Flurazepam Hydrochloride

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 )

Flurazepam Hydrochloride Capsules, USP are available containing either 15 mg or 30 mg of Flurazepam Hydrochloride, USP. Flurazepam Hydrochloride Capsules, USP 15 mg are Size #2 hard gelatin capsules, Blue opaque cap with white opaque body, imprinted with “ CE ” on the cap and “ 28 ” on the body with black ink, filled with white to off-white powder. Flurazepam Hydrochloride Capsules, USP 30 mg are Size #2 hard gelatin capsules, Blue opaque cap with white opaque body, imprinted with “ CE ” on the cap and “ 29 ” on the body with black ink, filled with white to off-white powder. 15 mg and 30 mg capsules. ( 3 )

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 )

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 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 a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [ see Drug Abuse and Dependence ( 9.3 ) ]. 5.4 CNS-Depressant Effects and 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 a 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 a full night of sleep remaining (7 to 8 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 a 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 a physical and/or psychiatric disorder, symptomatic treatment of insomnia should be initiated only after a careful evaluation of the patient. The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness that should be evaluated. Worsening of insomnia or the emergence of new thinking or behavior abnormalities may be the consequence of an unrecognized psychiatric or physical disorder. Such findings have emerged during the course of treatment with sedative-hypnotic drugs.

5.6 Severe Anaphylactic 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. […]

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.

Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, and death. ( 7.1 ) CNS Depressants: Downward dose adjustment may be necessary due to additive effects. ( 7.2 )

7.1 Opioids 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 GABA A 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. 7.2 CNS 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.

Lactation: Breastfeeding not recommended. ( 8.2 )

8.1 Pregnancy Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including flurazepam, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https://womensmentalhealth.org/pregnancyregistry/ . Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [ see Warnings and Precautions ( 5.9 ) and Clinical Considerations]. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Monitor neonates exposed to flurazepam during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to HALCION during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions ( 5.9 )]. Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings. Animal Data Administration of flurazepam to pregnant animals did not indicate a 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.

8.2 Lactation Risk Summary There are no data on the presence of flurazepam in human or animal milk. There are reports of sedation, poor feeding and poor weight gain in infants exposed to benzodiazepines through breast milk. The effects of flurazepam on milk production are unknown. Because of the flurazepam’s long half-life, the potential for flurazepam to accumulate in breast milk, and the potential for serious adverse reactions, including sedation and withdrawal symptoms in breastfed infants, advise patients that breastfeeding is not recommended during treatment with flurazepam.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Flurazepam may cause confusion and over-sedation in the elderly. Elderly patients generally should be started on a 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.