Temazepam Product Monograph

RECENT MAJOR LABEL CHANGES

TABLE OF CONTENTS

Sections or subsections that are not applicable at the time of authorization are not listed.

RECENT MAJOR LABEL CHANGES ..................................................................................... 2

TABLE OF CONTENTS .......................................................................................................... 2

PART I: HEALTH PROFESSIONAL INFORMATION............................................................... 4

1 INDICATIONS .................................................................................................................. 4

1.1 Pediatrics................................................................................................................. 4

1.2 Geriatrics ................................................................................................................. 4

2 CONTRAINDICATIONS ................................................................................................... 4

3 SERIOUS WARNINGS AND PRECAUTIONS BOX .......................................................... 4

4 DOSAGE AND ADMINISTRATION .................................................................................. 5

4.1 Dosing Considerations ............................................................................................. 5

4.2 Recommended Dose and Dosage Adjustment.......................................................... 6

4.4 Administration .......................................................................................................... 6

4.5 Missed Dose ............................................................................................................ 6

5 OVERDOSAGE................................................................................................................ 6

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ............................ 7

7 WARNINGS AND PRECAUTIONS ................................................................................... 7

7.1 Special Populations ............................................................................................... 12

7.1.1 Pregnant Women .................................................................................................. 12

7.1.2 Breast-feeding ...................................................................................................... 12

7.1.3 Pediatrics.............................................................................................................. 12

7.1.4 Geriatrics .............................................................................................................. 12

8 ADVERSE REACTIONS................................................................................................. 13

8.1 Adverse Reaction Overview ................................................................................... 13

8.2 Clinical Trial Adverse Reactions ............................................................................. 13

8.3 Less Common Clinical Trial Adverse Reactions ...................................................... 14

8.5 Post-Market Adverse Reactions ............................................................................. 14

9 DRUG INTERACTIONS.................................................................................................. 15

9.1 Serious Drug Interactions ....................................................................................... 15

9.2 Drug Interactions Overview .................................................................................... 15

9.3 Drug-Behavioural Interactions ................................................................................ 15

9.4 Drug-Drug Interactions ........................................................................................... 15

9.5 Drug-Food Interactions .......................................................................................... 16

9.6 Drug-Herb Interactions ........................................................................................... 16

9.7 Drug-Laboratory Test Interactions .......................................................................... 16

10 CLINICAL PHARMACOLOGY ....................................................................................... 16

10.1 Mechanism of Action.............................................................................................. 16

10.2 Pharmacodynamics ............................................................................................... 17

10.3 Pharmacokinetics .................................................................................................. 17

11 STORAGE, STABILITY AND DISPOSAL ....................................................................... 18

12 SPECIAL HANDLING INSTRUCTIONS.......................................................................... 18

PART II: SCIENTIFIC INFORMATION .................................................................................. 19

13 PHARMACEUTICAL INFORMATION............................................................................. 19

14 CLINICAL TRIALS ......................................................................................................... 19

14.2 Comparative Bioavailability Studies ........................................................................ 19

15 MICROBIOLOGY ........................................................................................................... 20

16 NON-CLINICAL TOXICOLOGY...................................................................................... 20

17 SUPPORTING PRODUCT MONOGRAPHS ................................................................... 21

PATIENT MEDICATION INFORMATION .............................................................................. 22

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

TEMAZEPAM (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.

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

1.1 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics: Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness.

Long-term use of TEMAZEPAM should be avoided in elderly patients. Enhanced monitoring is recommended (see 7 WARNINGS AND PRECAUTIONS, Falls and Fractures; 4.1 Dosing considerations).

