Monograph: |
Nitrazepam
A yellow, crystalline powder. Practically Insoluble in water;
slightly soluble in alcohol and in ether. Protect from light.
Dependence and Withdrawal
As for Diazepam.
For the purpose of withdrawal regimens, 5 mg of nitrazepam
may be considered roughly equivalent to 5 mg of diazepam.
Adverse Effects and Treatment
As for Diazepam.
Effects on the digestive system. Two children given ni-
trazepam as pan of their antiepileptic therapy developed
drooling, eating difficulty, and aspiration pneumonia; symp-
toms improved in one patient when the dosage of nitrazepam
was reduced. Manometric studies indicated that the onset of
normal cricopharyngeal relaxation in swallowing was de-
layed in these patients until after hypopharyngeal contraction,
resulting in impaired swallowing and spillover of material
into the trachea. Other workers have found similar effects on
swallowing and cricopharyngeal relaxation in children given
nitrazepam. Murphy et al.' reported the deaths of six epileptic
children under 5 years of age treated with nitrazepam. Three
of the deaths were unexpected, and in view of the previous
reports of swallowing difficulties and aspiration, they recom-
mended that the use of nitrazepam in young children be re-
stricted to those in whom seizure control fails to improve with
other antiepileptics. They also recommended that the dose
should be less than 0.8 mg per kg body-weight daily.
Precautions
As for Diazepam.
Porphyria. Nitrazepam has been associated with clinical ex-
acerbations of porphyria and is considered unsafe in porphy-
ric patients.
Interactions
As for Diazepam.
Pharmacokinetics
Nitrazepam is fairly readily absorbed from the gas-
tro-intestinal tract, although there is some individual
variation. It is extensively bound to plasma proteins.
It crosses the blood-brain and the placental barriers
and traces are found in breast milk. Nitrazepam is
metabolised in the liver, mainly by nitroreduction
followed by acetylation; none of the metabolites
possess significant activity. It is excreted in the urine
in the form of its metabolites (free or conjugated)
with only small amounts of a dose appearing un-
changed. Up to about 20% of an oral dose is found
in the faeces. Mean elimination half-lives of 24 to 30
hours have been reported.
Administration in hepatic impairment. A study of the
pharmacokinetics of intravenous nitrazepam in 12 patients
with cirrhosis of the liver compared with 9 healthy subjects
aged 22 to 49 years and 8 healthy elderly subjects aged 67 to
76 years. The mean elimination half-life of nitrazepam was
26 hours in young and 38 hours in elderly subjects, the differ-
ence, which was not significant, being chiefly due to the
greater volume of distribution in elderly subjects. Although
there was also no significant difference between young and
elderly subjects in percentage of unbound nitrazepam (.13.0
and 13.9% respectively) there was a substantially higher un-
bound fraction in the patients with cirrhosis, the mean value
being 18.9%. and clearance of unbound nitrazepam was re-
duced relative to healthy subjects.
Distribution Into breast milk. A mean milk-to-plasma ra-
tio of 0.27 was obtained after administration of nitrazepam
5 mg for 5 nights to 9 puerperal women.' The degree of ni-
trazepam accumulation in milk over the study period was
similar to that in plasma.
Metabolism. Although the acetylation of the reduced me-
tabolite of nitrazepam has been reported to be controlled by
acetylator phenotype, Swift et al. observed no significant
differences between either half-life or residual effects of ni-
trazepam in slow and fast acetylators.
Uses and Administration
Nitrazepam is an intermediate-acting benzodi-
azepine with general properties similar to those of
diazepam . It is used as a hypnotic in the
short-term management of insomnia and is
reported to act in 30 to 60 minutes to produce sleep
lasting for 6 to 8 hours. Nitrazepam has also been
used in epilepsy, notably for infantile spasms (as for
example in West's syndrome).
The usual dose for insomnia is 5 mg at night, al-
though 10 mg may be required. Elderly or debilitat-
ed patients should not be given more than half of the
normal adult dose.
Epilepsy. Benzodiazepines are sometimes employed in the
management of epilepsy , but their long-term use is
limited by problems of sedation, dependence, and tolerance to
the antiepileptic effects. Nitrazepam has perhaps been most
useful in the treatment of infantile spasms (as for example in
West's syndrome) and the so-called infantile myoclonic sei-
zures. There has been concern, however, over swallowing dif-
ficulties with subsequent aspiration associated with the use of
nitrazepam in young children (see Effects on the Digestive
System under Adverse Effects, above).
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