PRODUCT MONOGRAPH DIAZEPAM AUTOINJECTOR, USP. 5 mg/ml (2 ml/injector) THERAPEUTIC CLASSIFICATION. Anxiolytic-Sedative

Transcription

1 PRODUCT MONOGRAPH DIAZEPAM AUTOINJECTOR, USP 5 mg/ml (2 ml/injector) THERAPEUTIC CLASSIFICATION Anxiolytic-Sedative Meridian Medical Technologies, Inc Hermelin Drive St. Louis, Missouri USA Distributed by: King Pharma Canada Ltd. Date of Preparation: Kanata, Ontario K2K 1X5 January Control #

2 PRODUCT MONOGRAPH DIAZEPAM AUTOINJECTOR, USP 5 mg/ml (2 ml/injector) THERAPEUTIC CLASSIFICATION Anxiolytic-Sedative ACTIONS AND CLINICAL PHARMACOLOGY Diazepam is an anxiolytic-sedative drug useful in the symptomatic relief of anxiety and tension states. It has also adjunctive value in the relief of certain neurospastic conditions and in certain cases, its anticonvulsant activity has been found useful in controlling status epilepticus. The Diazepam Autoinjector is a sterile solution which is packaged within a device that delivers its entire 2 ml content, which contains 10 mg diazepam, automatically upon activation. Pharmacokinetics Absorption: Peak blood levels after the i.v. administration of diazepam are reached within 15 minutes as compared to 1 hour after a single oral dosing and are of the same magnitude. Distribution: Diazepam and its metabolites are highly bound to plasma proteins (diazepam 98%). The volume of distribution at steady state is 0.8 to 1.0 L/kg. In humans, comparable blood levels of diazepam were obtained in maternal and cord blood indicating rapid placental transfer of the drug. Metabolism: Diazepam is mainly metabolized to the pharmacologically active metabolites such as N- 2

3 desmethyldiazepam, temazepam and oxazepam. Elimination: The acute half-life is 2 to 3 hours with a slower decline thereafter (half-life up to 48 hours). Repeated doses further increase blood levels. The elimination half-life of the active metabolite N- desmethyldiazepam is up to 100 hours. Diazepam and its metabolites are excreted mainly in the urine, predominantly in their conjugated forms. The clearance of diazepam is 20 to 30 ml/min. Pharmacokinetics in Special Clinical Situations: The elimination half-life may be prolonged in the newborn, in the elderly and in patients with liver disease. In renal failure the half-life of diazepam is unchanged. Pharmacokinetics (Autoinjector): A study performed in 24 male subjects comparing the intramuscular (I.M.) injection of 10 mg of diazepam in a mid-anterior/lateral thigh by the Autoinjector versus 10 mg I.M. by a syringe (operated manually) indicate that the mean percent availability of the drug from the Autoinjector is 100% of that obtained from the syringe. The mean C max value of the Autoinjector was 314 ng/ml and 48.6 ng/ml for diazepam and N- desmethyldiazepam, respectively; the syringe gave corresponding values of 287 ng /ml and 47.2 ng/ml for diazepam and N-desmethyldiazepam, respectively. The corresponding Tmax values were 1.47 hours and 61.0 hours for diazepam and desmethyldiazepam for the Autoinjector, whereas the syringe gave values of 1.31 h and 54.5 hours for diazepam and N-desmethyldiazepam, respectively. INDICATIONS AND CLINICAL USE Diazepam is indicated in the symptomatic management of mild to moderate degrees of anxiety in conditions dominated by tension, excitation, agitation, fear or aggressiveness, such as may occur in: psychoneurosis; anxiety reactions due to stressful conditions; and anxiety states with somatic expression. Diazepam is indicated parenterally when a rapid response is desired and has been found useful: in acute anxiety or tension states related to stressful conditions or nonpsychotic emotional disorders; to alleviate the symptoms of acute alcoholic withdrawal, including delirium tremens; as an adjunct in relieving anxiety states that may be present before minor surgical procedures or prior to esophagoscopy and gastroscopy (when used under conditions in which resuscitative measures are available); to control prolonged seizure activity (status epilepticus) including severe recurrent seizures; for the relief of muscle spasm in cerebral palsy, athetosis, the rare stiff man syndrome and adjunctively in tetanus; as premedication for relief of 3

