. Benzodiazepines are often sought by individuals who abuse drugs and other substances, and by individuals with addictive disorders [see Warnings and Precautions (5.2)].The following adverse reactions have occurred with benzodiazepine abuse and/or misuse: abdominal pain, amnesia, anorexia, anxiety, aggression, ataxia, blurred vision, confusion, depression, disinhibition, disorientation, dizziness, euphoria, impaired concentration and memory, indigestion, irritability, muscle pain, slurred speech, tremors, and vertigo.The following severe adverse reactions have occurred with benzodiazepine abuse and/or misuse: delirium, paranoia, suicidal ideation and behavior, seizures, coma, breathing difficulty, and death. Death is more often associated with polysubstance use (especially benzodiazepines with other CNS depressants such as opioids and alcohol). 9.3 Dependence Physical Dependence. Flurazepam hydrochloride capsules may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.. Tolerance. Tolerance to flurazepam hydrochloride capsules may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of flurazepam hydrochloride capsules may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Flurazepam, like other central nervous system agents of the 1,4-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 Flurazepam hydrochloride is rapidly absorbed from the gastro-intestinal tract. Flurazepam is rapidly metabolized and is excreted primarily in the urine. Following single oral dose, peak flurazepam plasma concentrations ranging from 0.5 to 4.0 ng/mL occur at 30 to 60 minutes post-dosing. The harmonic mean apparent half-life of flurazepam is 2.3 hours. The blood level profile of flurazepam and its major metabolites was determined in man following the oral administration of 30 mg daily for weeks. The N1-hydroxyethyl-flurazepam was measurable only during the early hours after 30 mg dose and was not detectable after 24 hours. The major metabolite in blood was N1-desalkyl-flurazepam, which reached steady-state (plateau) levels after to 10 days of dosing, at levels approximately 5- to 6-fold greater than the 24-hour levels observed on Day 1. The half-life of elimination of N1-desalkyl-flurazepam ranged from 47 to 100 hours. The major urinary metabolite is conjugated N1-hydroxyethyl-flurazepam which accounts for 22% to 55% of the dose. Less than 1% of the dose is excreted in the urine as N1-desalkyl-flurazepam.This pharmacokinetic profile may be responsible for the clinical observation that flurazepam is increasingly effective on the second or third night of consecutive use and that for or nights after the drug is discontinued both sleep latency and total wake time may still be decreased.The single dose pharmacokinetics of flurazepam were studied in 12 healthy geriatric subjects (aged 61 to 85 years). The mean elimination half-life of desalkyl-flurazepam was longer in elderly male subjects (160 hours) compared with younger male subjects (74 hours), while mean elimination half-life was similar in geriatric female subjects (120 hours) and younger female subjects (90 hours). After multiple dosing, mean steady-state plasma levels of desalkyl-flurazepam were higher in elderly male subjects (81 ng/mL) compared with younger male subjects (53 ng/mL), while values were similar between elderly female subjects (85 ng/mL) and younger female subjects (86 ng/mL). The mean washout half-life of desalkyl-flurazepam was longer in elderly male and female subjects (126 and 158 hours, respectively) compared with younger male and female subjects (111 and 113 hours, respectively).1 Greenblatt DJ, Divoll M, Hammatz JS, MacLauglin DS, Shader RI: Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs. Clin Pharmacol Ther 30:475-486, 1981.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES Sleep laboratory studies have objectively determined that flurazepam hydrochloride capsules are effective for at least 28 consecutive nights of drug administration.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS Flurazepam hydrochloride capsules are contraindicated in patients with known hypersensitivity to flurazepam 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 flurazepam. 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 flurazepam.. oPregnancy (4)oHypersensitivity to flurazepam or other benzodiazepines. (4). oPregnancy (4). oHypersensitivity to flurazepam or other benzodiazepines. (4).

CONTROLLED SUBSTANCE SECTION.

9.1 Controlled Substance Flurazepam is Schedule IV controlled substance.

DEPENDENCE SECTION.

