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Flurazepam
Flurazepam
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Flurazepam
Clinical data
Trade namesDalmane, Dalmadorm, Fluzepam
AHFS/Drugs.comMonograph
MedlinePlusa682051
Pregnancy
category
  • X (Contraindicated in pregnancy)
Addiction
liability		Moderate
Routes of
administration		By mouth
Drug classBenzodiazepine
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability83%
MetabolismLiver
MetabolitesN-desalkylflurazepam (active metabolite)
Elimination half-life2.3 hours
N-desalkylflurazepam: 47–100 hours
ExcretionKidney
Identifiers
  • 7-Chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard100.037.795 Edit this at Wikidata
Chemical and physical data
FormulaC21H23ClFN3O
Molar mass387.88 g·mol−1
3D model (JSmol)
Melting point79.5 °C (175.1 °F)
  • FC1=CC=CC=C1C2=NCC(N(CCN(CC)CC)C3=C2C=C(C=C3)Cl)=O
  • InChI=1S/C21H23ClFN3O/c1-3-25(4-2)11-12-26-19-10-9-15(22)13-17(19)21(24-14-20(26)27)16-7-5-6-8-18(16)23/h5-10,13H,3-4,11-12,14H2,1-2H3 checkY
  • Key:SAADBVWGJQAEFS-UHFFFAOYSA-N checkY
  (verify)

Flurazepam[2] (marketed under the brand names Dalmane and Dalmadorm) is a drug which is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, hypnotic, sedative and skeletal muscle relaxant properties. It produces a metabolite with a long half-life, which may stay in the bloodstream for days.[3] Flurazepam was patented in 1968 and came into medical use the same year.[4] Flurazepam, developed by Roche Pharmaceuticals, was one of the first benzodiazepine hypnotic medications to be marketed.[5]

Medical uses

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Two Dalmane (flurazepam) capsules

Flurazepam is officially indicated for mild to moderate insomnia and as such it is used for short-term treatment of patients with mild to moderate insomnia such as difficulty falling asleep, frequent awakening, early awakenings or a combination of each.[6] Flurazepam is a long-acting benzodiazepine and is sometimes used in patients who have difficulty in maintaining sleep, though benzodiazepines with intermediate half-lives such as alprazolam, loprazolam, lorazepam, lormetazepam, oxazepam and temazepam are also indicated for patients with difficulty maintaining sleep.[7]

Flurazepam was temporarily unavailable in the United States when its sole producer, Mylan Pharmaceuticals, discontinued making it in January 2019.[8] In October 2019, the FDA informed pharmacies that they could expect to be resupplied by manufacturers in early to mid December 2019. After a delay, Chartwell Pharmaceuticals began manufacturing flurazepam again in November 2023, since then it is available in the U.S. in the form of 15 mg and 30 mg capsules.[8]

Side effects

[edit]

The most common adverse effects are dizziness, drowsiness, light-headedness, and ataxia. Flurazepam has abuse potential and should never be used with alcoholic beverages or any other substance that can cause drowsiness. Addictive and possibly fatal results may occur. Flurazepam users should only take this drug strictly as prescribed, and should only be taken directly before the user plans on sleeping a full night. Next day drowsiness is common and may increase during the initial phase of treatment as accumulation occurs until steady-state plasma levels are attained.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking hypnotic drugs compared to those taking a placebo.[9]

In September 2020, the U.S. Food and Drug Administration (FDA) required the boxed warning be updated for all benzodiazepine medicines to describe the risks of abuse, misuse, addiction, physical dependence, and withdrawal reactions consistently across all the medicines in the class.[10]

