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RESTORIL®
Novartis
Temazepam
Hypnotic
 
Action And Clinical Pharmacology: General: Temazepam is a benzodiazepine with hypnotic properties.

Benzodiazepines act as depressants of the CNS. It is believed that benzodiazepines enhance or facilitate the effects of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).

Benzodiazepines act as agonists at the benzodiazepine receptor sites. The benzodiazepine-GABA receptor-chloride ionophore complex functions mainly in the gating of the chloride channel. Benzodiazepines are thought to produce their pharmacological effects by facilitating GABA-mediated transmission in the CNS, which reportedly increase the frequency of the chloride channel opening.

In sleep laboratory studies, the effect of temazepam 15 and 30 mg, was compared to placebo over a 2-week period. There was a linear dose-response improvement in total sleep time and sleep latency with significant drug-placebo differences occurring for total sleep time at both doses, and for sleep latency at the higher dose. REM sleep was essentially unchanged and slow wave sleep was decreased.

Rebound Insomnia: A transient syndrome, known as "rebound insomnia", whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of hypnotic treatment. In the sleep laboratory studies, no measurable effects on daytime alertness or performance occurred following temazepam treatment or during the withdrawal period, even though a transient sleep disturbance in some sleep parameters was observed following the withdrawal of the higher doses.

The duration of hypnotic effect and the profile of unwanted effects may be influenced by the alpha (distribution) and beta (elimination) half-lives of the administered drug and any active metabolites formed. When half-lives are long, the drug or metabolite may accumulate during periods of nightly administration and be associated with impairments of cognitive and motor performance during waking hours. If half-lives are short, the drug and metabolites will be cleared before the next dose is ingested, and carry-over effects related to sedation or CNS depression should be minimal or absent. However, during nightly use and for an extended period, pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop.

If the drug has a very short elimination half-life, it is possible that a relative deficiency (i.e., in relation to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for two clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepine hypnotics: 1) increased wakefulness during the last third of the night and 2) the appearance of increased daytime anxiety (see Warnings).

Pharmacokinetics: Orally administered temazepam is well absorbed in man. In a single and multiple dose absorption, distribution, metabolism and excretion (ADME) study, using labelled drug, temazepam was found to have minimal (8%) first-pass metabolism. There were no active metabolites formed and the only significant metabolite present in blood was the O-conjugate. Oral administration of 15 to 45 mg temazepam in man resulted in rapid absorption with significant blood levels achieved in 30 minutes and peak levels at 2 to 3 hours. Drug levels in blood declined in a biphasic manner with a short half-life ranging from 0.4 to 0.6 hours and a terminal half-life from 3.5 to 18 hours (mean 9 hours). The inactive O-conjugate metabolite was formed with a half-life of 10 hours and excreted with a half-life of approximately 2 hours. Thus, O-conjugation is the rate limiting step in the biodisposition. In a multiple dose study, steady-state was approximated after the second daily dose with no evidence of accumulation after 5 consecutive daily doses of 30 mg temazepam. Steady-state plasma levels at 2.5 hours were 382±192 ng/mL.

Approximately 96% of unchanged drug is bound to plasma protein.

Twenty-four hours after a single oral dose of temazepam approximately 80 to 90% of the drug was recovered in urine, primarily as the O-conjugate. Total recovery from feces and urine in single- and multiple-dose studies was approximately 95%, with only 3 to 13% of the radioactivity detectable in feces. Less than 1% of the dose was excreted as unchanged drug or N-desmethyltemazepam. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15 to 30 mg dose range.

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

Indications And Clinical Uses: Sleep disturbance may be the presenting manifestation of a physical and/or psychiatric disorder. Consequently, a decision to initiate symptomatic treatment of insomnia should only be made after the patient has been carefully evaluated.

Temazepam is indicated for the symptomatic relief of transient and short-term insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings and/or early morning awakenings.

Treatment with temazepam should usually not exceed 7 to 10 consecutive days. Use for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for temazepam should be written for short-term use (7 to 10 days) and it should not be prescribed in quantities exceeding a 1-month supply.

The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning.

Contra-Indications: In patients with a known hypersensitivity to the drug, any component of its formulation, or to other benzodiazepines; myasthenia gravis; sleep apnea syndrome.

Temazepam is contraindicated in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

Manufacturers' Warnings In Clinical States: General: Benzodiazepines should be used with extreme caution in patients with a history of substance or alcohol abuse.

Geriatrics: The lowest possible effective dose should be prescribed for elderly patients. Inappropriate, heavy sedation in the elderly, may result in accidental events or falls.

The failure of insomnia to remit after 7 to 10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness or the presence of sleep state misperception.

Worsening of insomnia or the emergence of new abnormalities of thinking or behavior may be the consequence of an unrecognized psychiatric or physical disorder. These have also been reported to occur in association with the use of drugs that act at the benzodiazepine receptors.

