Flurazepam

Approved Indications:

• Insomnia
• Short-term treatment of insomnia characterized by difficulty falling asleep, frequent nocturnal awakenings, and/or early morning awakening.
• Particularly indicated in patients who experience significant daytime impairment due to lack of sleep.

Clinically Accepted Off-Label Uses:

• Nighttime Sedation in Preoperative Patients
• Used for short-term sedation prior to surgical procedures in certain hospitalized patients.
• Adjunct in Anxiety Disorders (short-term)
• Occasionally used to aid sleep in patients with anxiety-related insomnia, although not a primary anxiolytic.
• Sleep Maintenance Disorders in Geriatric Patients
• Used with caution and under close monitoring due to fall risk and cognitive side effects.

Route of Administration: Oral
Formulations Available: Capsules (15 mg, 30 mg)

Adults:

• Initial dose: 15 mg orally at bedtime.
• Maintenance dose: May be increased to 30 mg if needed.
• Duration: Use should be limited to 7–10 consecutive nights; reassess need thereafter.

Elderly or Debilitated Patients:

• Recommended dose: 15 mg at bedtime.
• Use lowest effective dose due to heightened sensitivity and risk of prolonged sedation and falls.

Pediatrics:

• Not recommended. Safety and efficacy in children have not been established.

Renal Impairment:

• No dosage adjustment formally recommended, but caution advised due to potential for accumulation of active metabolites.

Hepatic Impairment:

• Use with caution. Impaired hepatic metabolism may prolong drug half-life. Initiate with the lowest dose.

Important Administration Notes:

• Take immediately before bedtime.
• Do not take with or shortly after a high-fat meal (may delay onset of action).
• Avoid operating machinery or driving the next morning if drowsiness persists.

Flurazepam is a long-acting benzodiazepine that enhances the effect of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-A receptor. It binds to a specific benzodiazepine site on the receptor complex, increasing the frequency of chloride channel opening, leading to membrane hyperpolarization. This results in sedative, anxiolytic, muscle relaxant, and anticonvulsant effects. Flurazepam's metabolite (N-desalkylflurazepam) is pharmacologically active and contributes to prolonged hypnotic effects, making it suitable for sleep maintenance.

• Absorption: Well absorbed orally; peak plasma concentrations in 30–60 minutes.
• Bioavailability: High (~80–90%)
• Distribution: Widely distributed; lipophilic; crosses blood-brain and placental barriers.
• Protein Binding: ~80%
• Metabolism: Extensively hepatic via cytochrome P450 (primarily CYP3A4).
• Major active metabolite: N-desalkylflurazepam (long half-life)
• Elimination Half-Life:
• Flurazepam: 2–3 hours
• N-desalkylflurazepam: 40–100 hours (responsible for long-lasting effects)
• Excretion: Primarily renal (urine); some fecal excretion.

Pregnancy:

• FDA Pregnancy Category: X (formerly D) – Not recommended during pregnancy.
• Benzodiazepines may cause fetal harm, including congenital malformations (e.g., cleft lip/palate), floppy infant syndrome, and neonatal withdrawal symptoms.

Lactation:

• Flurazepam is excreted into breast milk in small amounts.
• Recommendation: Avoid during breastfeeding. May cause sedation, respiratory depression, or poor feeding in the nursing infant.

Summary: Contraindicated in pregnancy. Use during lactation only if the potential benefit outweighs the risk.

• Primary Class: Benzodiazepine
• Subclass: Long-acting hypnotic benzodiazepine
• Pharmacological Class: CNS depressant

• Known hypersensitivity to flurazepam or any benzodiazepine derivative
• Acute narrow-angle glaucoma
• Severe respiratory insufficiency (e.g., sleep apnea syndrome)
• Myasthenia gravis
• Pregnancy (Category X)
• History of substance abuse or addiction (relative contraindication)

• CNS Depression: Risk of daytime drowsiness, confusion, memory impairment.
• Dependence & Withdrawal: Prolonged use may lead to physical and psychological dependence. Gradual tapering recommended.
• Fall Risk in Elderly: Due to long half-life and residual sedation.
• Paradoxical Reactions: May cause agitation, irritability, or aggression, especially in elderly or psychiatric patients.
• Respiratory Depression: Use with caution in patients with compromised respiratory function.
• Use with CNS Depressants: Increased risk of profound sedation, respiratory depression, coma, and death when used with opioids or alcohol.
• Driving & Machinery: May impair performance even the next day due to active metabolites.

Common (≥1%):

• CNS: Drowsiness, dizziness, next-day sedation, fatigue, headache, ataxia
• Gastrointestinal: Dry mouth, nausea, constipation
• Psychiatric: Confusion, irritability, impaired memory

Less Common:

• Blurred vision
• Muscle weakness
• Vertigo

Serious/Rare:

• Respiratory depression (especially with other CNS depressants)
• Anaphylaxis, angioedema
• Paradoxical reactions (agitation, hallucinations)
• Depression or suicidal ideation
• Dependency and withdrawal syndrome (after prolonged use)

Major Drug-Drug Interactions:

• CNS Depressants (opioids, alcohol, antihistamines, antipsychotics): Additive sedative effects; increased risk of respiratory depression and death.
• CYP3A4 Inhibitors (e.g., ketoconazole, erythromycin): May increase flurazepam levels and prolong sedation.
• CYP3A4 Inducers (e.g., rifampin, carbamazepine): May decrease efficacy by increasing metabolism.
• Theophylline & Caffeine: May reduce sedative effects.

Drug-Food Interactions:

• High-fat meals may delay onset of sleep-inducing action.
• Alcohol potentiates sedative effects and increases risk of toxicity.

Drug-Alcohol Interaction:
Contraindicated. Risk of extreme sedation, respiratory suppression, coma.

• FDA and EMA have reaffirmed that flurazepam is not recommended for chronic insomnia due to long half-life and dependency risk.
• Beers Criteria (2023): Flurazepam is strongly discouraged in elderly due to prolonged sedation and fall risk.
• Alternative agents with shorter half-lives (e.g., temazepam or zolpidem) are now preferred in most guidelines.
• Black Box Warning (class-wide): Risks of serious side effects when used with opioids, including death.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Excursions: Permitted between 15°C to 30°C (59°F to 86°F)
• Light: Store in a tight, light-resistant container
• Moisture: Protect from moisture; keep container tightly closed
• Handling Precautions: Keep out of reach of children. Avoid exposure to heat.
• Disposal: Discard unused medication properly; do not flush down the toilet unless instructed.