Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs in patients for whom alternative treatment options are inadequate. Limit dosages and durations to the minimum required. Follow patients for signs and symptoms of respiratory depression and sedation.
The use of benzodiazepines, including flurazepam, 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 and throughout treatment, assess each patient's risk for abuse, misuse, and addiction.
The continued use of benzodiazepines, including flurazepam, 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 after continued use may precipitate acute withdrawal reactions, which can be life-threatening. To reduce the risk of withdrawal reactions, use a gradual taper to discontinue flurazepam or reduce the dosage.
Insomnia: Limited data available: Adolescents ≥15 years: Oral: 15 mg at bedtime (Dalmane prescribing information 2007, Rudolph 1996)
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosing adjustments provided in the manufacturer's labeling.
There are no dosing adjustments provided in the manufacturer's labeling.
(For additional information see "Flurazepam: Drug information")
Note: Intended for short-term use (≤4 to 8 weeks), preferably in conjunction with nonpharmacologic therapies (ACP [Qaseem 2016]; ESRS [Riemann 2017]; Winkelman 2021). Limit long-term use to cases for which nonpharmacologic treatments are not available or not effective and benefits are felt to outweigh risks (AASM [Sateia 2017]).
Insomnia, sleep onset or sleep maintenance (alternative agent):
Note: Due to risk of next day impairment, dependence, and habituation, benzodiazepines should be reserved for patients in whom alternative, safer therapies for insomnia have failed (Neubauer 2021).
Oral: Initial: 15 mg at bedtime, as needed; may increase daily dose to 30 mg at bedtime based on response and tolerability.
Discontinuation of therapy : When prescribing benzodiazepines for insomnia, reduce by 25% of the original dose every 1 to 2 weeks until lowest available dose is reached, then discontinue (flurazepam can be reduced in 15 mg increments). Patients on long-term therapy or in whom discontinuation has previously failed may benefit from a slower taper in conjunction with cognitive behavioral therapy for insomnia (Bélanger 2009).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Generic: 15 mg, 30 mg
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as hydrochloride:
Som-Pam: 15 mg, 30 mg
Generic: 15 mg, 30 mg
C-IV
An FDA-approved patient medication guide, which is available with the product information and at http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/016721s077lbl.pdf, must be dispensed with this medication.
Oral: May be administered without regard to meals; administer dose at bedtime
Store at 20°C to 25°C (68°F to 77°F); protect from light.
Short-term treatment of insomnia (FDA approved in adults)
Flurazepam may be confused with temazepam
Dalmane may be confused with Demulen
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Beers Criteria: Flurazepam is identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older due to an increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents with benzodiazepine use. Older adults also have slower metabolism of long-acting benzodiazepines (eg, flurazepam). However, flurazepam may be appropriate in older adults when used for seizure disorders, rapid eye movement sleep behavior disorders, benzodiazepine or ethanol withdrawal, severe generalized anxiety disorder, or periprocedural anesthesia (Beers Criteria [AGS 2019]).
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Frequency not defined.
Cardiovascular: Chest pain, flushing, hypotension, palpitations, syncope
Central nervous system: Abnormal reflexes (slowing), apprehension, ataxia, bitter taste, body pain, confusion, depression, dizziness, drowsiness, drug dependence, dysarthria, euphoria, falling, hallucination, hangover effect, headache, irritability, memory impairment, nervousness, paradoxical reaction, restlessness, slurred speech, staggering, talkativeness
Dermatologic: Diaphoresis, pruritus, skin rash
Endocrine & metabolic: Weight gain, weight loss
Gastrointestinal: Constipation, decreased appetite, diarrhea, gastric distress, gastrointestinal pain, heartburn, increased appetite, nausea, sialorrhea, vomiting, xerostomia
Hematologic & oncologic: Granulocytopenia, leukopenia
Hepatic: Abnormal bilirubin levels (total bilirubin increased), cholestatic jaundice, increased serum alkaline phosphatase, increased serum ALT, increased serum AST
Neuromuscular & skeletal: Arthralgia, weakness
Ophthalmic: Accommodation disturbance, blurred vision, burning sensation of eyes
Respiratory: Apnea, dyspnea
<1%, postmarketing, and/or case reports: Anaphylaxis, angioedema, parasomnias (cooking while sleeping, making phone calls while sleeping, sleep driving, sleep eating)
Hypersensitivity to flurazepam, other benzodiazepines, or any component of the formulation; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling): Severe respiratory function impairment (eg, significant sleep apnea syndrome); myasthenia gravis; severe hepatic impairment.
Documentation of allergenic cross-reactivity for benzodiazepines is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.
Concerns related to adverse effects:
• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia (Nelson 1999).
• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
• Hypersensitivity reactions: Reports of hypersensitivity reactions, including anaphylaxis and angioedema, have been reported with flurazepam. Patients who develop angioedema should not be rechallenged with flurazepam.
• Paradoxical reactions: Paradoxical reactions, including hyperactive or aggressive behavior, have been reported with benzodiazepines; risk may be increased in adolescent/pediatric patients, geriatric patients, or patients with a history of alcohol use disorder or psychiatric/personality disorders (Mancuso 2004).
• Sleep-related activities: Hazardous sleep-related activities such as sleep-driving, cooking and eating food, and making phone calls while asleep have been noted with benzodiazepines (Dolder 2008).
Disease-related concerns:
• Depression: Use caution in patients with depression, particularly if suicidal risk may be present. Minimize risks of overdose by prescribing the least amount of drug that is feasible in suicidal patients. Worsening of depressive symptoms has also been reported with use of benzodiazepines.
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Respiratory disease: Use with caution in patients with respiratory disease.
• Sleep apnea: Benzodiazepines can suppress respiratory drive in patients with obstructive sleep apnea; use caution when prescribing for insomnia in this population (Webster 2020).
Special populations:
• Debilitated patients: Use with caution in debilitated patients.
• Elderly patients: Elderly patients may be at an increased risk of death with use; risk has been found highest within the first 4 months of use in elderly dementia patients (Jennum 2015; Saarelainen 2018).
• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury (Nelson 1999).
Other warnings/precautions:
• Abuse, misuse, and addiction: Counsel patients at increased risk on proper use and monitoring for signs and symptoms of abuse, misuse, and addiction. Institute early treatment or refer patients in whom substance use disorder is suspected. Limit dosages and durations to the minimum required.
• Appropriate use: Does not have analgesic, antidepressant, or antipsychotic properties. As a hypnotic, should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7 to 10 days may indicate psychiatric or medical illness. A worsening of insomnia or the emergence of new abnormalities of thought or behavior may represent unrecognized psychiatric or medical illness and requires immediate and careful evaluation.
• Dependence and withdrawal reactions: Some patients may develop a protracted withdrawal syndrome lasting >12 months; may be difficult to differentiate withdrawal symptoms from reemergence or continuation of symptoms for which benzodiazepines were prescribed. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.
• Rebound insomnia: Following withdrawal of therapy, transient insomnia may recur accompanied by other reactions, including restlessness, anxiety, and mood changes (Bélanger 2009).
• Tolerance: Flurazepam is a long half-life benzodiazepine. Duration of action after a single dose is determined by redistribution rather than metabolism. Tolerance develops to the hypnotic effects (Vinkers 2012). Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect.
• Withdrawal: A longer sleep-onset latency and increased awakenings during sleep may occur for 1 to 2 days following the discontinuation of GABA-mediated (GABAergic) medications. A more severe withdrawal syndrome may rarely occur following abrupt discontinuation or large decreases in dose after sustained use (>10 days), and is characterized by new-onset agitation, ataxia, depersonalization, dizziness, dysphoria, fatigue, headache, hypersensitivity to stimuli, irritability, muscle cramps or pain, nausea, sweating, twitching, vomiting, and weakness. This withdrawal syndrome generally resolves within weeks or upon reinitiation of the GABAergic medication. Intermittent dosing may reduce the risk of withdrawal symptoms (BAP [Wilson 2019]). Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms.
None known.
Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Risk C: Monitor therapy
Alizapride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Risk D: Consider therapy modification
Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromopride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Risk D: Consider therapy modification
Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products. Risk C: Monitor therapy
Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Risk D: Consider therapy modification
Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Risk C: Monitor therapy
CloZAPine: Benzodiazepines may enhance the adverse/toxic effect of CloZAPine. Management: Consider decreasing the dose of (or possibly discontinuing) benzodiazepines prior to initiating clozapine. Risk D: Consider therapy modification
CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Risk C: Monitor therapy
Daridorexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dose reduction of daridorexant and/or any other CNS depressant may be necessary. Use of daridorexant with alcohol is not recommended, and the use of daridorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Difelikefalin: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Risk C: Monitor therapy
Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Risk D: Consider therapy modification
Esketamine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Risk D: Consider therapy modification
Fosamprenavir: May increase the serum concentration of Flurazepam. Risk C: Monitor therapy
HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kava Kava: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Kratom: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Risk D: Consider therapy modification
Lisuride: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Melatonin: May enhance the sedative effect of Benzodiazepines. Risk C: Monitor therapy
Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Management: Clinicians should generally avoid concurrent use of methadone and benzodiazepines when possible; any combined use should be undertaken with extra caution. Risk D: Consider therapy modification
Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Risk D: Consider therapy modification
Metoclopramide: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Risk C: Monitor therapy
Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
OLANZapine: Benzodiazepines may enhance the adverse/toxic effect of OLANZapine. Management: Monitor closely for hypotension, respiratory or central nervous system depression, and bradycardia if olanzapine is combined with benzodiazepines. Use of parenteral benzodiazepines with IM olanzapine is not recommended. Risk C: Monitor therapy
Olopatadine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Risk X: Avoid combination
Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Risk X: Avoid combination
Oxybate Salt Products: Benzodiazepines may enhance the CNS depressant effect of Oxybate Salt Products. Risk X: Avoid combination
OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Risk D: Consider therapy modification
Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Risk X: Avoid combination
Perampanel: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Risk C: Monitor therapy
Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Risk C: Monitor therapy
Ritonavir: May increase the serum concentration of Flurazepam. Risk C: Monitor therapy
Ropeginterferon Alfa-2b: CNS Depressants may enhance the adverse/toxic effect of Ropeginterferon Alfa-2b. Specifically, the risk of neuropsychiatric adverse effects may be increased. Management: Avoid coadministration of ropeginterferon alfa-2b and other CNS depressants. If this combination cannot be avoided, monitor patients for neuropsychiatric adverse effects (eg, depression, suicidal ideation, aggression, mania). Risk D: Consider therapy modification
ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Risk C: Monitor therapy
Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Risk C: Monitor therapy
Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Risk C: Monitor therapy
Saquinavir: May increase the serum concentration of Flurazepam. Risk C: Monitor therapy
Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Risk D: Consider therapy modification
Teduglutide: May increase the serum concentration of Benzodiazepines. Risk C: Monitor therapy
Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Risk X: Avoid combination
Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Risk C: Monitor therapy
Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Valerian: May enhance the CNS depressant effect of CNS Depressants. Risk C: Monitor therapy
Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. Risk C: Monitor therapy
Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Risk D: Consider therapy modification
Benzodiazepine serum concentrations may be increased by grapefruit juice. Management: Limit or avoid grapefruit juice (Bjornsson 2003).
All benzodiazepines are assumed to cross the placenta. Teratogenic effects have been observed with some benzodiazepines; however, additional studies are needed. The incidence of premature birth and low birth weights may be increased following maternal use of benzodiazepines; hypoglycemia and respiratory problems in the neonate may occur following exposure late in pregnancy. Neonatal withdrawal symptoms may occur within days to weeks after birth and “floppy infant syndrome” (which also includes withdrawal symptoms) has been reported with some benzodiazepines (Bergman 1992; Iqbal 2002; Wikner 2007). Neonatal depression has been observed, specifically following exposure to flurazepam when used maternally for 10 consecutive days prior to delivery. Serum levels of N-desalkylflurazepam were measurable in the infant during the first 4 days of life. Use of flurazepam during pregnancy is contraindicated.
Patients exposed to flurazepam during pregnancy are encouraged to enroll themselves into the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334. Additional information is available at http://www.aedpregnancyregistry.org.
Binds to stereospecific benzodiazepine receptors on the postsynaptic GABA neuron at several sites within the central nervous system, including the limbic system, reticular formation. Enhancement of the inhibitory effect of GABA on neuronal excitability results by increased neuronal membrane permeability to chloride ions. This shift in chloride ions results in hyperpolarization (a less excitable state) and stabilization. Benzodiazepine receptors and effects appear to be linked to the GABA-A receptors. Benzodiazepines do not bind to GABA-B receptors (Vinkers, 2012).
Absorption: Rapid
Distribution: Flurazepam: Vd: 3.4 L/kg; N-desalkylflurazepam: Vd: 0.7 L/kg (Vozeh 1988)
Protein binding: Flurazepam: ~97%; N-desalkylflurazepam: ~98% (Vozeh 1988)
Metabolism: Hepatic to N-desalkylflurazepam (active) and N-hydroxyethylflurazepam
Half-life elimination:
Flurazepam: 2.3 hours
N-desalkylflurazepam:
Adults: Single dose: 74 to 90 hours; Multiple doses: 111 to 113 hours
Elderly (61 to 85 years): Single dose: 120 to 160 hours; Multiple doses: 126 to 158 hours
Time to peak, serum:
Flurazepam: 30 to 60 minutes
N-desalkylflurazepam: 10.6 hours (range: 7.6 to 13.6 hours) (Greenblatt 1989)
N-hydroxyethylflurazepam: ~1 hour (Greenblatt, 1989)
Excretion: Urine: N-hydroxyethylflurazepam (22% to 55%); N-desalkylflurazepam (<1%)
Capsules (Flurazepam HCl Oral)
15 mg (per each): $0.73
30 mg (per each): $0.88
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