Pregnancy: The use of temazepam during pregnancy is not recommended.

Benzodiazepines may cause fetal damage when administered during pregnancy. During the first trimester of pregnancy, several studies have suggested an increased risk of congenital malformations associated with the use of benzodiazepines. During the last weeks of pregnancy, ingestion of therapeutic doses of a benzodiazepine hypnotic has resulted in neonatal CNS depression due to transplacental distribution.

If the drug is prescribed to a woman of childbearing potential, the patient should be warned of the potential risk to a fetus and advised to consult her physician regarding the discontinuation of the drug if she intends to become pregnant or suspects that she is pregnant.

Memory Disturbance: Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines. The event is rare with temazepam. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk. Cases of transient global amnesia and "traveller's amnesia" have also been reported in association with benzodiazepines, the latter in individuals who have taken the drug, often in the middle of the night, to induce sleep while travelling.

Transient global amnesia and traveller's amnesia are unpredictable and not necessarily dose-related phenomena. Patients should be warned not to take temazepam under circumstances in which a full night's sleep and clearance of the drug from the body are not possible before they need again to resume full activity.

Abnormal thinking and psychotic behavioral changes have been reported to occur in association with the use of benzodiazepines including temazepam, although rarely.

Some of the changes may be characterized by decreased inhibition, e.g., aggressiveness or extroversion that seem excessive, similar to that seen with alcohol and other CNS depressants (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behavior and a history of unusual reactions to sedatives including alcohol and the benzodiazepines. Psychotic behavioral changes that have been reported with benzodiazepines include bizarre behavior, hallucinations, and depersonalization. Abnormal behaviors associated with the use of benzodiazepines have been reported more with chronic use and/or high doses but they may occur during the acute, maintenance or withdrawal phases of treatment.

It can rarely be determined with certainty whether a particular instance of abnormal behaviors listed above is drug induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation.

Confusion: The benzodiazepines affect mental efficiency, e.g., concentration, attention and vigilance. The risk of confusion is greater in the elderly and in patients with cerebral impairment.

Anxiety, Restlessness: An increase in daytime anxiety and/or restlessness have been observed during treatment with temazepam.

This may be a manifestation of interdose withdrawal due to the short elimination half-life of the drug.

Depression: Caution should be exercised if temazepam is prescribed to patients with signs or symptoms of depression that could be intensified by hypnotic drugs. The potential for self-harm (e.g., intentional overdose) is high in patients with depression and thus, the least amount of drug that is feasible should be available to them at any one time.

Potentiation of Drug Effects: Temazepam may potentiate the effects of other CNS depressant drugs such as alcohol, barbiturates, nonbarbiturate hypnotics, antihistamines, narcotics, antipsychotic and antidepressant drugs, and anticonvulsants. Therefore, different benzodiazepines should usually not be used simultaneously and careful consideration should be given if other CNS depressants are administered in combination with temazepam. Patients should be advised against the simultaneous use of other CNS depressant drugs and should be cautioned not to take alcohol because of the potentiation of effects that might occur.

Precautions: Drug Interactions : Temazepam may produce additive CNS depressant effects when coadministered with alcohol, sedative antihistamines, anticonvulsants, or psychotropic medications which themselves can produce CNS depression.

Compounds which inhibit certain hepatic enzymes (particularly cytochrome P450) may enhance the activity of benzodiazepines.

Drug Abuse, Dependence and Withdrawal: Withdrawal symptoms, similar in characteristic to those noted with barbiturates and alcohol (convulsions, tremor, abdominal and muscle cramps, vomiting, sweating dysphoria, perceptual disturbances and insomnia) have occurred following abrupt discontinuation of benzodiazepines, including temazepam.

The more severe symptoms are usually associated with higher dosages and longer usage, although patients given therapeutic dosages for as few as 1 to 2 weeks can also have withdrawal symptoms including daytime anxiety between nightly doses. Consequently, abrupt discontinuation should be avoided and a gradual dosage tapering schedule is recommended in any patient taking more than the lowest dose for more than a few weeks. The recommendation for tapering is particularly important in patients with a history of seizures.

The risk of dependence is increased in patients with a history of alcoholism, drug abuse, or in patients with marked personality disorders. Interdose daytime anxiety and rebound anxiety may increase the risk of dependency in temazepam treated patients. As with all hypnotics, repeat prescriptions should be limited to those who are under medical supervision.

Patients with Specific Conditions: Temazepam is O-conjugated in the liver and is primarily excreted by the kidney. Hence, temazepam should be given with caution to patients with impaired hepatic or renal function. Temazepam should also be given with caution to patients with severe pulmonary insufficiency: respiratory depression has been reported in patients with compromised respiratory function.

