Flurazepam

Pronunciation

(flure AZ e pam)

U.S. Brand Names

Dalmane®

Synonyms

Flurazepam Hydrochloride

Generic Available

Yes

Canadian Brand Names

Apo-Flurazepam®; Dalmane®

Use

Short-term treatment of insomnia

Restrictions

C-IV

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to flurazepam or any component of the formulation (cross-sensitivity with other benzodiazepines may exist); narrow-angle glaucoma; pregnancy

Warnings/Precautions

Use with caution in elderly or debilitated patients, patients with hepatic disease (including alcoholics), or renal impairment. Active metabolites with extended half-lives may lead to delayed accumulation and adverse effects. Use with caution in patients with respiratory disease, or impaired gag reflex. Avoid use in patients with sleep apnea.

Causes CNS depression (dose-related) resulting in sedation, dizziness, confusion, or ataxia which may impair physical and mental capabilities. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Use with caution in patients receiving other CNS depressants or psychoactive agents. Effects with other sedative drugs or ethanol may be potentiated. Benzodiazepines have been associated with falls and traumatic injury and should be used with extreme caution in patients who are at risk of these events (especially the elderly).

Use caution in patients with depression, particularly if suicidal risk may be present. Use with caution in patients with a history of drug dependence. Benzodiazepines have been associated with dependence and acute withdrawal symptoms on discontinuation or reduction in dose (may occur after as little as 10 days of use). Acute withdrawal, including seizures, may be precipitated in patients after administration of flumazenil to patients receiving long-term benzodiazepine therapy.

As a hypnotic, should be used only after evaluation of potential causes of sleep disturbance. Failure of sleep disturbance to resolve after 7-10 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.

Benzodiazepines have been associated with anterograde amnesia. Paradoxical reactions, including hyperactive or aggressive behavior have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients. Does not have analgesic, antidepressant, or antipsychotic properties.

Adverse Reactions

Frequency not defined.

Cardiovascular: Palpitations, chest pain

Central nervous system: Drowsiness, ataxia, lightheadedness, memory impairment, depression, headache, hangover effect, confusion, nervousness, dizziness, falling, apprehension, irritability, euphoria, slurred speech, restlessness, hallucinations, paradoxical reactions, talkativeness

Dermatologic: Rash, pruritus

Gastrointestinal: Xerostomia, constipation, increased/excessive salivation, heartburn, upset stomach, nausea, vomiting, diarrhea, increased or decreased appetite, bitter taste, weight gain/loss

Hematologic: Granulocytopenia

Hepatic: Elevated AST/ALT, total bilirubin, alkaline phosphatase, cholestatic jaundice

Neuromuscular & skeletal: Dysarthria, body/joint pain, reflex slowing, weakness

Ocular: Blurred vision, burning eyes, difficulty focusing

Otic: Tinnitus

Respiratory: Apnea, dyspnea

Miscellaneous: Diaphoresis, drug dependence

Overdosage/Toxicology

Symptoms of overdose include respiratory depression, hypoactive reflexes, unsteady gait, and hypotension. Treatment for benzodiazepine overdose is supportive. Flumazenil has been shown to selectively block the binding of benzodiazepines to CNS receptors, resulting in a reversal of benzodiazepine-induced CNS depression. Respiratory depression may not be reversed.

Drug Interactions

Substrate of CYP3A4 (major); Inhibits CYP2E1 (weak)

CNS depressants: Sedative effects and/or respiratory depression may be additive with CNS depressants; includes ethanol, barbiturates, narcotic analgesics, and other sedative agents; monitor for increased effect

CYP3A4 inducers: CYP3A4 inducers may decrease the levels/effects of flurazepam. Example inducers include aminoglutethimide, carbamazepine, nafcillin, nevirapine, phenobarbital, phenytoin, and rifamycins.

CYP3A4 inhibitors: May increase the levels/effects of flurazepam. Example inhibitors include azole antifungals, ciprofloxacin, clarithromycin, diclofenac, doxycycline, erythromycin, imatinib, isoniazid, nefazodone, nicardipine, propofol, protease inhibitors, quinidine, and verapamil.

Levodopa: Therapeutic effects may be diminished in some patients following the addition of a benzodiazepine; limited/inconsistent data

Oral contraceptives: May decrease the clearance of some benzodiazepines (those which undergo oxidative metabolism); monitor for increased benzodiazepine effect

Theophylline: May partially antagonize some of the effects of benzodiazepines; monitor for decreased response; may require higher doses for sedation

Ethanol/Nutrition/Herb Interactions

Ethanol: Avoid ethanol (may increase CNS depression).