2 CONTRAINDICATIONS

TEMAZEPAM is contraindicated in patients:

• with a known hypersensitivity to the drug, to other benzodiazepines or to any component of the drug’s formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• with myasthenia gravis.
• with sleep apnea syndrome.
• who in the past manifested paradoxical reactions to alcohol and/or sedative medications.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

• 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 should always be prescribed at the lowest effective dose for the shortest duration possible.
• TEMAZEPAM can produce withdrawal signs and symptoms or rebound phenomena following abrupt discontinuation or rapid dose reduction (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Withdrawal; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance). Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring.
• Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
• If a patient experiences withdrawal signs and symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
• Geriatric patients in particular may be more sensitive to benzodiazepines (see 7 WARNINGS AND PRECAUTIONS, Falls and Fractures).
• Long-term use of TEMAZEPAM should be avoided in elderly patients. Enhanced monitoring is recommended.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose

Adults: the recommended dose of TEMAZEPAM is 30 mg before retiring, 15 mg may be sufficient for some patients.

Elderly and/or Debilitated Patients: the initial dose should not exceed 15 mg before retiring (see 7.1.4 Geriatrics).

Pediatrics: TEMAZEPAM is not indicated for children under 18 years of age (see 7.1.3 Pediatrics).

Dosage Adjustment

The lowest effective dose of TEMAZEPAM should be used. 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.

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

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.

4.4 Administration

Capsules are for oral administration.

4.5 Missed Dose

If the patient misses a dose, inform the patient to skip the missed dose and take the next dose at the regular dosing schedule.

5 OVERDOSAGE

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). General supportive measures should be employed. Maintenance of adequate pulmonary ventilation is essential and fluids should be administered intravenously to encourage diuresis. The use of pressor agents, such as norepinephrine bitartrate or metaraminol, intravenously 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.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table 1 – Dosage Forms, Strengths, Composition and Packaging

TEMAZEPAM 15 mg: Capsules containing 15 mg of temazepam (pink opaque body, maroon opaque cap, hard gelatin capsule, imprinted APO 15, with white powder fill) are available in bottles of 100.

TEMAZEPAM 30 mg: Capsules containing 30 mg of temazepam (light blue opaque body, maroon opaque cap, hard gelatin capsule, imprinted APO 30, with white powder fill) are available in bottles of 100.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

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 behaviour 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.

Concomitant use with opioids: Concomitant use of benzodiazepines, including TEMAZEPAM, and opioids may result in profound sedation, respiratory depression, coma, and death. Because of these risks, reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are not possible (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant use with Opioids; 9.1 Serious Drug Interactions).

Observational studies have demonstrated that concomitant use of opioid analgesics and benzodiazepines increases the risk of drug-related mortality compared to use of opioid analgesics alone. Because of similar pharmacological properties, it is reasonable to expect similar risk with the concomitant use of other CNS depressant drugs with benzodiazepines.

If a decision is made to prescribe TEMAZEPAM concomitantly with opioids, prescribe the lowest effective dosages and minimum durations of concomitant use. In patients already receiving an opioid analgesic, prescribe a lower initial dose of TEMAZEPAM than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking TEMAZEPAM, prescribe a lower initial dose of the opioid analgesic and titrate based on clinical response. Follow patients closely for signs and symptoms of respiratory depression and sedation (see 5 OVERDOSAGE).

Advise both patients and caregivers about the risks of respiratory depression and sedation when TEMAZEPAM is used with opioids.

Advise patients not to drive or operate heavy machinery until the effects of concomitant use of the opioid have been determined.

Potentiation of Drug Effects: TEMAZEPAM may potentiate the effects of other central nervous system depressant drugs such as alcohol, barbiturates, non-barbiturate 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 (see 9.4 Drug-Drug Interactions).

Dependence/Tolerance

Use of benzodiazepines, such as TEMAZEPAM, can lead to abuse, misuse, addiction, physical dependence (including tolerance) and withdrawal reactions. Abuse and misuse can result in overdose or death, especially when benzodiazepines are combined with other medicines, such as opioids, alcohol, or illicit drugs.

The risk of dependence increases with higher doses and longer term use but can occur with short-term use at recommended therapeutic doses. The risk of dependence is greater in patients with a history of psychiatric disorders and/or substance (including alcohol) use disorder.