Temazepam should be used with caution in severely depressed patients or those in whom there is any evidence of latent depression; it should be recognized that suicidal tendencies may be present and protective measures may be necessary.

Patients Requiring Mental Alertness: Because of temazepam's CNS depressant effect, patients receiving the drug should be cautioned against engaging in hazardous occupations requiring complete mental alertness such as operating machinery or driving a motor vehicle. For the same reason, patients should be warned against the concomitant ingestion of temazepam and alcohol or CNS depressant drugs.

Pregnancy: For teratogenic effects see Warnings. Nonteratogenic effects: a child born to a mother who is on benzodiazepines may be at risk for withdrawal symptoms from the drug during the postnatal period. Also, neonatal flaccidity has been reported in an infant born to a mother who had been receiving benzodiazepines.

Lactation: It is not known whether or not temazepam is excreted in human milk. Therefore, it should not be given to nursing mothers.

Children: The safety and effectiveness of temazepam in children below the age of 18 have not been established.

Geriatrics and Debilitated Patients: Elderly patients are especially susceptible to dose-related adverse effects, such as drowsiness, dizziness, or impaired coordination. Inappropriate, heavy sedation may result in accidental events/falls. Therefore, the lowest possible dose should be used in these subjects.

Debilitated patients, or those with organic brain syndrome, are prone to CNS depression after even low doses of benzodiazepines and may experience paradoxical reactions to these drugs. Therefore, temazepam should be used only at the lowest possible dose and adjusted when necessary under careful observation, depending on the response of the patient.

Because temazepam is eliminated by O-conjugation, minimal accumulation occurs.

Adverse Reactions: During controlled clinical trials in which 1 076 patients received temazepam at bedtime, the adverse events occurring in 1% or more of patients are listed

The following adverse events have been reported with an incidence of 0.5 to 0.9%:

CNS: anorexia, ataxia, equilibrium loss, tremor, increased dreaming.

Cardiovascular: dyspnea, palpitations.

Gastrointestinal: vomiting.

Muskuloskeletal: backache.

Special Senses: hyperhidrosis, burning eyes.

The following adverse events have been reported with an incidence of less than 0.5%: amnesia, hallucinations, horizontal nystagmus and paradoxical reactions including restlessness, overstimulation, and agitation.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: 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 will result. If the patient is conscious, vomiting should be induced mechanically or with emetics (e.g., syrup of ipecac 20 to 30 mL). Gastric lavage should be employed as soon as possible, utilizing concurrently a cuffed endotracheal tube if the patient is unconscious, in order to prevent aspiration and pulmonary complications. Maintenance of adequate pulmonary ventilation is essential and fluids should be administered i.v. to encourage diuresis. The use of pressor agents, such as norepinephrine bitartrate or metaraminol, i.v. may be necessary to combat hypotension but only if considered essential. The value of dialysis in emergency therapy for benzodiazepine overdosage has not been determined. If excitation occurs, barbiturates should not be used. It should be borne in mind that multiple agents may have been ingested.

The benzodiazepine antagonist, flumazenil, is a specific antidote in known or suspected benzodiazepine overdose. For conditions of use see flumazenil product monograph.

Dosage And Administration: The lowest effective dose should be used. Treatment should usually not exceed 7 to 10 consecutive days.

Use of temazepam for more than 2 to 3 consecutive weeks requires complete re-evaluation of the patient.

An appropriate hypnotic dose should produce the desired hypnotic effect while avoiding oversedation and impairment of performance the next day.

Adults: The recommended adult dose is 30 mg before retiring, 15 mg may be sufficient for some patients.

Geriatrics and debilitated patients: The initial dose should not exceed 15 mg before retiring (see Precautions).

Temazepam is intended only for short-term use and therefore, should not be prescribed in quantities exceeding those required for that cycle of administration. Prescription should not be renewed without further assessment of the patient's needs.

Children: Not indicated in children under 18 years of age.



Availability And Storage: 15 mg: Each maroon and flesh, size 3 hard shell gelatin capsule, printed SANDOZ and ä in white, contains: temazepam 15 mg. Nonmedicinal ingredients: colloidal silicon dioxide, D&C Red #28, D&C Yellow #10, FD&C Blue #1, gelatin, lactose, magnesium stearate, sodium lauryl sulfate and titanium dioxide. The agents used to polish the capsules are alcohol, canner special salt and Tween 60. Bottles of 100.

30 mg: Each maroon and blue, size 3 hard shell gelatin capsule, printed SANDOZ and ĺ in white, contains: temazepam 30 mg. Nonmedicinal ingredients: colloidal silicon dioxide, D&C Red #28, FD&C Blue #1, gelatin, lactose, magnesium stearate, sodium lauryl sulfate and titanium dioxide. The agents used to polish the capsules are alcohol, canner special salt and Tween 60. Bottles of 100.

Store at controlled room temperature (15 to 30°C). Protect from moisture and light.