Tolerance, dependence and withdrawal

[edit]
Main article: Benzodiazepine withdrawal syndrome

A review paper found that long-term use of flurazepam is associated with drug tolerance, drug dependence, rebound insomnia and central nervous system (CNS) related adverse effects. Flurazepam is best used for a short time period and at the lowest possible dose to avoid complications associated with long-term use. Non-pharmacological treatment options however, were found to have sustained improvements in sleep quality.[11] Flurazepam and other benzodiazepines such as fosazepam, and nitrazepam lost some of their effect after seven days administration in psychogeriatric patients.[12] Flurazepam shares cross tolerance with barbiturates and barbiturates can easily be substituted by flurazepam in those who are habituated to barbiturate sedative hypnotics.[13]

After discontinuation of flurazepam a rebound effect or benzodiazepine withdrawal syndrome may occur about four days after discontinuation of medication.[14]

Contraindications and special caution

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Benzodiazepines require special precaution if used in the elderly, during pregnancy, in children, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[15]

Elderly

[edit]

Flurazepam, similar to other benzodiazepines and nonbenzodiazepine hypnotic drugs causes impairments in body balance and standing steadiness in individuals who wake up at night or the next morning. Falls and hip fractures are frequently reported. The combination with alcohol increases these impairments. Partial, but incomplete tolerance develops to these impairments.[16] An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines including flurazepam, the nonbenzodiazepine sedative-hypnotics appeared to offer few, if any, significant clinical advantages in efficacy in elderly persons. Tolerability in elderly patients, however, is improved marginally in that benzodiazepines have moderately higher risks of falls, memory problems, and disinhibition ("paradoxical agitation") when compared to non-benzodiazepine sedatives. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin agonists, hold promise for the management of chronic insomnia in elderly people. Chronic use of sedative-hypnotic drugs for the management of insomnia does not have an evidence base and has been discouraged due to concerns including potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of sedative hypnotics has been determined to be no better than placebo after 3 months of therapy and worse than placebo after 6 months of therapy.[17]

Pharmacology

[edit]

Flurazepam is a "classical" benzodiazepine; some other classical benzodiazepines include diazepam, clonazepam, oxazepam, lorazepam, nitrazepam, bromazepam, and clorazepate.[18] Flurazepam generates an active metabolite, N-desalkylflurazepam, with a very long elimination half-life.[3] Flurazepam could be therefore unsuitable as a sleeping medication for some individuals due to next-day sedation; however, this same effect may also provide next-day anxiety relief. Residual 'hangover' effects after nighttime administration of flurazepam, such as sleepiness, impaired psychomotor and cognitive functions, may persist into the next day, which may impair the ability of users to drive safely and increase risks of falls and hip fractures.[19]

Flurazepam is lipophilic, is metabolized hepatically via oxidative pathways. The main pharmacological effect of flurazepam is to increase the effect of GABA at the GABAA receptor via binding to the benzodiazepine site on the GABAA receptor causing an increase influx of chloride ions into the GABAA neuron.[20][21]

Flurazepam is contraindicated in pregnancy. It is recommended to withdraw flurazepam during breast feeding, as flurazepam is excreted in breast milk.[22]

Misuse

[edit]
See also: Benzodiazepine drug misuse

Flurazepam is a drug with potential for misuse. Two types of drug misuse can occur, either recreational misuse where the drug is taken to achieve a high, or when the drug is continued long term against medical advice.[23]

[edit]

Flurazepam is a Schedule IV drug under the Convention on Psychotropic Substances.[24]