• Discuss the risks of treatment with TEMAZEPAM with the patient, considering alternative (including non-drug) treatment options.
• Carefully evaluate each patient’s risk of abuse, misuse and addiction, considering their medical condition and concomitant drug use, prior to prescribing TEMAZEPAM. In individuals prone to substance use disorder, TEMAZEPAM should only be administered if deemed medically necessary, employing extreme caution and close supervision.
• TEMAZEPAM should always be prescribed at the lowest effective dose for the shortest duration possible.
• All patients receiving benzodiazepines should be routinely monitored for signs and symptoms of misuse and abuse. If a substance use disorder is suspected, evaluate the patient and refer them for substance abuse treatment, as appropriate.

Withdrawal: Benzodiazepines, such as TEMAZEPAM, can produce withdrawal signs and symptoms, ranging from mild to severe and even life threatening, following abrupt discontinuation or rapid dose reduction. Other factors that may precipitate withdrawal are switching from a long-acting to a short-acting benzodiazepine, decreasing blood levels of the drug or administration of an antagonist. The risk of withdrawal is higher with higher dosages and/or prolonged use, but can occur with short-term use at recommended therapeutic doses.

The onset of withdrawal signs and symptoms can range from hours to weeks following drug cessation and occur even with tapered dosage. Some symptoms can persist for months. Since symptoms are often similar to those for which the patient is being treated, it may be difficult to distinguish from a relapse of the patient’s condition.

Severe or life-threatening signs and symptoms of withdrawal include catatonia, delirium tremens, depression, dissociative effects (e.g. hallucinations), mania, psychosis, seizures (including status epilepticus) and suicidal ideation and behaviour.

Other withdrawal signs and symptoms include abdominal cramps, cognitive impairment, diarrhea, dysphoria, extreme anxiety or panic attacks, headache, hypersensitivity to light, noise and physical contact, insomnia, irritability, muscle pain or stiffness, paresthesia, restlessness, sweating, tension, tremors and vomiting. There is also a possibility of rebound anxiety or rebound insomnia.

• Abrupt discontinuation should be avoided and treatment - even if only of short duration - should be terminated by gradually tapering the dosage schedule under close monitoring.
• Tapering should be tailored to the specific patient. Special attention should be given to patients with a history of seizure.
• If a patient experiences withdrawal symptoms, consider postponing the taper or raising the benzodiazepine to the previous dosage prior to proceeding with a gradual taper.
• Inform patients of risk of discontinuing abruptly, reducing dosage rapidly or switching medications.
• Stress the importance of consulting with their health care professional in order to discontinue safely.
• Patients experiencing withdrawal symptoms should seek immediate medical attention.

(see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse; 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Withdrawal; 4.1 Dosing Considerations)

Driving and Operating Machinery

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.

Falls and Fractures

There have been reports of falls and fractures among benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), the elderly or debilitated patients.

Hepatic/Biliary/Pancreatic

Temazepam is O-conjugated in the liver. Hence, TEMAZEPAM should be given with caution to patients with impaired hepatic function.

Immune

Severe Anaphylactic and Anaphylactoid Reactions: Rare cases of angioedema involving the tongue, glottis or larynx have been reported in patients after taking the first or subsequent doses of sedative-hypnotics, including temazepam. Some patients have had additional symptoms such as dyspnea, throat closing or nausea and vomiting that suggest anaphylaxis. Some patients have required medical therapy in the emergency department. If angioedema involves the throat, glottis or larynx, airway obstruction may occur and be fatal. Patients who develop angioedema after treatment with TEMAZEPAM should not be rechallenged with the drug.

Neurologic

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.

Psychiatric

Abnormal thinking and psychotic behavioural 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 depressant (e.g., sedative/hypnotics). Particular caution is warranted in patients with a history of violent behaviour and a history of unusual reactions to sedatives including alcohol and the benzodiazepines. Psychotic behavioural changes that have been reported with benzodiazepines include bizarre behaviour, hallucinations, and depersonalization. Abnormal behaviours 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 behaviours listed above is drug-induced, spontaneous in origin, or a result of an underlying psychiatric disorder. Nevertheless, the emergence of any new behavioural sign or symptom of concern requires careful and immediate evaluation.