4 anxiety states prior to surgical procedures. CONTRAINDICATIONS INTRAVENOUS ADMINISTRATION OF DIAZEPAM WITH THE AUTOINJECTOR IS CONTRAINDICATED. Diazepam Autoinjector is contraindicated in myasthenia gravis, infants, children, elderly, debilitated patients and in patients with a known hypersensitivity to diazepam or other drugs of the benzodiazepine class. Use of diazepam is not recommended in patients with acute closed angle glaucoma or open angle glaucoma unless patients are receiving appropriate therapy. WARNINGS The Diazepam Autoinjector is to be administrated only by the intramuscular (i.m.) route. Extreme care must be used in administering diazepam to very ill patients and to those with limited pulmonary response because of the possibility that apnea and/or cardiac arrest may occur. Concomitant use of barbiturates, alcohol or other central nervous system (CNS) depressants increase depression with increased risk of apnea. Resuscitative facilities should be readily available. PRECAUTIONS Occupational Hazards: Patients receiving diazepam should be advised to proceed cautiously wherever mental alertness and physical coordination is required, such as with the operation of dangerous machinery. Benzodiazepines should be used with extreme caution in patients with a history of alcohol or drug abuse. Chronic Respiratory Insufficiency: A lower dose is recommended for patients with chronic respiratory insufficiency, due to the risk of respiratory depression. The usual precautions in treating patients with impaired renal and hepatic functions should be observed. If diazepam is administered for protracted periods, periodic blood counts and liver function tests may be advisable. Psychiatric and Paradoxical Reactions: Paradoxical reactions such as restlessness, agitation, irritability, 4

5 aggressiveness, delusion, rages, nightmares, hallucinations, psychoses, inappropriate behavior and other adverse behavioral effects are known to occur when using benzodiazepines. Should this occur, the use of the drug should be discontinued. Emotional Disorders: Diazepam is not recommended in the treatment of psychotic or severely depressed patients. Precautions are indicated for severely depressed patients or those who show any evidence of impending depression, particularly the recognition that suicidal tendencies may be present and 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. Pregnancy: The safety of diazepam for use in pregnancy has not been established. An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested. Diazepam should not be used during pregnancy except if absolutely necessary. Continuous administration of benzodiazepines during pregnancy may give rise to hypotension, reduced respiratory function and hypothermia in the newborn child. Withdrawal symptoms in newborn infants have occasionally been reported with this class of drugs. Special care must be taken when diazepam is used during labor and delivery, as high single doses may produce irregularities in the fetal heart rate and hypotonia, poor sucking, hypothermia and moderate respiratory depression in the neonate. With new born infants it must be remembered that the enzyme system involved in the breakdown of the drug is not yet fully developed (especially in premature infants). Lactation: Since diazepam passes into breast milk, diazepam should not be administered to breastfeeding mothers. Obstetrics: The safety and efficacy in obstetrics have not yet been established. Before Bronchoscopy and Laryngoscopy: Since there are insufficient data available to establish the safety of diazepam prior to bronchoscopy and laryngoscopy, its use is not recommended. Before Gastroscopy, Esophagoscopy and Surgical Procedures: Diazepam should be used only under conditions in which safeguards are available should laryngospasm and circulatory or respiratory depression occur. Concurrent use of narcotics and barbiturates with diazepam may produce a potentiation of effect and, when such combinations are used, appropriate reduction of dosage is required. 5

6 Status Epilepticus: Diazepam is not recommended as a substitute for standard anticonvulsant medication in the long-term control of epilepsy. Appropriate anticonvulsant therapy should be instituted or continued when necessary, as soon as possible after interruption of the status epilepticus. Although diazepam is used to control status epilepticus, diazepam may occasionally induce or aggravate seizures in some patients with convulsive disorders. Drug Dependence: Abrupt cessation of large doses of diazepam after prolonged periods may precipitate acute withdrawal symptoms and, in these cases, the drug should be discontinued gradually. Caution should be exercised when it is considered necessary to administer diazepam to addiction-prone individuals. Drug Interactions : Careful consideration should be given if diazepam is to be combined with other centrally acting agents, such as antipsychotics, anxiolytics/sedatives, antidepressants, hypnotics, antiepileptic drugs, narcotic analgesics, anesthetics and sedative antihistamines because the pharmacological action of these agents might potentiate or be potentiated by the action of diazepam. Patients should be advised to abstain from alcohol during treatment with diazepam. In view of possible adverse reactions and potentiation of effects, patients should be advised to abstain from CNS depressant drugs during treatment with diazepam. There is a potentially relevant interaction between diazepam and compounds which inhibit certain hepatic enzymes (particularly cytochrome P450 III A). Data indicate that these compounds influence the pharmacokinetics of diazepam and may lead to increased and prolonged sedation. At present this reaction is known to occur with cimetidine, ketoconazole, fluvoxamine, fluoxetine and omeprazole. There have also been reports that the metabolic elimination of phenytoin is affected by diazepam. Interference with Serum Creatinine Phosphokinase Determinations: As with a number of other i.m. dosage forms, i.m. administration of diazepam (but not oral or i.v. administration), can lead to a rise in serum creatinine phosphokinase activity. A maximum level is usually noticed between 12 and 24 hours after i.m. injection. These elevated readings should be taken into account in the event of differential diagnosis of myocardial infarction. ADVERSE REACTIONS 6

