Clorazepate 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

4.5 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................................................................................................ 12

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

8.5 Post-Market Adverse Reactions .............................................................................. 13

9 DRUG INTERACTIONS ............................................................................................... 13

9.1 Serious Drug Interactions ....................................................................................... 13

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

9.5 Drug-Food Interactions ........................................................................................... 13

9.6 Drug-Herb Interactions ........................................................................................... 13

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

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

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

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

10.3 Pharmacokinetics .............................................................................................. 14

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 ................................................................................. 19

PART I: HEALTH PROFESSIONAL INFORMATION

1 INDICATIONS

CLORAZEPATE (clorazepate dipotassium) is indicated for:

• the short-term symptomatic relief of excessive anxiety and tension in psychoneurotic patients including those with functional somatic complaints.
• the adjunctive management of acute alcohol withdrawal.

Anxiety or tension associated with the stress of everyday life usually does not require treatment with an anxiolytic.

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 (> 65 years of age): Evidence from clinical studies and experience suggests that use in the geriatric population is associated with differences in safety or effectiveness. See 4.2 Recommended Dose and Dosage Adjustment; 7.1.4 Geriatrics.

Long-term use of CLORAZEPATE should be avoided in elderly patients. Enhanced monitoring is recommended. See 7 WARNINGS AND PRECAUTIONS,

Falls and fractures; 4.1 Dosing considerations.

2 CONTRAINDICATIONS

CLORAZEPATE is contraindicated in:

• Patients with known hypersensitivity to clorazepate dipotassium or to any non-medicinal ingredient in the formulation. For a complete listing, See 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Patients with myasthenia gravis.

3 SERIOUS WARNINGS AND PRECAUTIONS BOX

Serious Warnings and Precautions

4 DOSAGE AND ADMINISTRATION

4.1 Dosing Considerations

The dosage of CLORAZEPATE (clorazepate dipotassium) must be individualized and carefully titrated in order to avoid excessive sedation or mental and motor impairment.

As with other anxiolytic sedatives, short courses of treatment should usually be the rule for the symptomatic relief of disabling anxiety in psychoneurotic patients and the initial course of treatment should not last longer than 1 week without reassessment of the need for a limited extension. Initially, not more than 1 week's supply of the drug should be provided and automatic prescription renewals should not be allowed. Subsequent prescriptions, when required, should be limited to short courses of therapy.

• CLORAZEPATE should always be prescribed at the lowest effective dose for the shortest duration possible.
• CLORAZEPATE 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 CLORAZEPATE should be avoided in elderly patients. Enhanced monitoring is recommended.

4.2 Recommended Dose and Dosage Adjustment

Anxiety

CLORAZEPATE (clorazepate dipotassium) is administered orally in divided doses.

Usual adult daily dose: The usual adult daily dose is 30 mg. The dose should be adjusted gradually within the range of 15 to 60 mg in accordance with the response of the patient. After the patient has been stabilized on a suitable dosage, the frequency of dosing may be decreased in some patients to twice daily or once daily with the major portion of the dosage given at night, provided that the physician can ascertain that such a schedule will produce the desired anxiolytic effect without a period of drowsiness or impairment of mental functions.

Elderly or Debilitated Patients: In these patients, treatment should be initiated with 3.75 mg once a day, preferably at night. The dosage should be very carefully and gradually adjusted, depending on tolerance and response. See 7.1.4 Geriatrics.

Since anxiolytic sedatives are indicated for the treatment of current or state anxiety, administration of CLORAZEPATE should generally be limited to the duration of the episode requiring symptomatic relief.

Acute alcoholic withdrawal

For the management of acute alcoholic withdrawal, the following dosages may be used: 30-90 mg in divided doses in the first 24 hours, depending on individual tolerance and response. In the second 24 hours, the dosage should be reduced to not more than 60 mg in divided doses.

Subsequently, the daily dosage should be reduced gradually, usually to not more than 15-30 mg on the 4th day, and should then be tapered off more rapidly and discontinued as soon as possible.

Pediatrics (<18 years of age)

No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use. See 7.1.3 Pediatrics.

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

Symptoms

Clorazepate dipotassium overdosage may be manifested by varying degrees of CNS depression ranging from drowsiness, confusion, ataxia to coma. Hyporeflexia may occur. Unless the overdosage is extreme, effects on pulse, blood pressure and respiration are minimal.

Treatment

There are no specific antidotes for clorazepate. The treatment of overdosage should consist of the general measures employed in the management of overdosage of any CNS depressant.