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Flurazepam

View on Grokipedia
from Grokipedia
Flurazepam is a long-acting medication primarily prescribed for the short-term treatment of , characterized by difficulty falling or staying asleep. Chemical and Pharmacological Profile
Chemically designated as 7-chloro-1-[2-(diethylamino)ethyl]-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one monohydrochloride, flurazepam belongs to the 1,4- class and acts as a .
It exerts its effects by binding to the benzodiazepine site on GABA-A receptors, enhancing the inhibitory actions of the gamma-aminobutyric acid (GABA), which leads to , anxiolysis, and muscle relaxation.
Following , flurazepam is extensively metabolized in the liver to active metabolites, including desalkylflurazepam, contributing to its prolonged of 40–250 hours and extended duration of action that can persist for 1–2 nights after a single dose. Clinical Use and History
Approved by the U.S. (FDA) in 1970 as the first hypnotic, flurazepam revolutionized treatment by offering efficacy superior to earlier barbiturates, though its use has declined with the advent of shorter-acting alternatives.
It is typically dosed at 15–30 mg capsules taken at bedtime, with improvement in onset and maintenance expected within 7–10 days, but should not exceed 7–10 days to minimize risks.
As a Schedule IV controlled substance, flurazepam carries a high potential for physical and , tolerance, and severe withdrawal symptoms upon abrupt discontinuation. Side Effects and Precautions
The most common adverse effects are dose-related and include daytime drowsiness, , light-headedness, and coordination impairment, particularly in elderly or debilitated patients.
Serious risks encompass respiratory depression (especially when combined with opioids or alcohol), , sleep-driving behaviors without recollection, and rare instances of such as cholestatic .
Precautions include avoiding use in (due to fetal risks), , or with a history of ; gradual tapering is advised for discontinuation to prevent rebound or seizures.

Medical Uses

Indications

Flurazepam is approved for the short-term treatment of , specifically addressing symptoms such as difficulty falling asleep, frequent nocturnal awakenings, and early morning awakening. It is effective for managing recurring , poor sleeping habits, and situations involving acute or chronic medical conditions that disrupt restful sleep. Given the often transient and intermittent nature of insomnia, short-term administration is typically sufficient, with use generally limited to 7-10 consecutive days to prevent dependence. that persists beyond this duration may signal an underlying psychiatric or medical issue necessitating further evaluation. Sleep laboratory studies support its efficacy for transient and short-term over periods of up to 28 nights, aligning with clinical guidelines that emphasize brief therapy for these cases. As a , flurazepam exhibits and effects inherent to its class, which historically contributed to broader applications among benzodiazepines, though it is not approved for anxiety or related disorders. Flurazepam's long-acting characteristics enable sustained maintenance, setting it apart from short-acting hypnotics that focus more on sleep initiation.

Dosage and Administration

Flurazepam is available in oral capsule form in strengths of 15 mg and 30 mg. For adults, the recommended initial dose is 15 to 30 mg taken orally immediately before bedtime, with 30 mg being the usual adult dose and 15 mg sufficient for some patients. In elderly or debilitated patients, a lower initial dose of 15 mg is recommended due to increased sensitivity to the drug's effects. Pediatric use is not recommended for individuals under 15 years of age, as safety and efficacy have not been established in this population. The medication should be administered orally right before , ensuring the patient is able to obtain 7 to 8 hours of uninterrupted to minimize risks such as drowsiness or impaired coordination. Dosing should be individualized based on clinical response, with if necessary, but not exceeding 30 mg per day. Upon discontinuation after prolonged use, gradual tapering of the dose is advised to prevent withdrawal symptoms. Regular monitoring for efficacy and adverse effects is recommended after 7 to 10 days of , with reassessment of the need for continued treatment.

Pharmacology

Pharmacodynamics

Flurazepam is classified as a long-acting derivative, primarily utilized for its hypnotic properties in treating . It exerts its effects through positive allosteric modulation of the GABA_A receptor complex, binding to the stereospecific benzodiazepine recognition site located at the interface of the alpha and gamma subunits. This binding increases the receptor's affinity for the inhibitory gamma-aminobutyric acid (GABA), thereby enhancing the frequency of opening. The resulting influx of chloride ions hyperpolarizes neurons, reducing their excitability and potentiating inhibitory throughout the . This mechanism underlies flurazepam's therapeutic effects, including and , anxiolysis, activity, and muscle relaxation. Flurazepam demonstrates high affinity for the benzodiazepine site on the GABA_A receptor, facilitating GABA-mediated inhibition without directly activating the receptor or opening the independently. The drug's receptor interaction primarily targets postsynaptic sites in the , where it amplifies signaling to suppress neuronal firing. Upon administration, flurazepam undergoes rapid hepatic to produce active metabolites, notably N-desalkylflurazepam (desalkylflurazepam) and N1-hydroxyethylflurazepam, both of which retain the ability to bind to the benzodiazepine site on GABA_A receptors and contribute to the compound's extended duration of action. These metabolites extend the modulation of GABA_A receptors, sustaining inhibitory effects over prolonged periods. In terms of effects, flurazepam depresses activity across multiple levels, including the , , and cortical areas, which collectively mediate its sedative-hypnotic profile by dampening and promoting .

