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Temazepam
Temazepam is a benzodiazepine hypnotic agent. The chemical name is 7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiaz epin-2-one. Temazepam is a white, crystalline substance, very slightly soluble in water and sparingly soluble in alcohol. Temazepam capsules, 7.5 mg, 15 mg and 30 mg, are for oral administration. Restoril 7.5 mg, 15 mg and 30 mg Capsules: Active Ingredient: Temazepam Restoril 7.5 mg Capsules: Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, sodium lauryl sulfate, synthetic red ferric oxide, and titanium dioxide. May also include: benzyl alcohol, butylparaben, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide, sodium propionate, and another ingredient. Restoril 15 mg Capsules: Inactive Ingredients: FD&C Blue #1, FD&C Red #3, gelatin, lactose, magnesium stearate, sodium lauryl sulfate, synthetic red ferric oxide, and titanium dioxide. May also include: benzyl alcohol, butylparaben, edetate calcium disodium, methylparaben, propylparaben, silicon dioxide, sodium propionate, and another ingredient. Restoril 30 mg Capsules: Inactive Ingredients: FD&C
Blue #1, FD&C Red #3, gelatin, lactose, magnesium
stearate, sodium lauryl sulfate, and titanium
dioxide. May also include: benzyl alcohol, butylparaben, edetate
calcium disodium, methylparaben,
propylparaben, silicon dioxide, sodium
propionate, and another ingredient.
Pharmacokinetics In a single and multiple dose absorption, distribution, metabolism, and excretion (ADME) study, using 3H labeled drug. Temazepam was well absorbed and 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. The unchanged drug was 96% bound to plasma proteins. The blood level decline of the parent drug was biphasic and the short half-life ranging from 0.4-0.6 hours and the terminal half life ranging from 3.5-18.4 hours (mean 8.8 hours), depending on the study population and the method of determination. Metabolites were 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. A dose-proportional relationship has been established for the area under the plasma concentration/time curve over the 15-30 mg dose range. Temazepam was completely metabolized through conjugation prior to excretion: 80%-90% of the dose appeared in the urine. The major metabolite was th O-conjugate of temazepam (90%): the O-conjugate of N- desmethyl temazepam was a minor metabolite (7%). Bioavailability, Induction, and Plasma Levels Following ingestion of a 30 mg temazepam capsule, measurable plasma concentrations were achieved 10-20 minutes after dosing with peak plasma levels ranging from 666-982 ng/ml (mean 865 ng/ml) occurring approximately 1.2-1.6 hours (mean 1.5 hours) after dosing. In a 7 day study, in which subjects were given a 30 mg temazepam capsule 1 hour before retiring, steady-state (as measured by the attainment of maximal trough concentrations) was achieved by the third dose. Mean plasma levels of temazepam (for days 2-7) were 260 ± 210 ng/ml at 9 hours and 75 ± 80 ng/ml at 24 hours after dosing. A slight trend toward declining 24 hour plasma levels was seen after day 4 in the study, however, the 24 hour plasma levels were quite variable. At a dose of 30 mg once-a-day for 8 weeks, no evidence of enzyme induction was found in man. Elimination Rate of Benzodiazepine Hypnotics and Profile of Common Untoward Effects The type and duration of unwanted effects during administration of benzodiazepine hypnotics may be influenced by the biologic half-life of the administered drug and for some hypnotics, the half-life of any active metabolites formed. Benzodiazepine hypnotics have a spectrum of half- lives from short (<4 hours) or long (>20 hours). When half-lives are long, drug (and for some drugs their inactive metabolites) may accumulate during periods of nightly administration and may be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychoactive drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug (and for some drug their active metabolites may be accumulate during periods of nightly administration and be associated with impairments of cognitive and/or motor performance during waking hours; the possibility of interaction with other psychotropic drugs or alcohol will be enhanced. In contrast, if half-lives are shorter, drug (and, where appropriate, its active metabolites) will be cleared before the next dose is ingested, and carry-over effects related to excessive sedation or CNS depression should be minimized or absent. However, during nightly use for an extended period , pharmacodynamic tolerance or adaptation to some effects of benzodiazepine hypnotics may develop. If the drug has a short elimination half-life, it is possible that a relative deficiency of the drug, or, if appropriate, its active metabolites (i.e., in relationship to the receptor site) may occur at some point in the interval between each night's use. This sequence