9.3 Dependence Physical Dependence. Flurazepam hydrochloride capsules may produce physical dependence from continued therapy. Physical dependence is state that develops as result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or significant dose reduction of drug. Abrupt discontinuation or rapid dosage reduction of benzodiazepines or administration of flumazenil, benzodiazepine antagonist, may precipitate acute withdrawal reactions, including seizures, which can be life-threatening. Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages (i.e., higher and/or more frequent doses) and those who have had longer durations of use [see Warnings and Precautions (5.3)]. To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage [see Dosage and Administration (2.3) and Warnings and Precautions (5.3)]. Acute Withdrawal Signs and Symptoms Acute withdrawal signs and symptoms associated with benzodiazepines have included abnormal involuntary movements, anxiety, blurred vision, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe acute withdrawal signs and symptoms, including life-threatening reactions, have included catatonia, convulsions, delirium tremens, depression, hallucinations, mania, psychosis, seizures, and suicidality. Protracted Withdrawal Syndrome Protracted withdrawal syndrome associated with benzodiazepines is characterized by anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that persists beyond to weeks after initial benzodiazepine withdrawal. Protracted withdrawal symptoms may last weeks to more than 12 months. As result, there may be difficulty in differentiating withdrawal symptoms from potential re-emergence or continuation of symptoms for which the benzodiazepine was being used.. Tolerance. Tolerance to flurazepam hydrochloride capsules may develop from continued therapy. Tolerance is physiological state characterized by reduced response to drug after repeated administration (i.e., higher dose of drug is required to produce the same effect that was once obtained at lower dose). Tolerance to the therapeutic effect of flurazepam hydrochloride capsules may develop; however, little tolerance develops to the amnestic reactions and other cognitive impairments caused by benzodiazepines.

DESCRIPTION SECTION.