Pharmacokinetics

Flurazepam is rapidly absorbed from the following , with peak plasma concentrations of 0.5–4.0 ng/mL typically occurring within 0.5–1 hour post-dose. The drug is highly lipophilic (logP ≈ 3.8), facilitating widespread distribution throughout the body, including crossing the blood-brain barrier to exert effects; its is approximately 3.4 L/kg. Flurazepam undergoes extensive hepatic metabolism primarily via the enzymes and , yielding active metabolites such as N1-desalkylflurazepam and N1-hydroxyethylflurazepam, which are further conjugated to inactive glucuronides. The parent drug has a short elimination of 2–3 hours, but its active metabolites exhibit prolonged ranging from 40–250 hours (average around 74–100 hours), resulting in accumulation upon repeated dosing and steady-state plasma levels achieved after 7–10 days (approximately 1–2 weeks). This extended metabolite contributes to the sustained effects of flurazepam beyond the initial dosing period. Excretion occurs primarily via the kidneys as inactive conjugated metabolites, with less than 1% of the dose eliminated unchanged or as active metabolites. Pharmacokinetic parameters are influenced by age and liver function; clearance decreases in the elderly, leading to longer half-lives (up to 160 hours in geriatric males) and higher steady-state concentrations, while impaired hepatic function reduces and prolongs elimination.

Contraindications and Precautions

Contraindications

Flurazepam is contraindicated in patients with known to flurazepam, other benzodiazepines, or any component of the formulation, as this may lead to severe allergic reactions including or . Absolute contraindications also include acute narrow-angle , due to the drug's potential to exacerbate through mydriatic effects. Relative contraindications encompass conditions where the risks significantly outweigh benefits, such as severe respiratory depression or untreated , as flurazepam's CNS depressant effects may further impair breathing and lead to hypoxia. Severe hepatic impairment is another relative , given the drug's metabolism via in the liver, which could result in accumulation and prolonged sedation. A history of , depression, or warrants avoidance, as benzodiazepines like flurazepam carry a high potential for misuse, dependence, and exacerbation of psychiatric symptoms. Acute is relatively contraindicated due to additive CNS depression that increases the risk of profound sedation and . Use in patients with requires caution, as benzodiazepines may worsen muscle weakness by enhancing GABA-mediated inhibition at the . Concomitant administration with strong inhibitors (e.g., , ) requires dose adjustment and monitoring, as these can substantially increase flurazepam plasma levels, heightening the risk of excessive and respiratory depression. Use during pregnancy is contraindicated, formerly classified as FDA Pregnancy Category X (indicating risks outweigh benefits), due to risks of congenital malformations (particularly if used in the first trimester), neonatal floppy (characterized by , , and respiratory depression), and withdrawal symptoms in the newborn. In the current FDA labeling system (post-2015), flurazepam is associated with risks of fetal harm and neonatal complications, and use is not recommended unless potential benefits outweigh risks. Flurazepam is also contraindicated in individuals, as it is excreted into and may cause , poor feeding, and weight gain issues in the .