If vomiting has not occurred spontaneously and the patient is fully awake, it may be induced with syrup of ipecac 20 to 30 mL.

Hypovolemia, indicated by reduced central venous pressure, should be treated, if present, with a balanced salt solution.

Although hypotension is rarely reported, it may occur with large overdoses and in this situation the use of pressor agents, such as levarterenol or metaraminol, should be considered.

6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING

Table – Dosage Forms, Strengths, Composition and Packaging

Each CLORAZEPATE 3.75 mg capsule contains 3.75 mg of clorazepate dipotassium. Each 3.75 mg hard gelatin capsule consists of an iron gray opaque body and a white opaque cap, imprinted 3.75 in black pharmaceutical ink.

Each CLORAZEPATE 7.5 mg capsule contains 7.5 mg of clorazepate dipotassium. Each 7.5 mg hard gelatin capsule consists of an iron gray body and maroon opaque cap, imprinted 7.5 in black pharmaceutical ink.

Each CLORAZEPATE 15 mg capsule contains 15 mg of clorazepate dipotassium. Each 15 mg hard gelatin capsule consists of and iron gray opaque body and cap, imprinted 15 in black pharmaceutical ink.

CLORAZEPATE is supplied as capsules, in bottles of 100, 500 and 1000.

7 WARNINGS AND PRECAUTIONS

General

Concomitant use with opioids: Concomitant use of benzodiazepines, including CLORAZEPATE, 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 CLORAZEPATE 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 CLORAZEPATE than indicated, and titrate based on clinical response. If an opioid analgesic is initiated in a patient already taking CLORAZEPATE, 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 CLORAZEPATE is used with opioids.

Advise patients not to drive or operate heavy machinery with concomitant use of the opioid.

Dependence/Tolerance

Use of benzodiazepines, such as CLORAZEPATE, 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 CLORAZEPATE 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 CLORAZEPATE. In individuals prone to

  • substance use disorder, CLORAZEPATE should only be administered if deemed medically necessary, employing extreme caution and close supervision.
• CLORAZEPATE 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 CLORAZEPATE, 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 ness, 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 healthcare 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, Withdrawal

; 4.1 Dosing Considerations.

Driving and Operating Machinery

Patients on clorazepate dipotassium should be cautioned against engaging in hazardous occupations requiring mental alertness, such as operating dangerous machinery, including motor vehicles.

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.

Hematology

Patients on CLORAZEPATE for prolonged periods should have blood counts and liver function tests periodically.

Hepatic

Patients on CLORAZEPATE for prolonged periods should have blood counts and liver function tests periodically. The usual precautions in treating patients with impaired hepatic function should also be observed.

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 CLORAZEPATE. 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 CLORAZEPATE should not be rechallenged with the drug.

Monitoring and Laboratory Tests

Patients on CLORAZEPATE for prolonged periods should have blood counts and liver function tests periodically.

Neurologic

Since clorazepate dipotassium has a central nervous system depressant effect, patients should be advised against the simultaneous use of other CNS depressant drugs and cautioned that the effects of alcohol may be increased.

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 CLORAZEPATE. 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 CLORAZEPATE appears to increase the risk of such behaviours, as does the use of CLORAZEPATE at doses exceeding the maximum recommended dose. CLORAZEPATE 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 CLORAZEPATE should be strongly considered for patients who report any such complex sleep-related behaviours.

Memory disturbance: Anterograde amnesia of varying severity has been reported following therapeutic doses of benzodiazepines. The event is rare with CLORAZEPATE. Anterograde amnesia is a dose-related phenomenon and elderly subjects may be at particular risk.

Ophthalmologic

Narrow-angle Glaucoma: CLORAZEPATE should be given with caution, if at all, to patients with acute narrow-angle glaucoma.

Psychiatric

CLORAZEPATE (clorazepate dipotassium) is not recommended for use in depressive neuroses or in psychotic reactions.

Abnormal thinking and psychotic behavioural changes have been reported to occur in association with the use of benzodiazepines including CLORAZEPATE, 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.

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 CLOREZEPATE 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.

Use in Mental and Emotional Disorders: Benzodiazepines, such as CLORAZEPATE, are not recommended in the treatment of psychotic or severely depressed patients. It should be recognized that suicidal tendencies may be present and that protective measures may be necessary. Since excitement and other paradoxical reactions may result from the use of the drug in psychotic patients, it should not be used in ambulatory patients suspected of having psychotic tendencies.

Renal

The usual precautions in treating patients with impaired renal function should also be observed.

Reproductive Health: Female and Male Potential

Teratogenic Risk: Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines, chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregnancy. Malformations in the infant of a mother who had taken clorazepate during the first trimester of pregnancy has been reported.