11 DESCRIPTION Flurazepam hydrochloride is chemically 7-chloro-1-[2-(diethylamino)ethyl]-5-(o-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one dihydrochloride. It is pale yellow, crystalline compound, freely soluble in alcohol and very soluble in water. It has molecular weight of 460.81 and the following structural formula:Each capsule for oral administration contains either 15 mg or 30 mg of flurazepam hydrochloride, USP and the following inactive ingredients: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 3, gelatin, magnesium stearate, microcrystalline cellulose, powdered cellulose, sodium lauryl sulfate and titanium dioxide. The imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.. Flurazepam Hydrochloride Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oUse the lowest dose effective for the patient.oRecommended initial dose is 15 mg for women and 15 mg or 30 mg for men. (2.1)oElderly or debilitated patients: recommended dose is 15 mg. (2.2). oUse the lowest dose effective for the patient.. oRecommended initial dose is 15 mg for women and 15 mg or 30 mg for men. (2.1). oElderly or debilitated patients: recommended dose is 15 mg. (2.2). 2.1 Dosage in Adults Use the lowest dose effective for the patient, as important adverse effects of flurazepam hydrochloride capsules are dose related.The recommended initial dose is 15 mg for women and either 15 mg or 30 mg for men. The 15 mg dose can be increased to 30 mg if necessary for efficacy.The recommended initial doses for women and men are different because flurazepam clearance is lower in women [see Pharmacokinetics (12.3)]. 2.2 Dosage in Elderly or Debilitated Patients Elderly or debilitated patients may be especially sensitive to flurazepam. Since the risk of the development of oversedation, dizziness, confusion and/or ataxia increases substantially with larger doses in elderly or debilitated patients, it is recommended that in such patients the dosage be limited to 15 mg. Staggering and falling have also been reported, particularly in geriatric patients [see Warnings and Precautions (5.2)]. 2.3Discontinuation or Dosage Reduction of Flurazepam Hydrochloride Capsules To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage. If patient develops withdrawal reactions, consider pausing the taper or increasing the dosage to the previous tapered dosage level. Subsequently decrease the dosage more slowly [see Warnings and Precautions (5.3) and Drug Abuse and Dependence (9.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, and death. (7.1)oCNS Depressants: Downward dose adjustment may be necessary due to additive effects. (7.2). oConcomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, and death. (7.1). oCNS Depressants: Downward dose adjustment may be necessary due to additive effects. (7.2). 7.1Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABAA sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists. Limit dosage and duration of concomitant use of benzodiazepines and opioids, and follow patients closely for respiratory depression and sedation.. 7.2CNS Depressants Benzodiazepines, including flurazepam, produce additive CNS depressant effects when co-administered with ethanol or other CNS depressants (e.g., psychotropic medications, anticonvulsants, antihistamines). Downward dose adjustment of flurazepam and/or concomitant CNS depressants may be necessary because of additive effects.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Flurazepam Hydrochloride Capsules, USP are available containing either 15 mg or 30 mg of flurazepam hydrochloride, USP.The 15 mg capsule is hard-shell gelatin capsule with white opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4415 in black ink on both the cap and body. They are available as follows:NDC 0378-4415-01bottles of 100 capsulesThe 30 mg capsule is hard-shell gelatin capsule with powder blue opaque cap and powder blue opaque body filled with off-white to yellow powder. The capsule is axially printed with MYLAN over 4430 in black ink on both the cap and body. They are available as follows:NDC 0378-4430-01bottles of 100 capsulesStore at 20 to 25C (68 to 77F). [See USP Controlled Room Temperature.]Protect from light.Dispense in tight, light-resistant container as defined in the USP using child-resistant closure.PHARMACIST: Dispense Medication Guide with each prescription.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Flurazepam hydrochloride capsules are indicated for the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings [see Clinical Studies (14)]. Since insomnia is often transient and intermittent, short-term use is usually sufficient. Prolonged use of hypnotics is usually not indicated and should only be undertaken concomitantly with appropriate evaluation of the patient.. Flurazepam, 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).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Risks from Concomitant Use with Opioids: Advise both patients and caregivers about the risks of potentially fatal respiratory depression and sedation when flurazepam hydrochloride capsules are used with opioids and not to use such drugs concomitantly unless supervised by healthcare provider [see Warnings and Precautions (5.1), Drug Interactions (7.1)]. Abuse, Misuse, and Addiction: Inform patients that the use of flurazepam hydrochloride capsules, even at recommended dosages, exposes users to risks of abuse, misuse, and addiction, which can lead to overdose and death, especially when used in combination with other medications (e.g., opioid analgesics), alcohol, and/or illicit substances. Inform patients about the signs and symptoms of benzodiazepine abuse, misuse, and addiction; to seek medical help if they develop these signs and/or symptoms; and on the proper disposal of unused drug [see Warnings and Precautions (5.2) and Drug Abuse and Dependence (9.2)]. Withdrawal Reactions: Inform patients that the continued use of flurazepam hydrochloride capsules may lead to clinically significant physical dependence and that abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules may precipitate acute withdrawal reactions, which can be life-threatening. Inform patients that in some cases, patients taking benzodiazepines have developed protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months. Instruct patients that discontinuation or dosage reduction of flurazepam hydrochloride capsules may require 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 flurazepam 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 flurazepam. Tell patients that daytime impairment may persist for several days following discontinuation of flurazepam. Advise patients that increased drowsiness and decreased consciousness may increase the risk of falls in some patients [see Warnings and Precautions (5.4)].Abnormal Thinking and Behavior Change: Instruct patients that sedative hypnotics can cause abnormal thinking and behavior change, including sleepdriving 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)].Severe Allergic Reactions: Inform patients that severe allergic reactions can occur from flurazepam. Describe the signs/symptoms of these reactions and advise patients to seek medical attention immediately if these occur.Worsening of Depression: Tell patients that flurazepam 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 prescription. Advise patients that alcohol generally should not be used during treatment with flurazepam.Pregnancy: Instruct patients to inform you if they are nursing or pregnant, or may become pregnant while taking flurazepam. If woman becomes pregnant while taking flurazepam, she should discontinue use immediately.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action Flurazepam, like other central nervous system agents of the 1,4-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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of FertilityStudies to assess the genotoxic or carcinogenic potential of flurazepam or the effects of flurazepam on fertility have not been conducted.

OVERDOSAGE SECTION.