Anxiety/Restlessness: An increase in daytime anxiety and/or restlessness have been observed during treatment with temazepam. This may be a manifestation of inter dose withdrawal due to the short elimination half-life of the drug.

Complex Sleep-Related Behaviours: Complex sleep-related behaviours such as “sleep-driving” (i.e., driving while not fully awake after ingestion of a sedative-hypnotic, with amnesia for the event) have been reported in patients who have taken temazepam. Other potentially dangerous behaviours have been reported in patients who got out of bed after taking a sedative-hypnotic and were not fully awake, including preparing and eating food, making phone calls, leaving the house, etc. As with “sleep-driving”, patients usually do not remember these events. The use of alcohol and other CNS-depressants with temazepam appears to increase the risk of such behaviours, as does the use of temazepam at doses exceeding the maximum recommended dose. TEMAZEPAM is not to be taken with alcohol (see 9.3 Drug-Behavioural Interactions). Caution is needed with concomitant use of other CNS depressant drugs (see 9.4 Drug-Drug Interactions). Due to the risk to the patient and the community, discontinuation of TEMAZEPAM should be strongly considered for patients who report any such complex sleep-related behaviours.

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.

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.

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.

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.

Renal

Temazepam is primarily excreted by the kidney. Hence, TEMAZEPAM should be given with caution to patients with impaired renal function.

Reproductive Health: Female and Male Potential

• Fertility

The clinical data for the effect of temazepam on fertility is not available.

• Teratogenic Risk

There are no adequate and well-controlled studies of temazepam in pregnant women. Animal studies with other anxiolytic-sedative agents have suggested increased risk of congenital malformations (see 7.1.1 Pregnant women; 16 NON-CLINICAL TOXICOLOGY,

Reproductive and Developmental Toxicology).

Respiratory

TEMAZEPAM should be given with caution to patients with severe pulmonary insufficiency: respiratory depression has been reported in patients with compromised respiratory function.

7.1 Special Populations

7.1.1 Pregnant Women

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.

Non-teratogenic 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.

7.1.2 Breast-feeding

It is not known whether or not temazepam is excreted in human milk. Therefore, it should not be given to breast-feeding mothers.

7.1.3 Pediatrics

Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

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.

Long-term use of TEMAZEPAM should be avoided in elderly or debilitated patients who may be more sensitive to benzodiazepines. There is an increased risk of cognitive impairment, delirium, falls, fractures, hospitalizations and motor vehicle accidents in these users. Enhanced monitoring is recommended in this population.

8 ADVERSE REACTIONS

8.1 Adverse Reaction Overview

In clinical trials, drowsiness, dizziness, and confusion occurred at a higher incidence in temazepam-treated patients as compared with placebo-treated patients.

Ataxia has been reported with an incidence of 0.5 to 0.9 % in clinical trials.

There have been reports of falls and fractures in benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia (See 7 WARNINGS AND PRECAUTIONS, Falls and Fractures).

8.2 Clinical Trial Adverse Reactions

Clinical trials are conducted under very specific conditions. The adverse reaction rates observed in the clinical trials; therefore, may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials may be useful in identifying and approximating rates of adverse drug reactions in real-world use.

During controlled clinical trials in which 1076 patients received temazepam at bedtime, the Adverse Events occurring in 1% or more of patients are listed below.

Table 2 - Treatment Emergent Adverse Events Incidence in Insomnia Placebo-Controlled Studies

8.3 Less Common Clinical Trial Adverse Reactions

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

Cardiac Disorders: dyspnea, palpitations.

Eye disorders: burning eyes.

Gastrointestinal disorders: vomiting.

Metabolism and nutrition disorders: anorexia.

Musculoskeletal and connective tissue disorder: backache.

Nervous system disorders: ataxia, equilibrium loss, tremor, increased dreaming.

Skin and subcutaneous tissue disorders: hyperhidrosis.

The following adverse events have been reported with an incidence of less than 0.5%:

Eye disorders: horizontal nystagmus.

Nervous system disorders: restlessness, overstimulation, agitation.