Special Populations

In elderly patients, flurazepam dosing should begin at 15 mg at bedtime due to increased sensitivity to benzodiazepines, which stems from age-related declines in hepatic, renal, or cardiac function leading to slower and higher plasma levels. This population faces heightened risks of oversedation, , , , staggering, and falls, with studies linking benzodiazepine use to increased incidence of hip fractures. The American Geriatrics Society recommends avoiding flurazepam and other benzodiazepines in older adults owing to these risks of , , and motor instability. Patients with hepatic or renal impairment require dose reductions and close monitoring, as flurazepam's metabolism and elimination are primarily hepatic, leading to drug accumulation and prolonged effects in , while renal dysfunction may exacerbate overall clearance issues. Usual precautions include starting at the lowest effective dose and assessing for excessive or respiratory depression. Flurazepam is not approved for pediatric use, with safety and efficacy not established in children under 15 years due to insufficient clinical data and potential for adverse effects on developing nervous systems. Limited studies highlight risks of behavioral changes and dependency, underscoring the need for non-pharmacologic alternatives in this group. In patients with , caution is warranted due to altered drug distribution from increased , which may prolong flurazepam's effects as a lipophilic , though specific dosing adjustments are not well-defined. For those with (COPD), flurazepam should be used judiciously at reduced doses because of the risk of respiratory depression exacerbating and increasing adverse events like acute failure. In individuals with psychiatric disorders, particularly depression, flurazepam carries a risk of worsening depressive symptoms, hallucinations, or , necessitating protective measures and careful evaluation.

Adverse Effects

Common Side Effects

Flurazepam's common side effects, defined as those occurring in more than 1% of users, are predominantly mild and transient, stemming from its sedative-hypnotic mechanism that enhances GABA activity in the . These effects are dose-related and often manifest immediately after administration or as residual next-day symptoms due to the drug's long and active metabolites, such as N-desalkylflurazepam, which contribute to its prolonged action. Central nervous system effects are the most prevalent, including drowsiness (frequently appearing as next-day or daytime ), , , , and , which may increase the risk of falls, particularly in elderly patients. Additional common CNS-related complaints encompass , (or ), and slurred speech. Gastrointestinal effects, while less frequent, may include . Rare gastrointestinal effects include bitter taste and dry mouth. The overall incidence of adverse effects with flurazepam is approximately 7%, with drowsiness and being the most reported. Management of these side effects focuses on dose reduction to the lowest effective level or temporary discontinuation, allowing symptoms to resolve as the drug clears the system. Patients should be counseled to avoid operating machinery or until alertness returns, and elderly individuals may require starting doses of 15 mg to minimize residual effects.

Serious Adverse Effects

Serious adverse effects of flurazepam, though less common, include , complex sleep-related behaviors such as sleep-driving or sleep-eating without recollection, and respiratory depression, particularly when combined with opioids, alcohol, or other CNS depressants. Paradoxical reactions, such as increased anxiety, excitation, aggression, or hallucinations, may occur, especially in elderly patients or those with psychiatric conditions. Rare instances of , including cholestatic , have been reported. These risks underscore the importance of short-term use and careful monitoring.

