FLURAZEPAM HCL
DESCRIPTION:
Flurazepam hydrochloride is chemically 7-chloro- 1-(2-(diethylamino)ethyl)-5-(O-
fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin- 2-one dihydrochloride. It is a
pale yellow, crystalline compound, freely soluble in USP alcohol and very
soluble in water. It has a molecular weight of 460.826.
ACTIONS/CLINICAL PHARMACOLOGY:
Flurazepam hydrochloride is rapidly absorbed from the GI tract. Flurazepam is
rapidly metabolized and is excreted primarily in the urine. Following a single
oral dose, peak flurazepam plasma concentrations ranging from 0.5 to 4.0 ng/mL
occur at 30 to 60 minutes post-dosing. The harmonic mean apparent half-life of
flurazepam is 2.3 hours. The blood level profile of flurazepam and its major
metabolites was determined in man following the oral administration of 30 mg
daily for 2 weeks. The N1-hydroxyethyl-flurazepam was measurable only during the
early hours after a 30-mg dose and was not detectable after 24 hours. The major
metabolite in blood was N1-desalkyl- flurazepam, which reached steady-state
(plateau) levels after 7 to 10 days of dosing, at levels approximately 5 to 6-
fold greater than the 24-hour levels observed on Day 1. The half-life of
elimination of N1-desalkyl-flurazepam ranged from 47 to 100 hours. The major
urinary metabolite is conjugated N1-hydroxyethyl- flurazepam which accounts for
22% to 55% of the dose. Less than 1% of the dose is excreted in the urine as N1-
desalkyl-flurazepam.
This pharmacokinetic profile may be responsible for the clinical observation
that flurazepam is increasingly effective on the second or third night of
consecutive use and that for 1 or 2 nights after the drug is discontinued both
sleep latency and total wake time may still be decreased.
INDICATIONS AND USAGE:
NINDRAL is a hypnotic agent useful for the treatment of insomnia characterized
by difficulty in falling asleep, frequent nocturnal awakenings, and/or early
morning awakening. NINDRAL can be used effectively in patients with recurring
insomnia or poor sleeping habits, and in acute or chronic medical situations
requiring restful sleep. Sleep laboratory studies have objectively determined
that NINDRAL is effective for at least 28 consecutive nights of drug
administration. Since insomnia is often transient and intermittent, short-term
use is usually sufficient. Prolonged use of hypnotics is usually not indicated
and should only be undertaken concomitantly with appropriate evaluation of the
patient.
CONTRAINDICATIONS:
NINDRAL is contraindicated in patients with known hypersensitivity to the drug.
Usage In Pregnancy: Benzodiazepines may cause fetal damage when administered
during pregnancy. An increased risk of congenital malformations associated with
the use of diazepam and chlordiazepoxide during the first trimester of pregnancy
has been suggested in several studies.
NINDRAL is contraindicated in pregnant women. Symptoms of neonatal depression
have been reported; a neonate whose mother received 30 mg of NINDRAL nightly for
insomnia during the 10 days prior to delivery appeared hypotonic and inactive
during the first 4 days of life. Serum levels of N1-desalkyl-flurazepam in the
infant indicated transplacental circulation and implicate this long-acting
metabolite in this case. If there is a likelihood of the patient becoming
pregnant while receiving flurazepam, she should be warned of the potential risks
to the fetus. Patients should be instructed to discontinue the drug prior to
becoming pregnant. The possibility that a woman of childbearing potential may be
pregnant at the time of institution of therapy should be considered.
WARNINGS:
Patients receiving NINDRAL should be cautioned about possible combined effects
with alcohol and other CNS depressants. Also, caution patients that an additive
effect may occur if alcoholic beverages are consumed during the day following
the use of NINDRAL for nighttime sedation. The potential for this interaction
continues for several days following discontinuance of flurazepam, until serum
levels of psychoactive metabolites have declined.
Patients should also be cautioned about engaging in hazardous occupations
requiring complete mental alertness such as operating machinery or driving a
motor vehicle after ingesting the drug, including potential impairment of the
performance of such activities which may occur the day following ingestion of
NINDRAL.
Usage In Children: Clinical investigations of NINDRAL have not been carried out
in children. Therefore, the drug is not currently recommended for use in persons
under 15 years of age.
Withdrawal symptoms of the barbiturate type have occurred after the
discontinuation of benzodiazepines. (See DRUG ABUSE AND DEPENDENCE section.)