Psychiatric disorders: amnesia, hallucinations

8.5 Post-Market Adverse Reactions

Injury, Poisoning and Procedural Complications

There have been reports of falls and fractures in benzodiazepine users due to adverse reactions such as sedation, dizziness and ataxia. The risk is increased in those taking concomitant sedatives (including alcoholic beverages), the elderly and debilitated patients.

Dependence/Withdrawal

Development of physical dependence and withdrawal following discontinuation of therapy has been observed with benzodiazepines such as temazepam. Severe and life-threatening symptoms have been reported (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Addiction, Abuse and Misuse; 7 WARNINGS AND PRECAUTIONS, Dependence/Tolerance).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

TEMAZEPAM may produce additive CNS depressant effects when co-administered with alcohol, sedative antihistamines, anticonvulsants, or psychotropic medications which themselves can produce CNS depression. (see 9.3 Drug-Behavioural Interactions; 9.4 Drug-Drug Interactions)

The activity of benzodiazepines, including TEMAZEPAM, may be enhanced by compounds which inhibit certain hepatic enzymes such as cytochrome P450 enzymes. (see 9.4 Drug-Drug Interactions)

9.3 Drug-Behavioural Interactions

TEMAZEPAM may produce additive CNS depressant effects when co-administered with alcohol. Patients should be cautioned not to take alcohol because of the potentiation of effects that might occur.

9.4 Drug-Drug Interactions

CNS depressant drugs: TEMAZEPAM may potentiate the effects of other central nervous system depressant drugs such as alcohol, barbiturates, non-barbiturate 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 because of the potentiation of effects that might occur.

Cytochrome P450: Compounds, which inhibit certain hepatic enzymes (particularly cytochrome P450), may enhance the activity of benzodiazepines, including TEMAZEPAM. Examples include cimetidine or erythromycin.

Opioids: Due to additive CNS depressant effect, the concomitant use of benzodiazepines, including TEMAZEPAM, and opioids increases the risk of profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing of these drugs for use in patients for whom alternative treatment options are inadequate. Limit dosages and durations of concomitant use of benzodiazepines and opioids to the minimum required. Follow patients closely for respiratory depression and sedation (see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX, Risks from Concomitant use with Opioids; 7 WARNINGS AND PRECAUTIONS, General, Concomitant use with opioids).

9.5 Drug-Food Interactions

Interactions with food have not been established.

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10 CLINICAL PHARMACOLOGY

10.1 Mechanism of Action

Temazepam is a benzodiazepine with hypnotic properties.

Benzodiazepines act as depressants of the central nervous system (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 receptors 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 mg and 30 mg, was compared to placebo over a two 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.

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 day-time anxiety (see 7 WARNINGS AND PRECAUTIONS, Psychiatric, Anxiety/Restlessness).

10.2 Pharmacodynamics

In animals, temazepam produces sedative and muscle relaxant effects. At higher doses it has some cardiovascular depressant effects. In unanesthetized rabbits and dogs, temazepam caused slight but significant decreases in blood pressure at oral doses from 5 to 20 mg/kg.

Temazepam decreases spontaneous activity at doses of 2.5 to 5 mg/kg p.o. in the mouse, 20 mg/kg p.o. in the rat and at 10 mg/kg p.o. in the dog. It produces ataxia in the mouse and rat at 10 mg/kg p.o. and in the dog at 20 mg/kg p.o. Loss of righting reflex occurs in mouse and rat at 40 mg/kg p.o. and muscle tone is decreased in the mouse at 10 to 40 mg/kg p.o. and in the rat and dog at 20 mg/kg p.o. Ptosis, myosis and piloerection occur in the mouse at 2.5 to 5 mg/kg p.o., in the rat at 10 to 20 mg/kg p.o., and in the dog bradycardia occurs at 20 to 40 mg/kg and photophobia at 80 mg/kg p.o.

Temazepam potentiates the sleep-enhancing effects of hexobarbitone, induces sleep in cebus monkeys at the minimum effective dose of 3.75 mg/kg p.o. and blocks the lingomandibular reflex in cats at the dose of 0.1 to 1 mg/kg i.v. Temazepam also blocks pentylenetetrazol-induced convulsions in mice at the dose of 0.23 mg/kg p.o.