Tolerance, Dependence, and Withdrawal

Tolerance to flurazepam, a long-acting , develops relatively rapidly, particularly to its effects, often within 1-2 weeks of continuous use, leading to diminished efficacy in promoting initiation and maintenance. This tolerance arises from adaptive changes in the , including downregulation of GABA_A receptor sensitivity, which reduces the drug's and actions over time. In contrast, tolerance to effects may develop more slowly, though overall responsiveness to the therapeutic effects can wane, necessitating dose adjustments or discontinuation. Little tolerance develops to the amnestic or effects, which may persist or even intensify with prolonged use. Physical dependence on flurazepam occurs through neuroadaptive alterations in function, resulting in a reliance on the drug to maintain normal CNS activity, while involves conditioned responses to the drug's calming effects. As a long-acting with an extended due to active metabolites, flurazepam carries a higher of dependence compared to shorter-acting agents, especially with durations exceeding 4 weeks or at higher doses. Individuals with a history of substance , such as or other drug dependencies, face elevated risks and require close monitoring. Prevalence of dependence among users with prolonged therapeutic exposure is estimated at 30-50%, reflecting the broader pattern observed in long-term therapy. Withdrawal from flurazepam typically manifests 1-4 days after discontinuation, delayed by its prolonged elimination , and includes rebound , heightened anxiety, tremors, and, in cases of high-dose chronic use, potentially life-threatening seizures. Other symptoms may encompass abdominal or muscle cramps, , sweating, and , resembling those seen with or alcohol withdrawal, with milder forms appearing after months of standard dosing. A protracted withdrawal syndrome can persist for weeks to over 12 months, featuring ongoing anxiety, cognitive deficits, and disturbances. Management of flurazepam dependence and withdrawal emphasizes gradual dose tapering over several weeks to minimize symptom severity, starting with small reductions (e.g., 10-25% every 1-2 weeks) based on response. Abrupt cessation should be avoided, particularly in high-risk , and adjunctive therapies such as supportive counseling or short-term use of alternative agents may be employed for severe cases to alleviate acute symptoms like seizures or profound . Close clinical supervision is essential to adjust the taper pace if withdrawal emerges, ensuring safe discontinuation while addressing underlying sleep or anxiety issues.

Overdose and Toxicity

Symptoms and Management

Overdose with flurazepam typically presents with , manifesting as extreme drowsiness (), , , slurred speech, and in severe cases, progression to . Respiratory depression, , , and diminished reflexes may also occur, though profound respiratory compromise is uncommon in isolated flurazepam ingestions. Paradoxical reactions, such as excitation or agitation, can rarely emerge in some individuals during overdose. In severe cases, and may develop, particularly when flurazepam is combined with opioids, alcohol, or other depressants, increasing the risk of fatality. is primarily clinical, based on and presentation, as serum flurazepam levels are not routinely useful for guiding acute . of flurazepam overdose focuses on supportive care, beginning with assessment and stabilization of airway, breathing, and circulation (ABC). , including respiration, , and , should be continuously monitored, with intravenous fluids administered to address and an adequate airway maintained, potentially requiring endotracheal in cases of or . If ingestion occurred within the past hour, activated charcoal may be given to reduce absorption, though is rarely indicated unless the airway is protected. Flumazenil, a , can be used cautiously in hospitalized patients to reverse and , but only after securing the airway and intravenous access; it is not routinely recommended due to risks of precipitating seizures, particularly in chronic users or mixed overdoses. There is no specific for flurazepam beyond supportive measures, and dialysis is of undetermined value. Prognosis is generally favorable with prompt intervention, as isolated flurazepam overdoses are rarely fatal, though outcomes worsen with co-ingestants. Toxicology studies indicate a high margin of , with oral LD50 values exceeding 500 mg/kg in animals (e.g., 870 mg/kg in mice, 1,232 mg/kg in rats).

Risk Factors

Several risk factors contribute to the increased likelihood and severity of flurazepam overdose or toxicity. Concurrent use of flurazepam with other (CNS) depressants, such as alcohol, opioids, or other sedatives, significantly heightens the risk due to synergistic effects on respiratory depression and . This polydrug interaction is a leading cause of fatal outcomes, as it amplifies the effects beyond what either substance alone would produce. Patient-specific factors play a critical role in overdose vulnerability. Elderly individuals are particularly susceptible because of age-related pharmacokinetic changes, including a prolonged elimination of flurazepam's (desalkyl-flurazepam), which can extend to 160 hours compared to 74 hours in younger adults, leading to drug accumulation and enhanced CNS depression. Hepatic impairment further exacerbates this risk by impairing and clearance, resulting in higher systemic exposure and potential even at standard doses. Additionally, a history of increases the propensity for misuse and intentional high-dose ingestion, compounding overdose potential. Behavioral and pharmacological elements also elevate risks. Intentional overdose often occurs in suicide attempts, where flurazepam may be chosen for its properties. Accidental overdoses are more common in children or cognitively impaired patients due to unintentional or dosing errors. Pharmacologically, flurazepam's long-acting nature, driven by its metabolite's extended , predisposes users to unintentional accumulation with repeated dosing, mimicking overdose symptoms over time. Epidemiologically, flurazepam overdoses as a sole agent are rare, but benzodiazepines like flurazepam contribute substantially to broader patterns of drug-related visits, often alongside other substances. From 2019 to 2020, benzodiazepine overdose emergency visits rose by 23.7%, with notable increases in cases involving opioids. Prevention strategies focus on mitigating these risks through targeted measures. Limiting prescription quantities and durations to the minimum necessary reduces accumulation potential, as recommended for concurrent use with other depressants. on recognizing early signs of overdose, avoiding alcohol or other CNS depressants, and adhering to dosing instructions is essential to minimize accidental or intentional misuse.