7 Side effects most commonly reported are drowsiness, fatigue, muscle weakness and ataxia; they are usually dose-related. These phenomena occur predominantly at the start of therapy and usually disappear with prolonged administration. Other reactions noted less frequently are dizziness, nausea, blurred vision, diplopia, vertigo, headache, slurred speech, tremors, hypoactivity, dysarthria, euphoria, impairment of memory, confusion, numbed emotions, reduced alertness, anterograde amnesia, depression, incontinence or urinary retention, constipation, gastrointestinal disturbances, skin rash, generalized exfoliative dermatitis, hypotension, tachycardia, variations in pulse rate, flushing, hematuria, changes in libido, dry mouth or hypersalivation, pain at the site of injection and phlebitis following i.v. administration. The more serious adverse reactions occasionally reported are leukopenia, jaundice, hypersensitivity and paradoxical reactions. Circulatory and respiratory depression may follow rapid i.v. administration. Very rarely, elevated transaminases and alkaline phosphatase as well as cases of cardiac arrest have been observed. Paradoxical reactions such as hyperexcited states, anxiety, excitement, hallucinations, increased muscle spasticity, insomnia, rage, as well as sleep disturbances and stimulation, have been reported: should these occur, the drug should be discontinued. Minor changes in EEG patterns have been observed in patients on diazepam therapy. These changes consist of low to moderate voltage fast activity, 20 to 30 cycles/second and are of no known significance. In animals, i.m. administration has produced localized irritation of tissue at injection sites. A mild hemolytic effect was observed in in vitro and in vivo tests in dogs. SYMPTOMS AND TREATMENT OF OVERDOSAGE The main symptoms of overdosage are drowsiness, oversedation and ataxia followed by overstimulation as the drug overdose begins to wear off. If necessary, a CNS stimulant such as caffeine or methylphenidate may be administered with caution. Supportive measures should be instituted as indicated: maintenance of an adequate airway, levarterenol or metaraminol for hypotension. Dialysis appears to be of little value. The effects of overdosage can be controlled with the benzodiazepine antagonist flumazenil. Caution should be observed in the use of flumazenil in epileptics treated with benzodiazepines. 7

8 DOSAGE AND ADMINISTRATION The i.m. route should be preferred whenever the indication and urgency of the clinical situation permit. The i.m. route is also indicated when diazepam is used as premedication to relieve anxiety states prior to surgical procedures (usually 30 to 45 minutes before the procedure). While dosage should be individualized for maximum beneficial effect, as a general rule the usual dosage ranges for the i.m. route are as listed below: Caution: Because the Autoinjector automatically delivers a fixed dose of 10 mg of diazepam, it cannot be used in situations requiring lower doses or those in which small incremental increases of diazepam are required. Acute anxiety or tension states related to stressful conditions or nonpsychotic emotional disorders: 2 to 10 mg i.m.. Repeat in 3 to 4 hours, if necessary. Acute alcoholic withdrawal: To alleviate the symptoms of acute alcoholic withdrawal including delirium tremens: 10 mg i.m. initially, then 5 to 10 mg in 3 to 4 hours, if necessary. Premedication to surgical procedures: For the relief of anxiety states (if atropine, scopolamine or other premedication are desired, they must be administered in separate syringes): 10 mg i.m. (preferred route), 1 to 2 hours before surgery. Minor surgical procedures including esophagoscopy and gastroscopy: As an adjunct in relieving anxiety states that may be present before these procedures: 5 to 10 mg i.m. approximately 30 minutes prior to procedures. For the relief of muscle spasm in cerebral palsy, athetosis, the rare stiff man syndrome and adjunctively in tetanus: 5 to 10 mg i.m. initially; then 5 to 10 mg in 3 to 4 hours, if necessary. For tetanus, larger doses may be required. Status epilepticus including severe recurrent seizures: For the control of prolonged seizure activity: 10 mg i.m. initially. Repeat in 2 to 4 hours if necessary. The Diazepam Autoinjector should be injected deeply into the muscle, preferably the mid outer thigh. In acute conditions, the injection may be repeated within 1 hour although an interval of 3 to 4 hours is usually 8

