Flurazepam 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 ................................. 6

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

7.1 Special Populations .......................................................................................... 11

7.1.1 Pregnant Women ....................................................................................... 11

7.1.2 Breast-feeding............................................................................................ 11

7.1.3 Pediatrics ................................................................................................... 11

7.1.4 Geriatrics ................................................................................................... 11

8 ADVERSE REACTIONS................................................................................................. 12

8.1 Adverse Reaction Overview.............................................................................. 12

8.5 Post-Market Adverse Reactions........................................................................ 12

9 DRUG INTERACTIONS ................................................................................................ 12

9.1 Serious Drug Interactions ................................................................................. 12

9.2 Drug Interactions Overview.............................................................................. 13

9.3 Drug-Behavioural Interactions.......................................................................... 13

9.4 Drug-Drug Interactions .................................................................................... 13

9.5 Drug-Food Interactions .................................................................................... 14

9.6 Drug-Herb Interactions .................................................................................... 14

9.7 Drug-Laboratory Test Interactions .................................................................... 14

10 CLINICAL PHARMACOLOGY ........................................................................................ 14

10.1 Mechanism of Action.................................................................................. 14

10.2 Pharmacodynamics .................................................................................... 14

10.3 Pharmacokinetics ....................................................................................... 15

11 STORAGE, STABILITY AND DISPOSAL .......................................................................... 15

12 SPECIAL HANDLING INSTRUCTIONS............................................................................ 15

PART II: SCIENTIFIC INFORMATION........................................................................................ 16

13 PHARMACEUTICAL INFORMATION ............................................................................. 16

14 CLINICAL TRIALS ........................................................................................................ 16

15 MICROBIOLOGY ........................................................................................................ 16

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

PATIENT MEDICATION INFORMATION................................................................................... 18

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

FLURAZEPAM (flurazepam hydrochloride) 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 awakening.

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

1.1 Pediatrics

Pediatrics (<15 years of age): Based on the data submitted and reviewed by Health Canada, the safety and efficacy of FLURAZEPAM in pediatric patients has not been established; therefore, Health Canada has not authorized an indication for pediatric use. (see 7.1.3 Pediatrics)

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 FLURAZEPAM should be avoided in elderly patients. Enhanced monitoring is recommended (see Falls and Fractures; 4.1 Dosing Considerations).

2 CONTRAINDICATIONS

FLURAZEPAM is contraindicated in patients:

• with known hypersensitivity to benzodiazepines, or any ingredient in the formulation, including any non-medicinal ingredient or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• with severe impairment of respiratory function, e.g., significant sleep apnea syndrome.
• who have myasthenia gravis
• with severe hepatic insufficiency.

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.
• The use of hypnotics should be restricted for insomnia where disturbed sleep results in impaired daytime functioning.
• Treatment with FLURAZEPAM should usually not exceed 7-10 consecutive days. Use for more than 2-3 consecutive weeks requires complete re-evaluation of the patient. Prescriptions for FLURAZEPAM should be written for short-term use (7-10 days) and it should not be prescribed in quantities exceeding a one-month supply.
• FLURAZEPAM should always be prescribed at the lowest effective dose for the shortest duration possible.

Discontinuation

• FLURAZEPAM can produce withdrawal signs and symptoms or rebound phenomena following abrupt discontinuation or rapid dose reduction (see Withdrawal; 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

• Geriatric patients in particular may be more sensitive to benzodiazepines (see Falls and Fractures).

• Long-term use of FLURAZEPAM should be avoided in elderly patients. Enhanced monitoring is

  • recommended.

4.2 Recommended Dose and Dosage Adjustment

Recommended Dose

Adults: The usual adult dosage is 30 mg before retiring. In some patients, 15 mg may suffice.

Elderly and/or Debilitated Patients: It is recommended that therapy be initiated with 15 mg until individual responses are determined.

Pediatrics: Health Canada has not authorized an indication for pediatric use. (see 7.1.3 Pediatrics)

Dosage Adjustment

Dosage should be individualized for maximal beneficial effects.