10 OVERDOSAGE Manifestations of flurazepam hydrochloride overdosage include somnolence, confusion and coma. Respiration, pulse and blood pressure should be monitored as in all cases of drug overdosage. General supportive measures should be employed, along with immediate gastric lavage. Intravenous fluids should be administered and an adequate airway maintained. Hypotension and CNS depression may be combated by judicious use of appropriate therapeutic agents. The value of dialysis has not been determined. If excitation occurs in patients following flurazepam hydrochloride overdosage, barbiturates should not be used. As with the management of intentional overdosage with any drug, it should be borne in mind that multiple agents may have been ingested.Flumazenil, specific benzodiazepine-receptor antagonist, is indicated for the complete or partial reversal of the sedative effects of benzodiazepines and may be useful in situations when an overdose with benzodiazepine is known or suspected. Prior to the administration of flumazenil, necessary measures should be instituted to secure airway, ventilation, and intravenous access. Flumazenil is intended as an adjunct to, not as substitute for, proper management of benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, respiratory depression, and other residual benzodiazepine effects for an appropriate period after treatment. The prescriber should be aware of risk of seizure in association with flumazenil treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. The complete flumazenil package insert including CONTRAINDICATIONS, WARNINGS, and PRECAUTIONS should be consulted prior to use.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 15 mg NDC 0378-4415-01FlurazepamHydrochlorideCapsules, USPCIV15 mgPHARMACIST: Dispense the accompanyingMedication Guide to each patient.Rx only 100 CapsulesEach capsule contains:Flurazepamhydrochloride, USP 15 mgDispense in tight, light-resistantcontainer as defined in the USPusing child-resistant closure.Keep container tightly closed.Keep this and all medicationout of the reach of children.Store at 20 to 25C (68 to 77F ).[See USP Controlled RoomTemperature.]Protect from light.Usual Adult Dosage: Seeaccompanying prescribinginformation.Mylan Pharmaceuticals Inc.Morgantown, WV 26505 U.S.A.Mylan.comRM4415A10. Flurazepam Hydrochloride Capsules 15 mg Bottle Label.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics Flurazepam hydrochloride is rapidly absorbed from the gastro-intestinal tract. Flurazepam is rapidly metabolized and is excreted primarily in the urine. Following single oral dose, peak flurazepam plasma concentrations ranging from 0.5 to 4.0 ng/mL occur at 30 to 60 minutes post-dosing. The harmonic mean apparent half-life of flurazepam is 2.3 hours. The blood level profile of flurazepam and its major metabolites was determined in man following the oral administration of 30 mg daily for weeks. The N1-hydroxyethyl-flurazepam was measurable only during the early hours after 30 mg dose and was not detectable after 24 hours. The major metabolite in blood was N1-desalkyl-flurazepam, which reached steady-state (plateau) levels after to 10 days of dosing, at levels approximately 5- to 6-fold greater than the 24-hour levels observed on Day 1. The half-life of elimination of N1-desalkyl-flurazepam ranged from 47 to 100 hours. The major urinary metabolite is conjugated N1-hydroxyethyl-flurazepam which accounts for 22% to 55% of the dose. Less than 1% of the dose is excreted in the urine as N1-desalkyl-flurazepam.This pharmacokinetic profile may be responsible for the clinical observation that flurazepam is increasingly effective on the second or third night of consecutive use and that for or nights after the drug is discontinued both sleep latency and total wake time may still be decreased.The single dose pharmacokinetics of flurazepam were studied in 12 healthy geriatric subjects (aged 61 to 85 years). The mean elimination half-life of desalkyl-flurazepam was longer in elderly male subjects (160 hours) compared with younger male subjects (74 hours), while mean elimination half-life was similar in geriatric female subjects (120 hours) and younger female subjects (90 hours). After multiple dosing, mean steady-state plasma levels of desalkyl-flurazepam were higher in elderly male subjects (81 ng/mL) compared with younger male subjects (53 ng/mL), while values were similar between elderly female subjects (85 ng/mL) and younger female subjects (86 ng/mL). The mean washout half-life of desalkyl-flurazepam was longer in elderly male and female subjects (126 and 158 hours, respectively) compared with younger male and female subjects (111 and 113 hours, respectively).1 Greenblatt DJ, Divoll M, Hammatz JS, MacLauglin DS, Shader RI: Kinetics and clinical effects of flurazepam in young and elderly noninsomniacs. Clin Pharmacol Ther 30:475-486, 1981.

PREGNANCY SECTION.

8.1 Pregnancy Teratogenic Effects. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Available human data on the risk of teratogenicity for benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy or neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in 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. Administration of flurazepam to pregnant animals did not indicate risk for adverse effects on morphological development at clinically relevant doses; however, animal data for other benzodiazepines suggest that possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) following prenatal exposure. Flurazepam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Pregnancy Registry To provide information regarding the effects of in utero exposure to flurazepam, physicians are advised to recommend that pregnant patients taking flurazepam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

RECENT MAJOR CHANGES SECTION.

Boxed Warning 2/2021Dosage and Administration (2.3) 2/2021Warnings and Precautions (5.1, 5.2, 5.3) 2/2021.

SPL MEDGUIDE SECTION.