9 satisfactory. Generally not more than 30 mg should be given within an 8 hour period. The Diazepam Autoinjector should be administered as follows: 1. Pull off gray safety cap 2. Place black end on mid outer thigh 3. Inject by pushing the injector hard against the thigh. Withdraw after 10 seconds. A physician who prescribes the Diazepam Autoinjector should take appropriate steps to ensure that the patient understands the indications and how to use the device correctly. The physician should review with the patient, in detail, the operation of the Autoinjector. 9

10 PHARMACEUTICAL INFORMATION Drug Substance: Common Name: Diazepam (a benzodiazepine derivative) Chemical Name: Structural formula: 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1, 4-benzodiazepin-2- one CH 3 N O Cl N Molecular Weight: Description: White to practically white crystalline powder, odourless, insoluble in water. Composition: Each ml contains: 5 mg diazepam compounded with 40% propylene glycol, 10% ethyl alcohol, 5% sodium benzoate, and benzoic acid as buffers, and 1.5% benzyl alcohol as preservative. Stability and Storage Recommendations: Store between 15EC-30EC AVAILABILITY OF DOSAGE FORMS The Diazepam Autoinjector is supplied as an individual disposable ampoule, 10 mg/2 ml (5mg/mL) 10

11 PHARMACOLOGY Diazepam is a benzodiazepine with CNS depressant properties and a somewhat flatter dose-response slope than the sedative-hypnotic drugs. In laboratory animals it produces, in varying doses, taming, disinhibitory, sedative, anticonvulsant, muscle relaxant, ataxic and hypnotic effects. As with the sedative-hypnotic drugs, at doses producing only mild sedation, it reduces slightly the behavioral arousal, increases responsiveness to environmental stimuli, suppresses passive avoidance behavior and increases approach behavior, while, at slightly higher doses, it appears to increase errors of commission in performing tasks and may produce drowsiness, muscle weakness and ataxia. The most selective behavioral properties observed in laboratory animals at low doses are suppression of passive avoidance behavior and trace avoidance conditioning, blocking the extinction of active avoidance behavior and increased food intake. Diazepam selectively suppresses subcutaneous metrazol-induced convulsions, but is less effective against maximal electroshock convulsions and relatively ineffective against minimal electroshock convulsions. It reduces body tone in the cat at sub-ataxic doses and is active in the inclined screen test, and in blocking decerebrate rigidity and the spinal reflex in the cat at higher doses. Parenteral administration decreases the amplitude of local evoked potentials recorded from the mesencephalic reticular formation, septal region, amygdaloid complex and hippocampus in the cat and monkey. It also depresses the cardiovascular and intestinal responses to stimulation of the hypothalamus in the cat. Diazepam is relatively devoid of autonomic effects and does not significantly reduce locomotor activity at low doses, or depress amphetamine-induced excitation. In high doses it activates the drug metabolizing enzymes in the liver. Diazepam also possesses dependence liability and may produce withdrawal symptoms, but has a wide margin of safety against poisoning. With the parenteral form, peak blood levels are reached within fifteen minutes after intravenous administration and are of the same magnitude as after oral administration. The respective half-life is approximately 2-3 hours. The distribution and fate of tritium labeled diazepam in man has indicated that the drug has a rapid and extensive uptake by tissues. Although the radioactivity in the blood appears to represent mainly the intact drug, diazepam was shown to be excreted exclusively in the form of its metabolites. The two major metabolites are oxazepam glucuronide and N-Demethylated diazepam. 11

12 TOXICOLOGY Acute toxicology studies in mice revealed the following results: 1) oral LD mg/kg 2) I.V. LD 50 ->100mg/kg In a forty-two week chronic toxicity study in rats, diazepam was administered in doses up to and including 240 mg/kg, no abnormalities were observed on normal growth, food consumption, blood counts, gross and microscopic findings. Reproduction studies in rats have been performed with diazepam in oral doses of 1, 10, 80 and 100 mg/kg. At the lower dose levels the survival of offspring was within normal limits. Further studies in rats at oral doses up to and including 80 mg/kg/day did not confirm a teratological effect on the offspring. At the 100 mg/kg dose level there was a decrease in the number of pregnancies and surviving offspring and several neonates showed skeletal or other defects. REFERENCES 1. Ashton H. Royal Victoria Infirmary, England. Drugs 1994; 48(1): Lorish TR, Thorsteinsson G, Howard FM. Stiff-man syndrome updated Mayo Clinic Proceedings 1989;64: