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Flurazepam

Pronunciation

Pronunciation

(flure AZ e pam)

Index Terms

  • Flurazepam Hydrochloride

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, Oral, as hydrochloride:

Generic: 15 mg, 30 mg

Pharmacologic Category

  • Hypnotic, Benzodiazepine

Pharmacology

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)

Metabolism

Hepatic to N-desalkylflurazepam (active) and N-hydroxyethylflurazepam

Excretion

Urine: N-hydroxyethylflurazepam (22% to 55%); N-desalkylflurazepam (<1%)

Time to Peak

Flurazepam: 30 to 60 minutes; N-desalkylflurazepam: 10.6 hours (range: 7.6 to 13.6 hours); N-hydroxyethylflurazepam: ~1 hour (Greenblatt, 1989)

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

Protein Binding

Flurazepam: ~97%; N-desalkylflurazepam: ~98% (Vozeh, 1988)

Use: Labeled Indications

Insomnia: For the treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early-morning awakenings.

Contraindications

Hypersensitivity to flurazepam, other benzodiazepines, or any component of the formulation; pregnancy

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.

Dosing: Adult

Insomnia: Adults: Oral: Initial: 15 mg at bedtime for women, and 15 to 30 mg at bedtime for men; may increase dose to 30 mg at bedtime as needed based on response

Dosing: Geriatric

Oral: 15 mg at bedtime

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling; use with caution.

Storage

Store at 20°C to 25°C (68°F to 77°F); protect from light.

Drug Interactions

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Aprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Bosentan: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

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 patches (Butrans brand) at 5 mcg/hr in adults when used with other CNS depressants. Consider therapy modification

Cannabis: May enhance the CNS depressant effect of CNS Depressants. 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. Consider therapy modification

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 Substrates. Monitor therapy

CYP3A4 Inhibitors (Strong): May decrease the metabolism of CYP3A4 Substrates. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates. Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification

Dasatinib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Dimethindene: May enhance the CNS depressant effect of CNS Depressants. 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. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (e.g., opioids, barbiturates) with concomitant use. Consider therapy modification

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates. Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosamprenavir: May increase the serum concentration of Flurazepam. Monitor therapy

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates. Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates. Avoid combination

Ivacaftor: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Luliconazole: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methadone: Benzodiazepines may enhance the CNS depressant effect of Methadone. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates. Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mirtazapine: CNS Depressants may enhance the CNS depressant effect of Mirtazapine. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates. Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

OLANZapine: May enhance the adverse/toxic effect of Benzodiazepines. Management: Avoid concomitant use of parenteral benzodiazepines and IM olanzapine due to risks of additive adverse events (e.g., cardiorespiratory depression). Olanzapine prescribing information provides no specific recommendations regarding oral administration. Avoid combination

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: When oxycodone is combined with another CNS depressant, a dose reduction of one or both agents should be considered. The extended release oxycodone starting dose should be reduced 50% to 67% when initiated in patients already receiving CNS depressants. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil [INT]: CNS Depressants may enhance the CNS depressant effect of Piribedil [INT]. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Ritonavir: May increase the serum concentration of Flurazepam. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Saquinavir: May increase the serum concentration of Flurazepam. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates. Monitor therapy

Sodium Oxybate: Benzodiazepines may enhance the CNS depressant effect of Sodium Oxybate. Avoid combination

St John's Wort: May decrease the serum concentration of CYP3A4 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates. Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

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. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Teduglutide: May increase the serum concentration of Benzodiazepines. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Theophylline Derivatives: May diminish the therapeutic effect of Benzodiazepines. Consider therapy modification

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Yohimbine: May diminish the therapeutic effect of Antianxiety Agents. 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. Consider therapy modification

Adverse Reactions

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% (Limited to important or life-threatening): Anaphylaxis, angioedema, parasomnias (cooking while sleeping, making phone calls while sleeping, sleep driving, sleep eating)

Warnings/Precautions

Concerns related to adverse effects:

• Anterograde amnesia: Benzodiazepines have been associated with anterograde amnesia.

• CNS effects: Abnormal thinking and behavior changes including symptoms of decreased inhibition (eg, excessive aggressiveness and extroversion), bizarre behavior, agitation, hallucinations, and depersonalization have been reported with the use of benzodiazepine hypnotics. Some evidence suggests symptoms may be dose related.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or 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 agitation, increased muscle spasticity, and sleep disturbances, have been reported with benzodiazepines, particularly in adolescent/pediatric or psychiatric patients.

• Sleep-related activities: An increased risk for hazardous sleep-related activities such as sleep-driving, cooking and eating food, having sex, and making phone calls while asleep have also been noted. Concurrent use of alcohol and other CNS depressants as well as increases in dose may increase the risk of these behaviors.

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.

• Drug abuse: Use with caution in patients with a history of drug abuse or acute alcoholism; potential for drug dependency exists. Tolerance, psychological and physical dependence may occur with prolonged use.

• 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.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Debilitated patients: Use with caution in debilitated patients.

• Fall risk: Use with extreme caution in patients who are at risk of falls; benzodiazepines have been associated with falls and traumatic injury.

Other warnings/precautions:

• 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.

• 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: Rebound or withdrawal symptoms may occur following abrupt discontinuation or large decreases in dose. Use caution when reducing dose or withdrawing therapy; decrease slowly and monitor for withdrawal symptoms. Flumazenil may cause withdrawal in patients receiving long-term benzodiazepine therapy.

Monitoring Parameters

Daytime alertness; respiratory rate; behavior profile

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in animal reproduction studies for benzodiazepines. 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.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue (next day). Have patient report immediately to prescriber signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), hallucinations, memory impairment, severe dizziness, change in balance, confusion, behavioral changes, or severe loss of strength and energy (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment, in diagnosing, treating, and advising patients.

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