PRECAUTIONS:
Since the risk of the development of oversedation, dizziness, confusion and/or
ataxia increases substantially with larger doses in elderly and debilitated
patients, it is recommended that in such patients the dosage be limited to 15
mg. If NINDRAL is to be combined with other drugs having known hypnotic
properties or CNS-depressant effects, due consideration should be given to
potential additive effects.
The usual precautions are indicated for severely depressed patients or those in
whom there is any evidence of latent depression; particularly the recognition
that suicidal tendencies may be present and protective measures may be
necessary.
The usual precautions should be observed in patients with impaired renal or
hepatic function and chronic pulmonary insufficiency.
Information For Patients: To assure the safe and effective use of
benzodiazepines, patients should be informed that since benzodiazepines may
produce psychological and physical dependence, it is advisable that they consult
with their physician before either increasing the dose or abruptly discontinuing
this drug.
DRUG INTERACTIONS:
SEE WARNINGS
ADVERSE REACTIONS:
Dizziness, drowsiness, light-headedness, staggering, ataxia and falling have
occurred, particularly in elderly or debilitated persons. Severe sedation,
lethargy, disorientation and coma, probably indicative of drug intolerance or
overdosage, have been reported.
Also reported were headache, heartburn, upset stomach, nausea, vomiting,
diarrhea, constipation, gastrointestinal pain, nervousness, talkativeness,
apprehension, irritability, weakness, palpitations, chest pains, body and joint
pains and genitourinary complaints. There have also been rare occurrences of
leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred
vision, burning eyes, faintness, hypotension, shortness of breath, pruritus,
skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria,
depression, slurred speech, confusion, restlessness, hallucinations, and
elevated SGOT, SGPT, total and direct bilirubins, and alkaline phosphatase.
Paradoxical reactions, eg, excitement, stimulation, and hyperactivity, have also
been reported in rare instances.
DRUG ABUSE AND DEPENDENCE:
Withdrawal symptoms, similar in character to those noted with barbiturates and
alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting and
sweating), have occurred following abrupt discontinuance of benzodiazepines. The
more severe withdrawal symptoms have usually been limited to those patients who
had received excessive doses over an extended period of time. Generally milder
withdrawal symptoms (eg, dysphoria and insomnia) have been reported following
abrupt discontinuance of benzodiazepines taken continuously at therapeutic
levels for several months.
Consequently, after extended therapy, abrupt discontinuation should generally be
avoided and a gradual dosage tapering schedule followed. Addiction-prone
individuals (such as drug addicts or alcoholics) should be under careful
surveillance when receiving flurazepam or other psychotropic agents because of
the predisposition of such patients to habituation and dependence.
OVERDOSAGE:
Manifestations of NINDRAL overdosage include somnolence, confusion and coma.
Respiration, pulse and blood pressure should be monitored as in all cases of
drug overdosage. General supportive measures should be employed, along with
immediate gastric lavage. Intravenous fluids should be administered and an
adequate airway maintained. Hypotension and CNS depression may be combated by
judicious use of appropriate therapeutic agents. The value of dialysis has not
been determined. If excitation occurs in patients following NINDRAL overdosage,
barbiturates should not be used. As with the management of intentional
overdosage with any drug, it should be borne in mind that multiple agents may
have been ingested.
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the
complete or partial reversal of the sedative effects of benzodiazepines and may
be used in situations when an overdose with a benzodiazepine is known or
suspected. Prior to the administration of flumazenil, necessary measures should
be instituted to secure airway, ventilation and intravenous access. Flumazenil
is intended as an adjunct to, not as a substitute for, proper management of
benzodiazepine overdose. Patients treated with flumazenil should be monitored
for resedation, respiratory depression and other residual benzodiazepine effects
for an appropriate period after treatment. THE PRESCRIBER SHOULD BE AWARE OF A
RISK OF SEIZURE IN ASSOCIATION WITH FLUMAZENIL TREATMENT, PARTICULARLY IN LONG-
TERM BENZODIAZEPINE USERS AND IN CYCLIC ANTIDEPRESSANT OVERDOSE. The complete
flumazenil package insert, including CONTRAINDICATIONS, WARNINGS and
PRECAUTIONS, should be consulted prior to use.
DOSAGE AND ADMINISTRATION:
Dosage should be individualized for maximal beneficial effects. The usual adult
dosage is 30 mg before retiring. In some patients, 15 mg may suffice. In elderly
and/or debilitated patients, 15 mg is usually sufficient for a therapeutic
response and it is therefore recommended that therapy be initiated with this
dosage.
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