Medication Guide Flurazepam Hydrochloride Capsules, USP CIV(flur az pam hye droe klor ide)What is the most important information should know about flurazepam hydrochloride capsulesoFlurazepam hydrochloride capsules are benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation). Do not drive or operate heavy machinery until you know how taking flurazepam hydrochloride capsules with opioids affect you.oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including flurazepam hydrochloride capsules, which can lead to overdose and serious side effects including coma and death.oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including flurazepam hydrochloride capsules. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take flurazepam hydrochloride capsules exactly as prescribed by your healthcare provider.oTake flurazepam hydrochloride capsules exactly as your healthcare provider prescribed.oDo not share your flurazepam hydrochloride capsules with other people.oKeep flurazepam hydrochloride capsules in safe place and away from children. oPhysical dependence and withdrawal reactions. Flurazepam hydrochloride capsules can cause physical dependence and withdrawal reactions, especially if you continue to take flurazepam hydrochloride capsules for several days to several weeks.oDo not suddenly stop taking flurazepam hydrochloride capsules. Stopping flurazepam hydrochloride capsules suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more flurazepam hydrochloride capsules than prescribed or take flurazepam hydrochloride capsules for longer than prescribed. oAfter taking flurazepam hydrochloride capsules, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with flurazepam hydrochloride capsules. Reported activities include:odriving car (sleep-driving)omaking and eating foodotalking on the phoneohaving sexosleep-walking Call your healthcare provider right away if you find out that you have done any of the above activities after taking flurazepam hydrochloride capsules.What are flurazepam hydrochloride capsulesoFlurazepam hydrochloride capsules are 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.oFlurazepam hydrochloride is federal controlled substance (C-IV) because it contains flurazepam that can be abused or lead to dependence. Keep in safe place to prevent misuse and abuse. Selling or giving away flurazepam hydrochloride capsules 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.oIt is not known if flurazepam hydrochloride capsules are safe and effective in children.Do not take flurazepam hydrochloride capsules if you:oare allergic to flurazepam hydrochloride, other benzodiazepines, or any of the ingredients in flurazepam hydrochloride capsules. See the end of this Medication Guide for complete list of ingredients in flurazepam hydrochloride capsules. Symptoms of serious allergic reaction can include: oswelling of your face, lips, and throat that may cause difficulty breathing or swallowingonausea and vomitingBefore you take flurazepam hydrochloride capsules, tell your healthcare provider about all of your medical conditions, including if you:ohave history of depression, mental illness or, suicidal thoughtsohave history of drug or alcohol abuse or addictionoare pregnant or planning to become pregnant. Flurazepam hydrochloride may harm your unborn baby. You and your healthcare provider should decide if you should take flurazepam hydrochloride capsules while you are pregnant.oare breastfeeding, or plan to breastfeed. Flurazepam hydrochloride may 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 flurazepam hydrochloride capsules.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Taking flurazepam hydrochloride capsules with certain other medicines can cause side effects or affect how well flurazepam hydrochloride capsules or the other medicines work. Do not start or stop other medicines without talking to your healthcare provider.Do not take flurazepam hydrochloride capsules with other medicines that can make you sleepy unless your healthcare provider tells you to.How should take flurazepam hydrochloride capsulesoSee What is the most important information should know about flurazepam hydrochloride capsulesoTake flurazepam hydrochloride capsules exactly as your healthcare provider tells you to take it.oTake flurazepam hydrochloride capsules right before you get into bed.oDo not take flurazepam hydrochloride capsules unless you are able to get full nights sleep before you must be active again.oIf you take too many flurazepam hydrochloride capsules, get emergency treatment right away.What are the possible side effects of flurazepam hydrochloride capsulesFlurazepam hydrochloride capsules may cause serious side effects, including:oSee What is the most important information should know about flurazepam hydrochloride capsulesoOther conditions. Call your healthcare provider if your insomnia worsens or is not better within to 10 days. This may mean that there is another condition causing your sleep problem.oSevere 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 flurazepam hydrochloride capsules.oAbnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts.oFlurazepam hydrochloride capsules can make you sleepy or dizzy and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how flurazepam hydrochloride capsules affect you.oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking flurazepam hydrochloride capsules without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, flurazepam hydrochloride capsules may make your sleepiness or dizziness much worse.oDepression. Pre-existing depression may emerge or worsen during use of benzodiazepines including flurazepam hydrochloride capsules.The most common side effects of flurazepam hydrochloride capsules include:odizzinessolight-headednessoloss of coordinationodrowsinessostaggeringofallingThese are not all the possible side effects of flurazepam hydrochloride capsules. