Flurazepam

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, a gamma-aminobutyric (GABA A ) agonist, is indicated for the treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. ( 1 )

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 a 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 2 weeks. The N1-hydroxyethyl-flurazepam was measurable only during the early hours after a 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 7 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 1 or 2 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 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.

2 DOSAGE AND ADMINISTRATION Use the lowest dose effective for the patient. Recommended initial dose is 15 mg for women and 15 mg or 30 mg for men. ( 2.1 ) Elderly 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 ) ]. 2.3 Discontinuation or Dosage Reduction of Flurazepam Hydrochloride Capsules To reduce the risk of withdrawal reactions, use a gradual taper to discontinue flurazepam hydrochloride capsules or reduce the dosage. If a 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 ) ].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: Risks from Concomitant Use with Opioids [see Warnings and Precautions ( 5.1 ) ] Abuse, Misuse, and Addiction [see Warnings and Precautions ( 5.2 )] Dependence and Withdrawal Reactions [see Warnings and Precautions ( 5.3 ) ] CNS-depressant effects and next-day impairment [see Warnings and Precautions ( 5.4 )] Severe Anaphylactic and Anaphylactoid Reactions [see Warnings and Precautions ( 5.6 )] Abnormal thinking and behavior changes, and complex behaviors [see Warnings and Precautions ( 5.7 )] Worsening of depression [see Warnings and Precautions ( 5.8 )] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions ( 5.9 )] Adverse reactions: dizziness, drowsiness, light-headedness, staggering, ataxia, falling. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 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.

5 WARNINGS AND PRECAUTIONS CNS 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 ) 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. ( 5.5 ) Severe anaphylactic/anaphylactoid reactions: Angioedema and anaphylaxis have been reported. Do not rechallenge if such reactions occur. ( 5.6 ) 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. ( 5.7 ) Worsening of depression or suicidal thinking may occur: Prescribe the least number of capsules feasible to avoid intentional overdose. ( 5.8 ) Neonatal Sedation and Withdrawal Syndrome: Flurazepam use during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.9 ) 5.1 Risks 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 a 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 )]. 5.2 Abuse, 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 patient’s risk for abuse, misuse, and addiction (e.g., using a 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 a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. 5.3 Dependence and Withdrawal Reactions To reduce the risk of withdrawal reactions, use a gradual taper to discontinue 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, may lead to

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. Hypersensitivity to flurazepam or other benzodiazepines. ( 4 )

10 OVERDOSAGE Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions ( 5.2 )] . Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting a poison center (1-800-222-1222), poisoncontrol.org , or a medical toxicologist for additional overdosage management recommendations.