Pharmacology - Temazepam (Restoril)

[Jatelka]

Temazepam is 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

The chemical formula is C16H13ClN2O2 and the molecular weight is 300.74.



It is a white, crystalline substance, very slightly soluble in water and sparingly soluble in alcohol.

Pharmacokinetics

Temazepam is well absorbed after oral administration and has minimal (8%) first pass metabolism. It has no active metabolites and is 96% bound to plasma proteins.

The plasma level decline is biphasic with a short half-life ranging from 0.4-0.6 hours and a terminal half-life of 3.5-18.4 hours (mean 8.8 hours).

Inactive metabolites are formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, formation of the major metabolite is the rate limiting step in the biodisposition of temazepam.

There is no accumulation of metabolites.

Temazepam is completely metabolized through conjugation prior to excretion; 80%-90% of a dose is excreted in the urine.

The major metabolite is the O-conjugate (90%); the O-conjugate of N-desmethyl temazepam is a minor metabolite (7%).

Bioavailability, Induction, and Plasma Levels

Following a 30mg dose measurable plasma concentrations are achieved after 10-20 minutes, with peak plasma levels ranging from 666-982 ng/mL occurring after 1.2-1.6 hours (mean 1.5 hours).

In a 7 day study, steady-state levels were achieved by the third dose. Mean plasma levels were 260±210 ng/mL at 9 hours and 75±80 ng/mL at 24 hour. A slight trend toward declining 24 hour plasma levels was seen after day 4.

At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man.

Research

Temazepam has been shown to improve sleep parameters in short-term clinical studies.

In 2 week, placebo controlled sleep study, there was a linear improvement in total sleep time and sleep latency with Temazepam. REM sleep was essentially unchanged and slow wave sleep was decreased. No measurable effects on daytime alertness or performance occurred although a transient sleep disturbance in some sleep parameters was observed following withdrawal of higher doses.

Indications

Temazepam is indicated for the short-term treatment of insomnia. Usual therapeutic dose is 15-30mg at night .

Adverse Effects

All the usual benzodiazepine things: Drowsiness, headache, fatigue, rebound anxiety, anterograde amnesia, dizziness, nausea and hangover effect.

Rare: Anorexia, ataxia, tremor, nightmares, palpitations, excessive salivation, excessive sweating and paradoxical reactions.

Interactions

As with all drugs metabolized by the cytochrome P450 system, the potential is huge.

Liver enzyme inhibitors (which may increase plasma levels of Temazepam): Amiodarone, Chloramphenicol, Cimetidine, Ciprofloxacin, Clarithromycin, Fluconazole, Fluoxetine, Grapefruit juice, Isoniazid, Metronidazole, Nefazodone, Sertraline, Star fruit.

Liver Enzyme Inducers (which may reduce plasma levels of Temazepam): Barbiturates, Carbamazepine Garlic supplements, Modafinil, Phenytoin, St. John's Wort.

Contraindications

All the usual: Hypersensitivity, Severe respiratory, hepatic or renal disease, pregnancy and lactation.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenicity has been observed in animal studies at doses up to 160mg/kg/day although hyperplastic liver nodules did occur (clinical significance unknown). Fertility in male and female rats was not adversely affected. No mutagenicity tests have been done with temazepam.

Overdose

The oral LD50 in mice is 1963mg/kg, 1833mg/kg in rats and greater than 2400mg/kg in rabbits.