Norkotral

Uses

Norkotral is used for the short-term treatment of insomnia (generally 7 to 10 days).

For patients with short-term insomnia, instructions in the prescription should indicate that Norkotral should be used for short periods of time (7 to 10 days).

The clinical trials performed in support of efficacy were 2 weeks in duration with the final formal assessment of sleep latency performed at the end of treatment.

Norkotral is also used to associated treatment for these conditions: Insomnia

How Norkotral works

Gamma-Aminobutyric acid (GABA) is considered the principal inhibitory neurotransmitter in the human body . When GABA binds to GABA(a) receptors found in neuron synapses, chloride ions are conducted across neuron cell membranes via an ion channel in the receptors . With enough chloride ions conducted, the local, associated neuron membrane potentials are hyperpolarized - making it more difficult or less likely for action potentials to fire, ultimately resulting in less excitation of the neurons .

Subsequently, benzodiazepines like temazepam can bind to benzodiazepine receptors that are components of various varieties of GABA(a) receptors . This binding acts to enhance the effects of GABA by increasing GABA affinity for the GABA(a) receptor, which ultimately enhances GABA ligand binding at the receptors . This enhanced ligand binding of the inhibitory neurotransmitter GABA to the receptors increases the aforementioned chloride ion conduction (perhaps reportedly via an increase in the frequency of the chloride channel opening), resulting in a hyperpolarized cell membrane that prevents further excitation of the associated neuron cells . Combined with the notion that such benzodiazepine receptor associated GABA(a) receptors exist both peripherally and in the CNS, this activity consequently facilitates various effects like sedation, hypnosis, skeletal muscle relaxation, anticonvulsant activity, and anxiolytic action .

Dosage

Norkotral dosage

While the recommended usual adult dose is 15 mg before retiring, 7.5 mg may be sufficient for some patients, and others may need 30 mg. Intransient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly or debilitated patients, it is recommended thattherapybe initiated with 7.5 mg until individual responses are determined.

May be taken with or without food.

Side Effects

Complex behaviour (e.g. sleep-driving, making phone calls, preparing and eating food). Dyspnoea, nausea and vomiting, throat closing, anterograde amnesia, agitation, restlessness, irritability, excitement, aggressiveness, rage, delusions, confusion, nightmares, psychoses, hallucinations, nervousness, dizziness, drowsiness, fatigue, headache, lethargy, hangover, anxiety, depression, euphoria, ataxia, anorexia, tremor and backache.

Toxicity

Manifestations of acute overdosage of temazepam, as with other benzodiazepines, can be expected to reflect the increasing CNS effects of the drug and include somnolence, confusion, and coma, with reduced or absent reflexes . With large overdoses, respiratory depression, hypotension, and finally coma can occur .

Benzodiazepines like temazepam might cause fetal harm when administered to a pregnant woman. Transplacental distribution has in the past resulted in neonatal CNS depression following the ingestion of therapeutic doses of related benzodiazepine hypnotics like diazepam during the last weeks of pregnancy .

It is not known whether this drug is excreted in human milk . Caution should, therefore, be exercised when temazepam is administered to a nursing woman .

Safety and effectiveness in pediatric patients have not been established .

Lower doses of temazepam, like 7.5 mg is recommended as the initial dosage for patients aged 65 and over since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls increases substantially with larger doses of benzodiazepines in elderly and debilitated patients .

No evidence of carcinogenicity was observed in animal studies although hyperplastic liver nodules were observed in female mice exposed to the highest doses of temazepam . The clinical significance of this finding is not known .

Fertility in male and female rats was not adversely affected by temazepam toxicity studies .

No mutagenicity tests have been done with temazepam .

Precaution

Patient with severe depression, chronic pulmonary insufficiency, personality disorders, history of alcohol or drug addiction. Avoid abrupt withdrawal. Renal and hepatic impairment. Elderly or debilitated patient. Lactation.

Interaction

May enhance CNS depressant effect with Na oxybate, antipsychotics, tranquilisers, neuroleptics, antidepressants, hypnotics, anaesth, analgesics, sedative antihistamines, barbiturates. Effect may be reduced with theophylline.

Food Interaction

• Avoid alcohol.
• Take with or without food.

Norkotral Alcohol interaction

[Moderate] GENERALLY AVOID:

Acute ethanol ingestion may potentiate the CNS effects of many benzodiazepines.

Tolerance may develop with chronic ethanol use.

The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition.

Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

Patients should be advised to avoid alcohol during benzodiazepine therapy.