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store flurazepam hydrochloride capsulesoStore at 20 to 25C (68 to 77F).oKeep flurazepam hydrochloride capsules in tightly closed container and out of the light.oKeep flurazepam hydrochloride capsules and all medicines out of the reach of children.General information about the safe and effective use of flurazepam hydrochloride capsules.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use flurazepam hydrochloride capsules for condition for which it was not prescribed. Do not give flurazepam hydrochloride capsules 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 flurazepam hydrochloride capsules that is written for healthcare professionals.What are the ingredients in flurazepam hydrochloride capsulesActive Ingredient: flurazepam hydrochlorideInactive Ingredients: colloidal silicon dioxide, FD&C Blue No. 1, FD&C Red No. 3, gelatin, magnesium stearate, microcrystalline cellulose, powdered cellulose, sodium lauryl sulfate and titanium dioxide. The imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Blue No. Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze. Manufactured by: Mylan Pharmaceuticals Inc., Morgantown, WV 26505 U.S.A. If you would like more information, call Mylan at 1-877-446-3679 (1-877-4-INFO-RX).This Medication Guide has been approved by the U.S. Food and Drug Administration.Mylan Pharmaceuticals Inc. Morgantown, WV 26505 U.S.A.Revised: 2/2021FLZ:R22m/MG:FLZ:R7m. oFlurazepam hydrochloride capsules are benzodiazepine medicine. Taking benzodiazepines with opioid medicines, alcohol, or other central nervous system (CNS) depressants (including street drugs) can cause severe drowsiness, breathing problems (respiratory depression), coma and death. Get emergency help right away if any of the following happens:oshallow or slowed breathingobreathing stops (which may lead to the heart stopping)oexcessive sleepiness (sedation).. oshallow or slowed breathing. obreathing stops (which may lead to the heart stopping). oexcessive sleepiness (sedation).. Do not drive or operate heavy machinery until you know how taking flurazepam hydrochloride capsules with opioids affect you.. oRisk of abuse, misuse, and addiction. There is risk of abuse, misuse, and addiction with benzodiazepines, including flurazepam hydrochloride capsules, which can lead to overdose and serious side effects including coma and death.oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including flurazepam hydrochloride capsules. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take flurazepam hydrochloride capsules exactly as prescribed by your healthcare provider.oTake flurazepam hydrochloride capsules exactly as your healthcare provider prescribed.oDo not share your flurazepam hydrochloride capsules with other people.oKeep flurazepam hydrochloride capsules in safe place and away from children. oSerious side effects including coma and death have happened in people who have abused or misused benzodiazepines, including flurazepam hydrochloride capsules. These serious side effects may also include delirium, paranoia, suicidal thoughts or actions, seizures, and difficulty breathing. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these serious side effects. oYou can develop an addiction even if you take flurazepam hydrochloride capsules exactly as prescribed by your healthcare provider.. oTake flurazepam hydrochloride capsules exactly as your healthcare provider prescribed.. oDo not share your flurazepam hydrochloride capsules with other people.. oKeep flurazepam hydrochloride capsules in safe place and away from children.. oPhysical dependence and withdrawal reactions. Flurazepam hydrochloride capsules can cause physical dependence and withdrawal reactions, especially if you continue to take flurazepam hydrochloride capsules for several days to several weeks.oDo not suddenly stop taking flurazepam hydrochloride capsules. Stopping flurazepam hydrochloride capsules suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.oDo not take more flurazepam hydrochloride capsules than prescribed or take flurazepam hydrochloride capsules for longer than prescribed. oDo not suddenly stop taking flurazepam hydrochloride capsules. Stopping flurazepam hydrochloride capsules suddenly can cause serious and life-threatening side effects, including unusual movements, responses, or expressions, seizures, sudden and severe mental or nervous system changes, depression, seeing or hearing things that others do not see or hear, an extreme increase in activity or talking, losing touch with reality, and suicidal thoughts or actions. Call your healthcare provider or go to the nearest hospital emergency room right away if you get any