4.4 Administration

The product should be taken orally just before going to bed. The patient should be checked regularly at the start of the treatment in order to decrease if necessary, the dose or frequency of administration to prevent overdose due to accumulation.

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 FLURAZEPAM overdosage include somnolence, confusion and coma. Respiration, pulse and blood pressure should be monitored as in all cases of drug overdosage. General supportive measures should be employed. Intravenous fluids should be administered and an adequate airway maintained. Hypotension and CNS depression may be combated by judicious use of appropriate therapeutic agents. The value of dialysis has not been determined. If excitation occurs in patients following FLURAZEPAM overdosage, barbiturates should not be used.

As with the management of intentional overdosage with any drug, 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

FLURAZEPAM 15 mg: Each orange/ivory, size #2 capsule imprinted '15' contains 15 mg flurazepam hydrochloride. Available in bottles of 100 and 1000.

FLURAZEPAM 30 mg: Each Swedish Orange/ivory, size #2 capsule imprinted '30' contains 30 mg flurazepam hydrochloride. Available in bottles of 100 and 1000.

7 WARNINGS AND PRECAUTIONS

Please see 3 SERIOUS WARNINGS AND PRECAUTIONS BOX.

General

FLURAZEPAM should be used with caution in patients who in the past manifested paradoxical reactions to alcohol and/or sedative medications. (see 9.3 Drug-Behavioural Interactions)

The failure of insomnia to remit after 7-10 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 FLURAZEPAM, 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 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 FLURAZEPAM 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 FLURAZEPAM than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking FLURAZEPAM, 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 FLURAZEPAM 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.

Dependence/Tolerance

Use of benzodiazepines, such as FLURAZEPAM, 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 FLURAZEPAM 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 FLURAZEPAM. In individuals prone to substance use disorder, FLURAZEPAM should only be administered if deemed medically necessary, employing extreme caution and close supervision.
• FLURAZEPAM 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 FLURAZEPAM, 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 Addiction, Abuse and Misuse; Withdrawal; 4.1 Dosing Considerations)

Driving and Operating Machinery

Because of FLURAZEPAM’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 FLURAZEPAM and alcohol or CNS- depressant drugs. (see 9.3 Drug-Behavioural Interactions; 9.4 Drug-Drug Interactions)

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

FLURAZEPAM 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 FLURAZEPAM. 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 FLURAZEPAM should not be rechallenged with the drug.

Monitoring and Laboratory Tests

Should FLURAZEPAM be used repeatedly, periodic blood counts, liver, and kidney function tests should be performed.

Neurologic

Memory disturbance: Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines. The event is rare with FLURAZEPAM. 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 benzodiazepines, 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 FLURAZEPAM 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 FLURAZEPAM, 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 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 behaviour 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 daytime anxiety and/or restlessness have been observed during treatment with short half-life benzodiazepines although the syndrome can apply on occasion to drugs with longer elimination half-lives as well. FLURAZEPAM has a long half-life.

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 FLURAZEPAM. 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 FLURAZEPAM appears to increase the risk of such behaviours, as does the use of FLURAZEPAM at doses exceeding the maximum recommended dose. FLURAZEPAM is not to be taken with alcohol. Caution is needed with concomitant use of other CNS depressant drugs. Due to the risk to the patient and the community, discontinuation of FLURAZEPAM should be strongly considered for patients who report any such sleep-related behaviours.

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

Depression: Caution should be exercised if FLURAZEPAM 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.

Rebound Insomnia: A transient syndrome whereby the symptoms that led to treatment with a benzodiazepines recur in an enhanced form, may occur on withdrawal of hypnotic treatment.

Renal

FLURAZEPAM should be given with caution to patients with impaired renal function.

Respiratory

Respiratory depression has been reported in patients with compromised respiratory function.

7.1 Special Populations

7.1.1 Pregnant Women

The use of FLURAZEPAM 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 FLURAZEPAM is prescribed to women 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 might be 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

The safety of FLURAZEPAM during lactation has not been established. Therefore, its use during nursing is not recommended.

7.1.3 Pediatrics

Based on the data submitted and reviewed by Health Canada, the safety and effecacy of FLURAZEPAM in children below the age of 15 have not been established; therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

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 (15 mg) should be used in these subjects.