Norkotral Drug Interaction

Major: acetaminophen / hydrocodoneModerate: aripiprazole, zolpidem, duloxetine, lamotrigine, escitalopram, pregabalin, metoprolol, quetiapine, alprazolam, sertralineUnknown: amphetamine / dextroamphetamine, aspirin, omega-3 polyunsaturated fatty acids, esomeprazole, fluoxetine, levothyroxine, cyanocobalamin, ascorbic acid, cholecalciferol

Norkotral Disease Interaction

Major: acute alcohol intoxication, closed-angle glaucoma, drug dependence, renal/liver disease, respiratory depression, seizuresModerate: depression, obesity, paradoxical reactions, sleep disorders

Volume of Distribution

The volume of distribution documented for temazepam is 1.3-1.5 L/kg body weight - and in particular, 43-68 L/kg for the unbound fraction .

Elimination Route

Studies demonstrate that between 90 to 100% of an orally administered temazepam dose is absorbed, making the medication very well absorbed . The oral administration of 15 to 45 mg temazepam resulted in rapid absorption with significant blood levels achieved in 30 minutes and peak levels at 2-3 hours . In particular, direct studies following the oral ingestion of 30 mg of temazepam revealed measurable plasma concentrations were obtained 10-20 minutes after dosing with peak plasma levels ranging between 666-982 ng/mL (with a mean of 865 ng/mL) presenting approximately 1.2-1.6 hours (with a mean of 1.5 hours) after the dosing . Finally, a dose-proportional relationship was established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range .

Half Life

The terminal half-life determined for temazepam is recorded as being between 3.5-18 hours, with a mean of 9 hours .

Clearance

Studies regarding the clearance of temazepam have recorded the values of 1.03 ml/min/kg and 31 ml/min/kg for the clearance of total temazepam and the clearance of unbound temazepam, respectively .

Elimination Route

Following a single dose, 80-90% of the dose appears in the urine, predominantly as the O-conjugate metabolite, and 3-13% of the dose appears in the faeces . Less than 2% of the dose is excreted unchanged or as N-desmethyltemazepam in the urine .

Pregnancy & Breastfeeding use

Pregnancy category X. Studies in animals or human beings have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience or both, and the risk of the use of the drug in pregnant women clearly outweighs any possible benefit. The drug is contraindicated in women who are or may become pregnant.

Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Restoril is administered to a nursing woman.

Contraindication

Benzodiazepines may cause fetal harm when administered to a pregnant woman. 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. Transplacental distribution has resulted in neonatal CNS depression following the ingestion of therapeutic doses of a benzodiazepine hypnotic during the last weeks of pregnancy.

Reproduction studies in animals with temazepam were performed in rats and rabbits. In a perinatal-postnatal study in rats, oral doses of 60 mg/kg/day resulted in increasing nursling mortality. Teratology studies in rats demonstrated increased fetal resorptions at doses of 30 and 120 mg/kg in one study and increased occurrence of rudimentary ribs, which are considered skeletal variants, in a second study at doses of 240 mg/kg or higher. In rabbits, occasional abnormalities such as exencephaly and fusion or asymmetry of ribs were reported without dose relationship. Although these abnormalities were not found in the concurrent control group, they have been reported to occur randomly in historical controls. At doses of 40 mg/kg or higher, there was an increased incidence of the 13th rib variant when compared to the incidence in concurrent and historical controls.

Restoril is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard 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.

Special Warning

Renal Impairment: Short-term management of insomnia: 5 mg at bedtime. May be increased to 10-20 mg in severe cases.

Hepatic Impairment: Short-term management of insomnia: 5 mg at bedtime. May be increased to 10-20 mg in severe cases.

Severe: Contraindicated.Premedication in surgery: Severe: Contraindicated.

Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

Geriatric Use: Clinical studies of Restoril did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in response between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy commonly observed in this population. Restoril 7.5 mg is recommended as the initial dosage for patients aged 65 and over since the risk of the development of oversedation, dizziness, confusion, ataxia and/or falls increases substantially with larger doses of benzodiazepines in elderly and debilitated patients.

Acute Overdose

Symptoms: Somnolence, confusion, coma, reduced or absent reflexes, resp depression, and hypotension.

Management: Supportive and symptomatic treatment. Empty stomach by vomiting or gastric lavage. Treat hypotension with IV pressor agents. IV fluids should be given to induce diuresis. Flumazenil may be used for the complete or partial reversal of the sedative effects but there is a risk of seizure esp in long-term benzodiazepine users and in cyclic antidepressant overdose.

Storage Condition

Store at 20° to 25°C

Innovators Monograph

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