of these symptoms. oSome people who suddenly stop benzodiazepines have symptoms that can last for several weeks to more than 12 months, including anxiety, trouble remembering, learning, or concentrating, depression, problems sleeping, feeling like insects are crawling under your skin, weakness, shaking, muscle twitching, burning or prickling feeling in your hands, arms, legs or feet, and ringing in your ears.. oPhysical dependence is not the same as drug addiction. Your healthcare provider can tell you more about the differences between physical dependence and drug addiction.. oDo not take more flurazepam hydrochloride capsules than prescribed or take flurazepam hydrochloride capsules for longer than prescribed.. oAfter taking flurazepam hydrochloride capsules, you may get up out of bed while not being fully awake and do an activity that you do not know you are doing. The next morning, you may not remember that you did anything during the night. You have higher chance for doing these activities if you drink alcohol or take other medicines that make you sleepy with flurazepam hydrochloride capsules. Reported activities include:. odriving car (sleep-driving). omaking and eating food. otalking on the phone. ohaving sex. osleep-walking. Call your healthcare provider right away if you find out that you have done any of the above activities after taking flurazepam hydrochloride capsules.. oFlurazepam hydrochloride capsules are 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.. oFlurazepam hydrochloride is federal controlled substance (C-IV) because it contains flurazepam that can be abused or lead to dependence. Keep in safe place to prevent misuse and abuse. Selling or giving away flurazepam hydrochloride capsules 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.. oIt is not known if flurazepam hydrochloride capsules are safe and effective in children.. oare allergic to flurazepam hydrochloride, other benzodiazepines, or any of the ingredients in flurazepam hydrochloride capsules. See the end of this Medication Guide for complete list of ingredients in flurazepam hydrochloride capsules. Symptoms of serious allergic reaction can include: oswelling of your face, lips, and throat that may cause difficulty breathing or swallowingonausea and vomiting. oswelling of your face, lips, and throat that may cause difficulty breathing or swallowing. onausea and vomiting. ohave history of depression, mental illness or, suicidal thoughts. ohave history of drug or alcohol abuse or addiction. oare pregnant or planning to become pregnant. Flurazepam hydrochloride may harm your unborn baby. You and your healthcare provider should decide if you should take flurazepam hydrochloride capsules while you are pregnant.. oare breastfeeding, or plan to breastfeed. Flurazepam hydrochloride may 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 flurazepam hydrochloride capsules.. oSee What is the most important information should know about flurazepam hydrochloride capsules. oTake flurazepam hydrochloride capsules exactly as your healthcare provider tells you to take it.. oTake flurazepam hydrochloride capsules right before you get into bed.. oDo not take flurazepam hydrochloride capsules unless you are able to get full nights sleep before you must be active again.. oIf you take too many flurazepam hydrochloride capsules, get emergency treatment right away.. oSee What is the most important information should know about flurazepam hydrochloride capsules. oOther conditions. Call your healthcare provider if your insomnia worsens or is not better within to 10 days. This may mean that there is another condition causing your sleep problem.. oSevere 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 flurazepam hydrochloride capsules.. oAbnormal thoughts and behavior. Symptoms include more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations, worsening of depression, and suicidal thoughts.. oFlurazepam hydrochloride capsules can make you sleepy or dizzy and can slow your thinking and motor skills.oDo not drive, operate heavy machinery, or do other dangerous activities until you know how flurazepam hydrochloride capsules affect you.oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking flurazepam hydrochloride capsules without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, flurazepam hydrochloride capsules may make your sleepiness or dizziness much worse.. oDo not drive, operate heavy machinery, or do other dangerous activities until you know how flurazepam hydrochloride capsules affect you.. oDo not drink alcohol or take other drugs that may make you sleepy or dizzy while taking flurazepam hydrochloride capsules without first talking to your healthcare provider. When taken with alcohol or drugs that cause sleepiness or dizziness, flurazepam hydrochloride capsules may make your sleepiness or dizziness much worse.. oDepression. Pre-existing depression may emerge or worsen during use of benzodiazepines including flurazepam hydrochloride capsules.. odizziness. olight-headedness. oloss of coordination. odrowsiness. ostaggering. ofalling. oStore at 20 to 25C (68 to 77F).. oKeep flurazepam hydrochloride capsules in tightly closed container and out of the light.. oKeep flurazepam hydrochloride capsules and all medicines out of the reach of children.

SPL UNCLASSIFIED SECTION.

2.1 Dosage in Adults Use the lowest dose effective for the patient, as important adverse effects of flurazepam hydrochloride capsules are dose related.The recommended initial dose is 15 mg for women and either 15 mg or 30 mg for men. The 15 mg dose can be increased to 30 mg if necessary for efficacy.The recommended initial doses for women and men are different because flurazepam clearance is lower in women [see Pharmacokinetics (12.3)].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS oPregnancy: Based on animal data, may cause fetal harm. (8.1). oPregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy Teratogenic Effects. Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Available human data on the risk of teratogenicity for benzodiazepines are inconclusive. There is insufficient evidence in humans to assess the effect of benzodiazepine exposure during pregnancy or neurodevelopment. Administration of benzodiazepines immediately prior to or during childbirth can result in 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. Administration of flurazepam to pregnant animals did not indicate risk for adverse effects on morphological development at clinically relevant doses; however, animal data for other benzodiazepines suggest that possibility of adverse developmental effects (including long-term effects on neurobehavioral and immunological function) following prenatal exposure. Flurazepam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. Pregnancy Registry To provide information regarding the effects of in utero exposure to flurazepam, physicians are advised to recommend that pregnant patients taking flurazepam enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves or their caregiver. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.. 8.2 Pediatric Use Safety and effectiveness in pediatric patients have not been established.. 8.3 Geriatric Use Flurazepam may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on low dose of flurazepam and observed closely.Elderly or 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS oCNS depressant effects: Impaired alertness and motor coordination, including risk of falling. Daytime impairment. Caution patients against driving and other activities requiring complete mental alertness. (5.4)oThe failure of insomnia to remit after to 10 days of treatment may indicate the presence of primary psychiatric and/or medical illness that should be evaluated. (5.5)oSevere anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.6)oSleep 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. (5.7)oWorsening of depression or suicidal thinking may occur: Prescribe the least number of capsules feasible to avoid intentional overdose. (5.8). oCNS depressant effects: Impaired alertness and motor coordination, including risk of falling. Daytime impairment. Caution patients against driving and other activities requiring complete mental alertness. (5.4). oThe failure of insomnia to remit after to 10 days of treatment may indicate the presence of primary psychiatric and/or medical illness that should be evaluated. (5.5). oSevere anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. (5.6). oSleep 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. (5.7). oWorsening of depression or suicidal thinking may occur: Prescribe the least number of capsules feasible to avoid intentional overdose. (5.8). 5.1Risks from Concomitant Use of Opioids Concomitant use of benzodiazepines, including flurazepam, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of benzodiazepines and opioids 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 decision is made to prescribe flurazepam 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. Advise both patients and caregivers about the risks of respiratory depression and sedation when flurazepam is used with opioids [see Drug Interactions (7)].. 5.2Abuse, Misuse, and Addiction The use of benzodiazepines, including flurazepam hydrochloride capsules, 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 flurazepam hydrochloride capsules and throughout treatment, assess each patients risk for abuse, misuse, and addiction (e.g., using standardized screening tool). Use of flurazepam hydrochloride capsules, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of flurazepam hydrochloride capsules 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 substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate.. 5.3Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use gradual taper to discontinue flurazepam hydrochloride capsules 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 flurazepam hydrochloride capsules, lead to clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction of flurazepam hydrochloride capsules 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 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 Next-Day Impairment Dizziness, drowsiness, light-headedness, staggering, ataxia and falling can occur, particularly in elderly or debilitated persons. Severe sedation, lethargy, disorientation and coma, probably indicative of drug intolerance or overdosage, have been reported.Flurazepam is central nervous system (CNS) depressant and can impair daytime function 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 flurazepam may develop, patients using flurazepam 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). Downward dose adjustment of flurazepam and concomitant CNS depressants should be considered. The potential for adverse drug interactions continues for several days following discontinuation of flurazepam, until serum levels of psychoactive metabolites decline.Use of flurazepam with other sedative-hypnotics is not recommended. Alcohol generally should not be used during treatment with flurazepam. The risk of next-day psychomotor impairment is increased if flurazepam is taken with less than full night of sleep remaining (7 to hours); if higher than the recommended dose is taken; if coadministered with other CNS depressants [see Dosage and Administration (2)]. Because flurazepam can cause drowsiness and decreased level of consciousness, patients, particularly the elderly, are at higher risk of falls.. 5.5 Need to Evaluate for Co-morbid Disorders Because sleep disturbances may be the presenting manifestation of physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after careful evaluation of the patient. The failure of insomnia to remit after to 10 days of treatment may indicate the presence of 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 or 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 flurazepam. 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 flurazepam 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 flurazepam. 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 flurazepam 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, flurazepam 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 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.