Food: Serum levels and response to flurazepam may be increased by grapefruit juice, but unlikely because of flurazepam's high oral bioavailability.

Herb/Nutraceutical: Avoid valerian, St John's wort, kava kava, gotu kola (may increase CNS depression).

Stability

Store in light-resistant containers

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Onset of action: Hypnotic: 15-20 minutes

Peak effect: 3-6 hours

Duration: 7-8 hours

Metabolism: Hepatic to N-desalkylflurazepam (active)

Half-life elimination: Desalkylflurazepam:

Adults: Single dose: 74-90 hours; Multiple doses: 111-113 hours

Elderly (61-85 years): Single dose: 120-160 hours; Multiple doses: 126-158 hours

Dosage

Oral:

Children: Insomnia:

15 years: Dose not established

>15 years: 15 mg at bedtime

Adults: Insomnia: 15-30 mg at bedtime

Elderly: Insomnia: Oral: 15 mg at bedtime; avoid use if possible

Monitoring Parameters

Respiratory and cardiovascular status

Reference Range

Therapeutic: 0-4 ng/mL (SI: 0-9 nmol/L); Metabolite N-desalkylflurazepam: 20-110 ng/mL (SI: 43-240 nmol/L); Toxic: >0.12 mcg/mL

Patient Education

Use exactly as directed; do not increase dose or frequency or discontinue without consulting prescriber. Drug may cause physical and/or psychological dependence. May take with food to decrease GI upset. While using this medication, do not use alcohol or other prescription or OTC medications (especially, pain medications, sedatives, antihistamines, or hypnotics) without consulting prescriber. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. You may experience drowsiness, dizziness, lightheadedness, or blurred vision (use caution when driving or engaging in tasks requiring alertness until response to drug is known); dry mouth, nausea, or vomiting (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); difficulty urinating (void before taking medication); or altered libido (resolves when medication is discontinued). Report CNS changes (confusion, depression, increased sedation, excitation, headache, abnormal thinking, insomnia, or nightmares, memory impairment, impaired coordination); muscle pain or weakness; respiratory difficulty; persistent dizziness, chest pain, or palpitations; alterations in normal gait; vision changes; ringing in ears; or ineffectiveness of medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are pregnant. Do not get pregnant during or for 1 month following therapy. Consult prescriber for instruction on appropriate contraceptive measures. This drug may cause severe fetal defects. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

Chronic use of this agent may increase the perioperative benzodiazepine dose needed to achieve desired effect. Abrupt discontinuation after sustained use (generally >10 days) may cause withdrawal symptoms.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Xerostomia and changes in salivation (normal salivary flow resumes upon discontinuation), and bitter taste.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Dosage Forms

Capsule, as hydrochloride: 15 mg, 30 mg

References

Maletta G, Mattox KM, and Dysken M, "Guidelines for Prescribing Psychoactive Drugs in the Elderly: Part 1," Geriatrics , 1991, 46(9):40-7.

Mokhlesi B, Leikin JB, Murray P, et al, "Adult Toxicology in Critical Care: Part II: Specific Poisonings," Chest , 2003, 123(3):897-922.

Reidenberg MM, Levy M, Warner H, et al, "Relationship Between Diazepam Dose, Plasma Level, Age, and Central Nervous System Depression," Clin Pharmacol Ther , 1978, 23(4):371-4.

Ruff RL, Kutt H, and Hafler D, "Prolonged Benzodiazepine Coma," N Y State J Med , 1981, 81(5):776-7.

Stringer MD, "Adult Respiratory Distress Syndrome Associated With Flurazepam Overdose," J R Soc Med , 1985, 78(1)1:74-5.

International Brand Names

Alcutin® (BD); Apo-Flurazepam® (CA); Benozil® (JP); Dalmadorm® (BR, CH, DE, HK, IT, NL, PT, SG, TH, ZA); Dalmane® (CA, GB, IE); Dormodor® (ES); Felison® (IT); Fluraz® (IN); Fluzepam® (HR, SI); Fordrim® (AR); Insumin® (JP); Morfex® (PT); Noctosom® (IL); Remdue® (IT); Somlan® (AR); Staurodorm® (BE, DE, EG, LU); Valdorm® (IT)

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