of events may account for 2 clinical findings reported to occur after several weeks of nightly use of rapidly eliminated benzodiazepines hypnotics, namely increased wakefulness during the last third of the night, and the appearance of daytime anxiety. CLINICAL STUDIESTemazepam improved sleep parameters in clinical studies. Residual medication effects ("hangover") were essentially absent. Early morning awakening, a particular problem in the geriatric patient, was significantly reduced. Patients with chronic insomnia were evaluated in 2 week, placebo controlled sleep laboratory studies with temazepam at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time and sleep latency, with significant drug-placebo differences at 2 weeks occurring only for total sleep differences at the 2 higher doses, and for sleep latency only at the highest dose. In these sleep laboratory studies, REM sleep was essentially unchanged and wave sleep was decreased. No measurable effects on daytime alertness or performance occurred following temazepam treatment or during the withdrawal period, even through a transient sleep disturbance in some sleep laboratory parameters was observed following withdrawal of the highest dose. There was no evidence of tolerance development in sleep laboratory parameters when patients were given temazepam nightly for at least 2 weeks. In addition, normal subjects with transient insomnia associated with first night adaptation to the sleep laboratory were evaluated in 24 hour, placebo controlled sleep laboratory studies with temazepam at doses of 7.5 mg, 15 mg, and 30 mg, given 30 minutes prior to bedtime. There was a linear dose-response improvement in total sleep time, sleep latency and number of awakenings, with significant drug-placebo differences occurring for sleep latency at all doses, for total sleep time at the 2 higher doses and for number of awakenings only at the 30 mg dose.
Temazepam is indicated for the short-term treatment of insomnia (generally 7-10 days). For patients in whom the drug is used for more than 2-3 weeks, periodic reevaluation is recommended to determine whether there is a continuing need. (See WARNINGS.) For patients with short-term insomnia, instructions in the prescription should indicate that temazepam should be used for short periods of time (7-10 days). Temazepam should not be prescribed in quantities exceeding a 1-month supply. Insomnia is characterized by complaints of difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings. Both sleep laboratory and outpatient studies provide support for the effectiveness of temazepam administered 30 minutes before bedtime in decreasing sleep latency and improving sleep maintenance in patients with chronic insomnia. In addition, sleep laboratory studies have confirmed similar effects in normal subjects with transient insomnia. (See CLINICAL PHARMACOLOGY.)
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. In transient insomnia, a 7.5 mg dose may be sufficient to improve sleep latency. In elderly and/or debilitated patients it is recommended that therapy be initiated with 7.5 mg until individual responses are determined.
During clinical studies in which 1076 patients received temazepam at bedtime, the drug was well tolerated. Side effects were usually mild and transient. Adverse reactions occurring in 1% or more of patients are presented in TABLE 1.
Central Nervous System: anorexia, ataxia, equilibrium loss, tremor, increased dreaming Cardiovascular: dyspnea, palpitations Gastrointestinal: vomiting Musculoskeletal: backache Special Senses: hyperhidrosis, burning eyes Amnesia, hallucinations, horizontal nystagmus, and paradoxical reactions including restlessness, overstimulation and agitation were rare (less than 0.5%). DRUG ABUSE AND DEPENDENCE Controlled Substance Temazepam is a controlled substance in Schedule IV. Abuse and Dependence Withdrawal symptoms, similar in character to those noted with barbiturates and alcohol (convulsions, tremor, abdominal, and muscle cramps, vomiting, and sweating), have occurred following abrupt discontinuance of benzodiazepines. The more severe withdrawal symptoms have usually been limited to those patients who received excessive doses over an extended period of time. Generally milder withdrawal symptoms (e.g., dysphoria and insomnia) have been reported following abrupt discontinuance of benzodiazepines taken continuously at therapeutic levels for several months. Consequently, after extended therapy at doses higher than 15 mg, abrupt discontinuation should generally be avoided and a gradual dosage tapering schedule followed. As with any hypnotic, caution must be exercised in administering temazepam to individuals known to be addiction-prone or to those whose history suggests they may increase the dosage on their own initiative. It is desirable to limit repeated prescriptions without adequate medical supervision.