Long-term use of FLURAZEPAM 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

The most common adverse reactions reported with FLURAZEPAM are dizziness, drowsiness, lightheadedness, and ataxia. These adverse effects are particularly common in elderly and debilitated patients. (See 7.1.4 Geriatrics) Severe sedation, lethargy, disorientation, and coma, probably indicative of drug intolerance or overdosage, have been reported. (see 5 OVERDOSAGE)

Isolated instances of headache, heartburn, upset stomach, nausea, vomiting, amnesia, constipation, diarrhea, gastrointestinal pain, nervousness, apprehension, irritability, weakness, palpitations, chest pains, and genito-urinary complaints have been reported. However, in controlled studies, these appeared as often or more often with placebo than with the active drug.

There have also been rare occurrences of leukopenia, granulocytopenia, sweating, flushes, difficulty in focusing, blurred vision, faintness, hypotension, shortness of breath, pruritus, skin rash, dry mouth, bitter taste, excessive salivation, anorexia, euphoria, depression, slurred speech, confusion, restlessness, hallucinations, nightmares, numbed emotions, reduced alertness, changes in libido, inappropriate behaviour and elevated SGOT, SGPT, total and direct bilirubins, and alkaline phosphatase. Paradoxical reactions such as excitement, stimulation, agitation, aggressiveness, rages, psychoses and hyperactivity have also been reported in rare instances when using drugs that act at the benzodiazepine receptors.

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 FLURAZEPAM. Severe and life-threatening symptoms have been reported. (see Addiction, Abuse and Misuse; Dependence/Tolerance).

9 DRUG INTERACTIONS

9.1 Serious Drug Interactions

9.2 Drug Interactions Overview

FLURAZEPAM may produce additive CNS depressant effects when co-administered with alcohol, sedative antihistamines, narcotic analgesics, 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. Examples include cimetidine or erythromycin.

9.3 Drug-Behavioural Interactions

FLURAZEPAM may produce additive CNS depressant effects when co-administered with alcohol.

9.4 Drug-Drug Interactions

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

Table 2 - Established or Potential Drug-Drug Interactions

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical

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

FLURAZEPAM (flurazepam hydrochloride), a benzodiazepine derivative, is a hypnotic agent which does not appear to decrease dream time as measured by rapid eye movements (REM). FLURAZEPAM decreases sleep latency and number of awakenings for a consequent increase in total sleep time.

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 arid 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 Psychiatric; Anxiety/Restlessness).

FLURAZEPAM is a benzodiazepine with a long half-life.

10.2 Pharmacodynamics

In animals, flurazepam hydrochloride has been demonstrated to produce sedative, anticonvulsant, taming, and muscle relaxant effects. At high doses, flurazepam hydrochloride exhibited sedative effects in rats (36 mg/kg), as well as a depressant effect on behaviour in squirrel monkeys (40 mg/kg). Some cardiovascular depressant effects were also observed, but were largely attributed to the central nervous system depressant effects of high doses.

FLURAZEPAM and its metabolites bind with high affinity to mouse brain membranes. In vitro specific binding affinities (Ki) for flurazepam, hydroxyethyl-flurazepam, flurazepam aldehyde and desalkyl-flurazepam were 10.7, 16.2, 10.6, and 0.85 nM, respectively. Flurazepam hydrochloride is rapidly absorbed from the gastrointestinal tract and is rapidly metabolized. Studies in rats with ¹⁴C-labelled flurazepam hydrochloride indicated that the drug is widely distributed throughout body tissues with no excessive accumulation of drug or metabolite in any one tissue.

10.3 Pharmacokinetics

Absorption

Following oral administration of 15 mg flurazepam hydrochloride to male and female volunteers, measurable concentrations for the parent compound were not detectable.

Distribution and Metabolism

FLURAZEPAM undergoes rapid and pronounced metabolism to two pharmacologically active metabolites, namely hydroxyethyl flurazepam and flurazepam aldehyde. In healthy volunteers, C_max values for the two metabolites were 8.6 and 2.5 ng/mL respectively. They were reached in an average of 1.0 and 1.2 hours, respectively.