Abuse Potential

Flurazepam, a long-acting , possesses moderate potential compared to other agents in its class, with laboratory assessments indicating a relative liability score of approximately 38% based on measures such as animal self-administration, human subjective liking, and documented misuse rates. At high doses, it can produce and profound , leading to recreational use primarily for its calming effects rather than intense psychoactive highs associated with shorter-acting benzodiazepines. This lower profile contributes to its reduced appeal among recreational users seeking rapid onset effects, though it remains a concern in populations with histories of substance misuse. Non-medical use of flurazepam typically involves oral administration, often through diversion from legitimate prescriptions or illicit procurement, with patterns frequently observed in polydrug contexts such as combinations with opioids, alcohol, or stimulants to enhance sedation or mitigate withdrawal. Misuse is more common among individuals self-medicating insomnia or anxiety rather than in party or high-dose binge scenarios. Chronic non-medical use of flurazepam carries a high of physical and , contributing to characterized by tolerance, compulsive seeking, and severe withdrawal upon cessation. This dependence arises from its long and active metabolites, which sustain effects and reinforce repeated dosing. Epidemiologically, flurazepam represents a relatively low share of reported benzodiazepine abuse cases in national surveys, reflecting its declining prevalence since the introduction of non- hypnotics like and , which offer shorter durations and reduced next-day impairment. As of 2024, approximately 3.9 million people in the reported past-year misuse of benzodiazepines, with flurazepam infrequently mentioned due to its limited current prescribing. Benzodiazepine misuse, including patterns potentially involving flurazepam, is more prevalent among young adults aged 18-25 with polydrug histories, though overall rates have declined slightly in recent years amid increased regulatory scrutiny. Due to its extended elimination profile, flurazepam and its metabolites can be detected in urine screens for 2-4 weeks following last use, complicating identification in monitoring and forensic contexts. Misuse of flurazepam heightens health risks including blackouts, impaired coordination leading to accidents, and potentiated respiratory depression when combined with other depressants, potentially resulting in overdose.

Regulatory Classification

In the United States, flurazepam is classified as a Schedule IV under the (CSA), administered by the (DEA), indicating a low potential for abuse relative to substances in Schedule III. As a Schedule IV drug, it requires a valid prescription from a licensed healthcare provider for dispensing, and pharmacists must adhere to federal and state regulations on handling and storage. This scheduling was established in 1975 through amendments to the CSA, with no rescheduling occurring as of 2025. Internationally, flurazepam is listed in Schedule IV of the (1971), which harmonizes controls across signatory nations to limit production, trade, and distribution while allowing medical and scientific use. In the , it is regulated as a prescription-only under Directive 2001/83/EC, aligning with the UN Schedule IV classification and requiring strict authorization for , and supply. Similarly, in , flurazepam is a Schedule IV substance under the , necessitating a prescription and subjecting it to federal monitoring for controlled substances. Prescription regulations for flurazepam in the permit up to five refills within six months of the original issuance under , though some states impose stricter limits, such as prohibiting automatic refills or requiring a new prescription after the initial fill. All prescriptions are monitored through state Prescription Drug Monitoring Programs (PDMPs), which track dispensing to prevent diversion and overuse. These controls extend to implications such as quantity limits—typically a 30-day supply per prescription—and mandatory reporting of theft or loss to the DEA or local authorities to curb potential misuse.

