Pharmacology - Lormetazepam (Noctamid)

[Jatelka]

Lormetazepam is 9-chloro-6-(2-chlorophenyl)-4-hydroxy-2-methyl-2,5-
diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one. It's chemical formula is C16H12Cl2N2O2 and it's molecular mass is 335.2.



It's a white crystalline powder, virtually insoluble in water, but soluble in alcohol

Pharmacokinetics

Lormetazepam is rapidly absorbed after oral administration. Maximal plasma
levels are reached 1.5 hours after ingestion. Postmaximal decrease of drug plasma levels is in two phases characterised by half-lives of 2 - 2.5 hours and about 10 hours. During absorption and first-pass through the liver about 20 % of the dose are inactivated presystemically. Thus, the absolute bioavailability is about 80 % of the dose.

Lormetazepam is extensively bound to plasma albumin. It is almost exclusively metabolized by glucuronidation. Lormetazepam glucuronide does not bind to the benzodiazepine-receptor, is the main metabolite and the only one found in plasma and is almost exclusively excreted with urine. Only less than 6 % of dose were found as N-demethylated lormetazepam glucuronide exclusively in urine. Excretion rate was in one phase, for which a half-life of 13.6 hours was calculated. In urine 86 % of dose were recovered. Renal clearance of lormetazepam glucuronide was about 0.65 ml/min/kg.

The pharmacokinetics of lormetazepam are dose linear within the range of 1 - 3 mg.

No sex differences in pharmacokinetics were found. Small differences in terms of lower metabolic clearance rate, longer half-life of the terminal disposition phase in plasma and higher steady-state drug levels in plasma were found in elderly volunteers as compared to young test subjects. The elimination of lormetazepam glucuronide from plasma was significantly slower in the elderly population (t ½ = 20 hours) than in a group of young subjects (t ½ = 12 hours).

Multiple (daily) dose pharmacokinetics of lormetazepam is predictable from single dose parameters. Steady-state conditions are reached within 3 days at latest and respective steady-state drug plasma levels increased by a factor of 1.3 (young) or 1.6 (elderly).
No drug/drug interactions are expected at the level of protein binding. At the level of phase I biotransformation no interaction was expected and found with cimetidine.

Terminal renal failure did not affect lormetazepam pharmacokinetics. The drug's glucuronide showed a dialysate clearance of 20 ml/min and inactive glucuronide levels decreased with a half-life of about 80 hours due to the forced biliary (instead of renal) elimination.

Liver cirrhosis did not alter the pharmacokinetics of lormetazepam or its glucuronide.

No enterohepatic recirculation of lormetazepam or its glucuronide was found.
Lormetazepam was not detectable in breast milk. By calculation at most 0.35 % of the daily dose of a breast feeding mother could reach the newborn.

Lormetazepam is indicated for the short-term treatment of insomnia

Standard therapeutic dose is 1mg

Contraindications

Myasthenia gravis, hypersensitivity to benzodiazepines, severe respiratory insufficiency (e.g. severe chronic obstructive pulmonary disease), sleep apnoea syndrome, pregnancy and lactation
Intoxication with alcohol, hypnotics, analgesics or psychotropic drugs (neuroleptics, antidepressants, lithium

Warnings/Precautions

As with all benzodiazepines, physical dependance and withdrawal can occur with as little as 14 days of continuous use. Lormetazepam should not be discontinued suddenly.

Adverse Effects

Drowsiness during the day, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision. These phenomena occur predominantly at the start of therapy and usually disappear with repeated administration. Other side effects like gastrointestinal disturbances, changes in libido or skin reactions have been reported occasionally

Paradoxical reactions including restlessness, agitation, irritability, aggressiveness, delusion, rages, nightmares and hallucinations can also occur

Interactions

Additive effect with other CNS depressants (including alcohol)

Overdosage

The symptoms of mild intoxication are drowsiness, tiredness, ataxic symptoms, hypotension, visual disturbances and, at higher doses, deep sleep ranging to unconsciousness, respiratory depression and circulatory collapse

[Fantasian]

SWIF finds that with Lormetazepam on him and patients he treats that much more natural sleep is gained than with the usual benzo's (diazepam and temazepam etc)

Users tend to awake more recuperated than the usual crappy benzo's sleep.