Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: Hypnotics and Sedatives, Benzodiazepine derivatives
ATC code: N05CD01
Flurazepam is a psychotropic substance from the class of 1,4-benzodiazepines. Onset of sedative effects occurs within 30 minutes. Due to accumulation of the active metabolite N1-desalkyl-flurazepam peak response is not observed before night 2-3 of treatment.
Flurazepam binds to specific benzodiazepine receptors located on GABA-ergic neurones and potentiates the inhibitory actions of GABA-ergic neurones in the nervous system.
After prolonged flurazepam treatment, development of tolerance has been observed. Chronic benzodiazepine use leads to compensating changes in the central nervous system. GABAA receptors may become less responsive to the continuing acute effects of benzodiazepines, either as a result of adaption in the GABAA receptor itself, intracellular mechanisms, or changes in the neurotransmitter systems. Probably multiple adaptive mechanisms simultaneously co-exist.
An increase in intensity and incidence of CNS toxicity with age has been observed, especially at high doses. Therefore the initial dose of Dalmane in elderly should not exceed 15 mg (see section 4.2). The increased CNS toxicity in elderly seems to be the result of the combination of pharmacokinetic and pharmacodynamic factors.
Under the treatment with 15 and 30 mg flurazepam impairment of psychomotor and cognitive performance was observed in several investigations. Especially the driving ability is affected (see section 4.7). In elderly patients the effect is more pronounced.
The pharmacokinetic properties of Dalmane make it particularly indicated for patients whose total duration of sleep is less than adequate. The dosage of the drug is important in balancing the duration of effect with the occurrence of residual effects.
Flurazepam hydrochloride is rapidly and almost completely absorbed after oral administration. Maximum plasma concentrations were measured after 1 to 3 hours. The maximum plasma concentrations of the two pharmacologically active major metabolites N1-hydroxyethyl-flurazepam and N1-desalkyl flurazepam were observed after 1 to 4 hours and 0.5 to 96 hours, respectively. In most subjects, the N1-desalkyl-flurazepam concentration reached a plateau value after 1 to 24 hours. The maximum plasma concentration of N1-hydroxyethyl-flurazepam ranges between 6 and 28 ng/ml and of N1-desalkyl-flurazepam ranges between 5 and 40 ng/ml after a single oral dose.
Flurazepam undergoes considerable first-pass metabolism.
The plasma protein binding is high for flurazepam (83%) and N1-desalkyl-flurazepam (96.5%) and lower for N1-hydroxyethyl-flurazepam (65%).
Taking flurazepam hydrochloride over a period of 15 days the N1-desalkyl-flurazepam accumulated. The plasma concentrations were 7.5 times higher on the 15th day versus the 1st day.
The concentration of flurazepam and its metabolites is 2 times (for N1-hydroxyethyl-flurazepam), 7 times (for flurazepam) or 8 times (for N1-desalkyl-flurazepam) higher in cerebrospinal fluid compared to plasma.
In animal models, flurazepam was eliminated from serum in biphasic fashion, consistent with two-compartment model and volume of distribution was between 2.65 and 5.5 l/kg.
Flurazepam and/or active metabolites cross the placental barrier in rodents. Human data are not available.
No information concerning secretion of flurazepam and metabolites in the breast milk are available. However in common with other benzodiazepines, its passage into breast milk might be expected.
The plasma half-life for flurazepam and N1-hydroxyethyl-flurazepam was 3.1 hours and 2.3 to 3.4 hours, respectively. For N1-desalkyl-flurazepam, the corresponding values were 19 to 133 hours. In elderly subjects (66-85 years) still higher values for N1-desalkyl-flurazepam were obtained (71-289 hours). The metabolites are further conjugated to glucuronides and/or sulfates for renal excretion
Flurazepam monohydrochloride and its metabolites are eliminated primarily by renal excretion (about 80%). The major urinary metabolite, N1-hydroxyethyl-flurazepam as glucuronide/sulphate conjugate accounts for 20-55% of an orally administered dose.
There is insufficient data available to evaluate the genotoxic potential of flurazepam. The limited studies performed to date showed no evidence of genotoxicity.
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