History and Society

Development and Approval

Flurazepam was synthesized in the 1960s by chemist Leo H. Sternbach and his team at Hoffmann-La Roche as part of the company's ongoing development program, which began with the discovery of chlordiazepoxide in 1955. This work built on Sternbach's earlier innovations in the 1,4- class, aiming to create compounds with enhanced properties for treating disorders. The specific synthesis of flurazepam, chemically known as 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one, was detailed in a key process filed in 1968, marking it as one of the earliest long-acting hypnotics. Clinical trials in the late 1960s demonstrated flurazepam's efficacy in treating , showing significant improvements in onset and maintenance compared to , with approval recommended for short-term use to minimize risks of tolerance. For instance, a study reported effective induction and reduced awakenings in subjects with after short- and long-term administration, supporting its profile without immediate evidence of severe adverse effects in controlled settings. The U.S. (FDA) approved flurazepam in 1970 under the brand name Dalmane for the short-term management of and anxiety symptoms, positioning it as a safer alternative to barbiturates then prevalent for similar indications. Following approval, research in the and increasingly focused on long-term risks, revealing issues such as tolerance, dependence, and withdrawal symptoms with prolonged use beyond the recommended short-term duration. A 1982 clinical pharmacology study, for example, examined extended use of flurazepam and found persistent efficacy but noted side effects like daytime sedation and potential for rebound upon discontinuation. In response to accumulating evidence on dependence risks, the FDA updated the Dalmane prescribing information in April 2007 to include strengthened warnings about the potential for , , and severe withdrawal, emphasizing short-term use only. Sales of Dalmane peaked in the 1970s as hypnotics gained widespread adoption for treatment, accounting for a significant share of the market at the time. However, usage declined in subsequent decades with the emergence of non- "Z-drugs" like in the early 1990s, which offered shorter half-lives and perceived lower risk of next-day impairment and dependence.

Availability and Brand Names

Flurazepam is available primarily as a generic medication following the expiration of the original for its brand name formulation in 1984. The original brand name, Dalmane, was marketed by and has since been discontinued in most markets, though generic versions of flurazepam capsules (typically in 15 mg and 30 mg strengths) are produced by several manufacturers, including Pharmaceuticals and others such as Teva and (prior to Mylan's discontinuation of production). In the United States, flurazepam remains available by prescription only for the short-term treatment of , with generic formulations accessible through pharmacies despite periodic shortages; for instance, after a manufacturing discontinuation by in 2019, relaunched supply in November 2023, and it continues to be used as of 2025, though regulatory delays have occasionally impacted availability. In , it is marketed under generic names by companies like AA Pharma and remains prescription-only. Within the , availability varies by country, with formulations such as Dalmadorm still accessible in select markets like and , but it requires a prescription and is subject to strict regulations. In the , flurazepam is not prescribable in NHS due to concerns over dependency risks and the availability of safer alternatives, though it remains licensed for use in secondary care; certain formulations or suppliers may have been discontinued. Flurazepam is no longer considered a first-line treatment for insomnia according to major clinical guidelines, which prioritize and non-benzodiazepine hypnotics like over long-acting benzodiazepines due to risks of tolerance and next-day impairment. Generic versions are low-cost, typically ranging from $20 to $50 for a month's supply of 30 capsules, and are often covered by for approved short-term uses in regions where it remains available. Access has been phased out in several markets in favor of newer, shorter-acting agents perceived as safer, contributing to its limited global presence. Additionally, there are no dedicated pediatric formulations, and use in children under 15 years is not recommended due to insufficient safety data.

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