The final active and principal metabolite, desalkyl flurazepam (DAFLZ), appears in the systemic circulation more slowly, with a mean C_max of 14 ng/mL attained an average of 10.6 hours after dosing.

Elimination

The mean elimination half-lives for hydroxyethyl flurazepam and flurazepam aldehyde were less than 2.5 hours.

The mean elimination half-life of DAFLZ is approximately 75 hours (range 50 to 100 hours). Therefore, multiple-dose therapy with flurazepam leads to the accumulation of DAFLZ.

More than 50% of the total dose of flurazepam appears in the urine in 24 hours, with eventual urinary excretion accounting for 80% or more of the total dose. The major urinary metabolite is conjugated hydroxyethyl flurazepam. Less than 1% of the dose is excreted in the urine as DAFLZ. Approximately 10% of the total dose of flurazepam appears in the feces.

Special Populations and Conditions

• Geriatrics: Following 15 days treatment with 15 mg flurazepam once daily, mean steady-state plasma levels of DAFLZ were higher in elderly than in young men (81 and 53 ng/rnL, p<0.05) but were similar in elderly and young women (86 and 85 ng/mL). The half-life of DAFLZ was found to be longer in elderly males than in young males (160 versus 74 hours, p<0.05), but was similar in elderly and young females (120 versus 90 hours, p=N.S.). DAFLZ was extensively bound to plasma protein. The unbound fraction increased with age regardless of sex.

11 STORAGE, STABILITY AND DISPOSAL

Keep in a tightly closed, light-resistant container. Store at 15-25°C.

12 SPECIAL HANDLING INSTRUCTIONS

None

PART II: SCIENTIFIC INFORMATION

13 PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: Flurazepam Hydrochloride

Chemical name: 7-chloro- 1- [2(diethylamino)ethyl]-5-(0-fluorophenyl)- 1, 3-dihydro-2H- 1, 4-benzodiazepin-2-one-dihydrochloride

Molecular formula and molecular mass: C₂₁H₂₃CIFN₃0.2HCl and 460.81

Structural formula:

Physicochemical properties: Flurazepam hydrochloride occurs as an off--white to yellow, nearly odorless, crystalline powder, with a melting point of 190-220°C.

Solubility Soluble 1 in 2 of water, 1 in 4 of alcohol, 1 in 90 of chloroform, 1 in 3 of methyl alcohol, and 1 in 69 of isopropyl alcohol; very slightly soluble in ether and petroleum spirit and in chloroform.

14 CLINICAL TRIALS

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

15 MICROBIOLOGY

No microbiological information is required for this drug product.

16 NON-CLINICAL TOXICOLOGY

General Toxicology: The oral LD50 was 870 mg/kg in mice, 1,232 mg/kg in rats and 568 mg/kg in rabbits. Chronic toxicity studies for one year indicated that the tolerated dose is 80 mg/kg/day in the rat and 10 mg/kg/day in the dog.

Reproductive and Developmental Toxicology: A two-cycle reproductive study in rats was carried out at doses of 5 and 50 mg/kg/day of flurazepam hydrochloride. There were no significant teratogenic or other adverse effects related to the drug. In the second series of rat reproductive studies, doses of 3 and 20 mg/kg/day of flurazepam hydrochloride did not induce changes in fertility and general reproductive performance. There were no significant teratogenic effects related to the drug or adverse effects in the perinatal and postnatal study. In another reproductive study in rats at doses of 10, 20, 40 and 80 mg/kg/day, no adverse effects on reproduction and no significant teratological changes were noted.

In rabbits, two sets of teratogenic studies were done. In the first, flurazepam hydrochloride was administered in doses of 5 and 20 mg/kg/day. Twenty-three live litters were obtained in this study. One animal which received 20 mg/kg/day had a litter of nine viable but deformed fetuses. In the second study, the dose of flurazepam hydrochloride was increased to 40 mg/kg/day without the occurrence of abnormalities in all eleven litters. In both studies, there were no significant differences between the control and treated groups in maternal weight, body weight of viable fetuses, fetal body weight and litter size.