10.3 Pharmacokinetics

Absorption

Orally administered temazepam is well absorbed in man. 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.

Distribution

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

Metabolism

In a single and multiple dose absorption, distribution, metabolism and excretion (ADME) study, using ³H-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. 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.

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

Elimination

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

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature 15°C to 25°C in well-closed, light-resistant containers.

Keep out of reach and sight of children.

TEMAZEPAM should never be disposed of in household trash. Disposal via a pharmacy take back program is recommended.

12 SPECIAL HANDLING INSTRUCTIONS

None

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Common name: temazepam

Chemical names: 1) 2H-1,4-Benzodiazepine-2-one,7-chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-;

1. 2) 7-Chloro-1,3-dihydro-3-hydroxy-1-methyl-5-phenyl-2H-1,4-benzodiazepine-2-one.

Molecular formula and molecular mass: C16H13ClN202 and 300.74 g/mol

Structural formula:

Physicochemical properties: A white or almost white odourless, crystalline powder. Practically insoluble in water; sparingly soluble in alcohol; freely soluble in chloroform. Melting point 156°C to 162°C.

14 CLINICAL TRIALS

The clinical trial data on which the original indication was authorized is not available.

14.2 Comparative Bioavailability Studies

A randomized, two-way, single-dose, crossover comparative bioavailability study of TEMAZEPAM 30 mg capsules (Apotex Inc.) with RESTORIL^® 30 mg capsules (Sandoz Canada Inc.) was conducted in healthy, adult, male subjects under fasting conditions. Comparative bioavailability data from 19 subjects that were included in the statistical analysis are presented in the following table:

SUMMARY TABLE OF THE COMPARATIVE BIOAVAILABILITY DATA

¹ TEMAZEPAM (temazepam) capsules, 30 mg (Apotex Inc.)

² RESTORIL^® (temazepam) capsules, 30 mg (Sandoz Canada Inc.)

³ Expressed as the median (range) only

⁴ Expressed as the arithmetic mean (CV%) only

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: In the acute toxicity studies the following LD50 for temazepam were determined:

Table 3 - Acute LD₅₀ of temazepam

Overt sedation was prominent in all acute tests and ataxia and decreased locomotion were observed in some tests.

Subacute toxicity experiments lasting from 6 to 13 weeks were conducted in rats (9 to 250 mg/kg/day p.o.) and dogs (80 to 200 mg/kg/day p.o.). In the rat changes in hepatic function were seen at the doses over 100 mg/kg/day.

In subacute studies in dogs treatment-related symptoms included decreased locomotion, sedation, abdominal distension and weight loss. Sporadic hyperexcitability was seen in some animals. Chronic toxicity studies of 6 to 12 months were performed in rats (10 to 160 mg/kg/day p.o.) and dogs (5 to 120 mg/kg/day p.o.). In the rat the major finding was a liver weight increase at high doses and minimal hepatic lipidosis at the mid and high doses. Dogs at the higher doses employed exhibited slight lethargy.

Two series of 18 month studies were performed in mice at doses from 11 to 158 mg/kg/day. In one study there was a 4% increase over controls in hepatocellular adenomas in female mice. This incidence is within that found in control groups for the species studied.

Reproductive and Developmental Toxicology: Rats (25 to 840 mg/kg/day) and rabbits (5 to 60 mg/kg/day) were utilized to assess potential reproductive and teratologic effects. Two segment II type studies in rats provided evidence of the possible increased incidence of fetal resorptions, at doses of 30 to 120 mg/kg. In perinatal and postnatal studies in rats at doses of 60 and 120 mg/kg/day, resulted in increasing nursling mortality. There were minimal untoward effects on the newborn survival rate. Two segment II type studies in rabbits produced no evidence of potential teratologic effects.

17 SUPPORTING PRODUCT MONOGRAPHS

1. 1. RESTORIL^® (Capsule, 15 mg and 30 mg), submission control 248569, Product Monograph, AA Pharma Inc. (NOV 16, 2021)