No information provided.
Sleep disturbance may be the presenting manifestation of an underlying 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. The failure of insomnia to remit after 7-10 days of treatment may indicate the presence of a primary psychiatric and/or medical illness. Worsening of insomnia may be the consequence of an unrecognized psychiatric or physical disorder as may be the emergence of new abnormalities of thinking or behavior. Such abnormalities have also been reported to occur in association with the central nervous system depressant activity, including those of the benzodiazepine class. Some of these changes may be characterized by decreased inhibition, e.g., aggressiveness and extroversion that seem out of character, similar to that seen with alcohol. Other kinds of behavioral changes can also occur, for example, bizarre behavior, agitation, hallucinations, depersonalization, and, in primarily depressed patients, the worsening of depression, including suicidal thinking. In controlled clinical trials involving 1076 patients on temazepam and 783 patients on placebo, reports of hallucinations, agitation, and overstimulation occurred at rates less than 1 in 100 patients. Hallucinations were reported in 2 temazepam patients and 1 temazepam patient; 2 temazepam patients reported overstimulation. There were no reports of worsening of depression or suicidal ideation, aggressiveness, extroversion, bizarre behavior or depersonalization in these controlled clinical trials. It can rarely determined with certainty whether a particular instance of the abnormal behavior listed above is induced, spontaneous in origin, or a result of an underlying psychiatric or physical disorder. Nonetheless, the emergence of any new behavioral sign or symptom of concern requires careful and immediate evaluation. Because some of the worrisome adverse effects of benzodiazepines,
including temazepam, appear to be dose
related (see Patients receiving temazepam should be cautioned about possible combined effects with alcohol and other CNS depressants. Withdrawal symptoms of the barbiturate type) have occurred after the abrupt discontinuation of benzodiazepines (see DRUG ABUSE AND DEPENDENCE).
General Since the risk of the development of over-sedation, dizziness, confusion, and/or ataxia increases substantially with larger doses of benzodiazepines in elderly and debilitated patients, 7.5 mg of temazepam is recommended as the initial dosage for such patients. Temazepam should be administered 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. The usual precautions should be observed in patients with impaired renal or hepatic function and in patients with chronic pulmonary insufficiency. If temazepam is to be combined with other drugs having known hypnotic properties or CNS-depressant effects, consideration should be given to potential additive effects. The possibility of a synergistic effect exists with the co-administration of temazepam and diphenhydramine. One case of stillbirth at term has been reported 8 hours after a pregnant patient received temazepam and diphenhydramine. A cause and effect relationship has not yet been determined. (See CONTRAINDICATIONS) Information for the Patient The text of a patient package insert is printed at the end of this insert. To assure safe and effective use of temazepam, the information and instructions provided in this patient package insert should be discussed with patients. Laboratory Tests The usual precautions should be observed in patients with impaired renal or hepatic function and in patients with chronic pulmonary insufficiency. Abnormal liver function tests as well as blood dyscrasias have been reported with benzodiazepines. Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenicity studies were conducted in rats at dietary diazepam doses up to 160 mg/kg/day for 24 months and in mice at dietary dose of 160 mg/kg/day for 18 months. No evidence of carcinogenicity was observed although hyperplastic liver nodules were observed in female mice exposed in female mice exposed to the highest dose. The clinical significance of this finding is not known. Fertility in male and female rats was not adversely affected by temazepam. No mutagenicity tests have been done with temazepam. Pregnancy Category X (See CONTRAINDICATIONS.) 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 temazepam is administered to a nursing woman. Pediatric Use Safety and effectiveness in children below the age of 18 years have not been established.
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