Nonteratogenic Risk: Nordiazepam, the active metabolite of clorazepate, crosses the human placenta. It is to be considered that the child born of a mother who is on benzodiazepines may be at some risk for withdrawal symptoms from the drug, during the postnatal period. Also, neonatal flaccidity has been reported in an infant born of a mother who had been receiving benzodiazepines.

7.1 Special Populations

7.1.1 Pregnant Women

The safety of use of clorazepate dipotassium in pregnancy has not been established. Therefore, CLORAZEPATE is not recommended for use during pregnancy. Nordiazepam, the active metabolite of clorazepate, crosses the human placenta. Several studies have suggested an increased risk of congenital malformations associated with the use of the benzodiazepines, chlordiazepoxide and diazepam, and meprobamate, during the first trimester of pregnancy. Malformations in the infant of a mother who had taken clorazepate during the first trimester of pregnancy has been reported. Since clorazepate dipotassium is also a benzodiazepine derivative, its administration is rarely justified in women of child-bearing potential. If the drug is prescribed to a woman of child-bearing potential, she should be warned to consult her physician regarding the discontinuation of the drug if she intends to become or suspects that she is pregnant.

7.1.2 Breast-feeding

CLORAZEPATE is not recommended for use during breast-feeding since nordiazepam, the active metabolite of clorazepate is excreted in human breast milk.

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

Geriatrics (> 65 years of age): Elderly and debilitated patients, or those with organic brain syndrome, have been found to be prone to CNS depression after even low doses of benzodiazepines. Therefore, medication should be initiated in these patients with very low initial doses, and increments should be made gradually, depending on the response of the patient, in order to avoid oversedation or neurological impairment.

Long-term use of CLORAZEPATE 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 side effect most frequently reported is drowsiness. Less commonly reported (in descending order of occurrence) are: dizziness, various gastrointestinal complaints, nervousness, blurred vision, dry mouth, headache and mental confusion. Other side effects include insomnia, transient skin rashes, fatigue, ataxia, genito-urinary complaints, irritability, diplopia, depression, slurred speech and hypotension.

There have been reports of abnormal liver and kidney function tests and of a decrease in hematocrit. Decrease in systolic blood pressure has been observed with clorazepate.

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 CLORAZEPATE. 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

9.4 Drug-Drug Interactions

Potentiation of Drug Effects

If CLORAZEPATE is to be combined with other drugs acting on the central nervous system, careful consideration should be given to the pharmacology of the agents to be employed. Animal experience indicates that clorazepate prolongs the sleeping time after hexobarbital or after ethyl alcohol, increases the inhibitory effects of chlorpromazine, but does not exhibit monoamine oxidase inhibition. Clinical studies have shown increased sedation with concurrent hypnotic medications. The action of the benzodiazepines may be potentiated by barbiturates, narcotics, phenothiazines, monoamine oxidase inhibitors, or other antidepressants.

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

CLORAZEPATE (clorazepate dipotassium) possesses anxiolytic and sedative properties that have been found to be of value for the symptomatic relief of pathological anxiety and tension states in psychoneurotic patients.

Clorazepate produces electroencephalographic changes similar to those of some of the other benzodiazepines, with an increased average frequency, frequency deviation and fast beta activity, while alpha activity and amplitudes decrease. In electroencephalographic studies of sleep, clorazepate produced decreased deep sleep stages with REM activity attenuated, although not significantly.

10.2 Pharmacodynamics

Clorazepate dipotassium has central nervous system depressant properties with a somewhat flatter dose-response curve than the sedative-hypnotic drugs.

Studies in laboratory animals showed that clorazepate dipotassium produced, in varying doses, taming, disinhibitory, sedative, anti-convulsant, muscle-relaxant, ataxic and hypnotic effects.

As with the sedative hypnotic drugs, benzodiazepines at sedative doses reduce slightly behavioural arousal, increase responsiveness to environmental stimuli, suppress passive avoidance behaviour, and increase approach behaviour. At slightly higher doses, they appear to increase errors of commission in performing tasks, produce drowsiness and ataxia, and decrease muscle tone. At low doses, clorazepate dipotassium does not reduce significantly locomotor activity.

Clorazepate dipotassium suppresses pentylenetetrazol-induced convulsions, but is relatively ineffective against maximal electroshock convulsions.

Clorazepate dipotassium has shown little or no effect on the autonomic nervous system.

