Flurazepam Hydrochloride – FLURAZEPAM®

• FLURAZEPAM®

• Benzodiazepine

• Flurazepam Hydrochloride Capsules USP 15 mg and 30 mg

• Sleep disturbance:
  • Symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakening.
  • Treatment should usually not exceed 7-10 consecutive days.

Pharmacodynamics:

• Mechanism of action: Long acting benzodiazepine that depresses all level of CNS (e.g. limbic and reticular formation) by increasing activity of GABA.

Pharmacokinetics: 

• Metabolism: Flurazepam undergoes rapid and pronounced metabolism to two pharmacologically active metabolites via glucuronic acid conjugation
• Excretion: mainly urine
• Half-life elimination: 48-120 hours
• Peak plasma time:5-3 hours
• Peak plasma concentration: 0.5-4 ng/ml

• Treatment should be as short as possible, and should not exceed 7-10 consecutive days.
• Dosage should be individualized for maximal beneficial effects.
• Adults:
  • Usual adult dosage: 30 mg before retiring
• Elderly and/or Debilitated Patients:
  • Initial recommended dosage: 15 mg

1. Produce additive CNS depressant effects when co-administered with:

• Alcohol,
• Sedative Antihistamines,
• Narcotic Analgesics,
• Anticonvulsants,
• Psychotropic Medications.

2. Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) enhance the activity of Flurazepam:

• Cimetidine
• Erythromycin

• Most Common:
  • Dizziness, drowsiness, lightheadedness, and ataxia.
• Less Common:
  • headache, heartburn, upset stomach, nausea, vomiting, amnesia, constipation, diarrhea, gastrointestinal pain, nervousness, apprehension, irritability, weakness, palpitations, chest pains, genitourinary complaints
• Rare symptoms:
  • leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations, nightmares, numbed emotions, reduced alertness, changes in libido, inappropriate behavior and elevated SGOT, SGPT, total and direct bilirubin, and alkaline phosphatase, Paradoxical reactions such as excitement, stimulation, agitation, aggressiveness, rages, psychoses and hyperactivity.

1. Hypersensitivity to benzodiazepines or any component of its formulation
2. Severe impairment of respiratory function (sleep apnea syndrome)
3. Myasthenia gravis
4. Severe hepatic insufficiency

• Pregnancy: category C
• Lactation: not recommended in nursing mothers.

1. Concomitant use with alcohol: should be used with extreme caution in patients with a history of alcohol abuse.
2. Elderly:
   1. Inappropriate and heavy sedation in the elderly, may result in accidental events/falls >>> the smallest possible effective dose should be prescribed.
   2. The lowest possible dose (15 mg) should be used in these subjects.
3. Failure of insomnia remission after 7-10 days: indicate the presence of a primary psychiatric and/or medical illness or the presence of sleep- state misperception.
4. Worsening of insomnia or the emergence of new abnormalities of thinking or behavior: may be the consequence of an unrecognized psychiatric or physical disorder.
5. Caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.
6. Anterograde amnesia:
   1. in the most common type of memory problem in patients using flurazepam,
   2. dose-related phenomenon,
   3. elderly are high risk group
7. Transient global amnesia and “traveler’s amnesia”:
   1. Especially in individuals who have taken benzodiazepines, often in the middle of the night, to induce sleep while travelling.
   2. Unpredictable
   3. Not necessarily dose-related phenomena.
8. Abnormal thinking and psychotic behavioral changes:
   1. Changes characterized by decreased inhibition, e.g., aggressiveness or extroversion
   2. Particular caution in patients with a history of violent behavior and unusual reactions to sedatives including alcohol and the benzodiazepines.
   3. Psychotic behavioral changes include: bizarre behavior, hallucinations, and depersonalization.
9. Confusion:
   1. The benzodiazepines affect mental efficiency (e.g., concentration, attention and vigilance.)
   2. The risk of confusion is in greater in: elderly, patients with cerebral impairment.
10. Anxiety & Restlessness: especially daytime anxiety and/or restlessness
11. Depression: Caution in patients with signs or symptoms of depression because:
    1. Flurazepam could intensify the disease,
    2. There is a potential risk for self-harm (e.g., intentional overdose)
12. Complex Sleep-related Behaviors:
    1. Complex sleep-related behaviors such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken flurazepam hydrochloride. Other potentially dangerous behaviors have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events.
13. Usage of alcohol and other CNS-depressants with flurazepam:
    1. Flurazepam should not to be taken with alcohol.
    2. Caution is needed with concomitant use of other CNS depressant drugs.
14. Severe Anaphylactic and Anaphylactoid Reactions:
    1. A severe and rare side effect involving the tongue, glottis or larynx
    2. Additional symptoms include dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis.
    3. If angioedema involves the throat, glottis or larynx >>> airway obstruction may occur and be fatal >>> Patients with history of angioedema after treatment should not be re-challenged with the drug.
15. Flurazepam additive CNS depressant effect:
    1. When co-administered with alcohol, sedative antihistamines, narcotic analgesics, anticonvulsants, or psychotropic medications.
16. Concomitant use with compounds which inhibit certain hepatic enzymes:
    1. Enhance the activity of benzodiazepines (e.g. Cimetidine or erythromycin)
17. Drug Abuse Dependence and Withdrawal:
    1. Withdrawal symptoms: convulsions, tremor, abdominal and muscle cramps, vomiting, sweating, dysphoria, perceptual disturbances and insomnia
    2. Gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks.
    3. The recommendation for tapering is particularly important in patients with a history of seizures.
    4. The risk of dependence increased in: patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders.
18. Influence on sleep:
    1. Flurazepam decreases sleep latency and number of awakenings for a consequent increase in total sleep time.
19. Rebound Insomnia:
    1. A transient syndrome whereby the symptoms that led to treatment with a benzodiazepines recur in an enhanced form, may occur on withdrawal of hypnotic treatment.
20. Caution in patients with Specific Conditions:
    1. Impaired hepatic and renal function
    2. Compromised respiratory function.
21. Caution in patients Requiring Mental Alertness:
    1. Because of Flurazepam’s (flurazepam hydrochloride) CNS depressant effect, patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle.
22. Use in Children: should not be used in children below the age of 15
23. Laboratory Tests in the case of repeated usage:
    1. periodic blood counts,
    2. liver, and kidney function tests
24. Overdosage:
    1. Manifestations overdosage include: somnolence, confusion and coma.
    2. Treatment is supportive.
    3. The benzodiazepine antagonist: flumazenil (‘Anexate’), is a specific antidote.