After treatment of rats for one week, there was no indication that clorazepate dipotassium enhanced the activity of liver microsomal enzymes. It, however, possesses dependence liability and may produce withdrawal symptoms, but has a wide margin of safety against poisoning.

In rats, conditioned avoidance response was inhibited at an oral dose of 10 mg/kg and sedation was induced at 32 mg/kg. In monkeys, aggressive behaviour was reduced at an oral dose of 0.25 mg/kg and sedation (ataxia) was induced at 7.5 mg/kg.

10.3 Pharmacokinetics

Absorption

Following ingestion, the drug is rapidly decarboxylated to form nordiazepam (N- desmethyldiazepam) which is absorbed rapidly and is the primary active metabolite.

Distribution:

Peak serum levels of nordiazepam appear in from 1 to 2 hours following a single dose and the serum half-life is about 48 hours. During multiple dosage with clorazepate steady-state plasma concentrations of nordiazepam are usually attained in 5 days to 2 weeks. The concurrent use of antacids with clorazepate may decrease the rate and extent of conversion of the drug to desmethyldiazepam resulting in a small reduction (12%) in drug bioavailability.

Metabolism:

Subsequent hydroxylation of nordiazepam in the liver leads to the formation of oxazepam and p-OH-nordiazepam, which are excreted in the urine in conjugated and unconjugated forms.

Elimination

In man, approximately 52% of the urine drug level is found to be conjugated oxazepam. In 2 volunteers given 15 mg of 14C- clorazepate, about 80% was recovered in the urine and faeces within 10 days. Excretion was primarily in the urine with about 1% excreted per day on day 10.

11 STORAGE, STABILITY AND DISPOSAL

Store at room temperature (15-25°C) in a tightly closed container.

Keep out of reach and sight of children.

CLORAZEPATE 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

Proper name: clorazepate dipotassium

Chemical name: dipotassium;7-chloro-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepine-3-carboxylate;hydroxide

Molecular formula and molecular mass: C₁₆H₁₁Cl K₂N₂0₄ and 408.9

Structural formula: Clorazepate dipotassium is a benzodiazepine and has the following structural formula:

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:

Acute Toxicity:

Mortality generally occurred over a 48 hour period post-dosing.

Signs of systemic toxicity were ptosis, reduced activity and ataxia, piloerection, dyspnea or bradypnea, epistaxis, lacrimation, perineal staining, hunchback and coma.

Necropsy of these animals generally revealed darkening of the liver, paleness of the kidney and/or spleen, distension and/or irritation/hemorrhage of the stomach and or small intestine, distention of the urinary bladder and pulmonary congestion. Animals killed routinely at the conclusion of the study generally revealed no abnormality.

Subacute Toxicity Studies

Rats: It has been reported that rats could tolerate 50 times the human dose of clorazepate dipotassium administered daily by intubation for 78 weeks except for sedation, muscle relaxation and drowsiness. At higher doses (100 to 150 times the human dose) these effects were more marked. Pituitary chromphobe adenomatous hyperplasia in 4 of 10 females was also observed at higher doses.

Dogs: A 22 month oral chronic toxicity study in 24 dogs involving doses up to 75 mg/kg/day indicated that dogs could tolerate about 20 times the human dose of clorazepate dipotassium except for sedation, weight gain and reversible liver function disturbance. Higher doses produced more severe sedation and liver function disturbance. Liver mass increase and hepatic canalicular bile stasis without evidence of obstruction were observed at necropsies.

Monkeys: Rhesus monkeys (18) given increasing oral doses (from 3 mg/kg to 36 mg/kg/day) of clorazepate dipotassium could tolerate 18 to 36 times the human dose daily for 52 weeks. No significant differences were found between treated and control groups. Although total leukocyte count remained within normal limits it tended to fall in female monkeys at the highest doses.

Examination of all organs revealed no alterations attributable to the drug. No alteration of liver function or structure was observed.

Carcinogenicity:

No long-term animal studies have been performed to evaluate carcinogenic potential.

Genotoxicity:

No long-term animal studies have been performed to evaluate mutagenic potential.

Reproductive and Developmental Toxicology:

Reproductive Studies: Fertility, reproduction and teratology studies in rats at doses up to 150 mg/kg/day and in rabbits at doses up to 15 mg/kg/day produced no abnormalities in the fetuses. An increased resorption was observed in the rabbits and retarded ossification in the fetuses of the treated higher dose dams. Clorazepate dipotassium did not alter the fertility indices or reproductive capacity of adult animals. The sedative effect of higher doses interfered with the care of the young by their mothers.

Special Toxicology:

Information is not available.

Juvenile Toxicity:

Information is not available.