TRADE NAME: NEURIL AMPOULE. GENERIC NAME: Diazepam. COMPOSITION: Each ampoule of 2 ml contains: Active ingredient: Diazepam 10 mg : Excipients Propylene glycol, absolute ethyl alcohol, sodium benzoate, benzoic acid, benzyl alcohol. PHARMACEUTICAL FORM: ampoules. WARNING: Not for use in neonates and infants. PHARMACOLOGICAL ACTION: Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties. It is used in the treatment of anxiety and tension states, as a sedative and pre-medicant, in the control of muscle spasm as in tetanus, and in the management of alcohol withdrawal symptoms. It is of value in patients undergoing orthopaedic procedures endoscopy and cardioversion. INDICATIONS: Diazepam is an anxiolytic, anticonvulsant and central muscle-relaxant. Diazepam is used to relieve anxiety and provide sedation in severe acute anxiety or agitation and for the management of agitation associated with delirium tremens. Diazepam is used to relieve acute muscle spasm and tetanus. Acute convulsions including status epilepticus, also convulsions due to poisoning and febrile convulsions. As an adjunct during endoscopy, in dentistry, surgery, radiology. Cardiac catheterisation, cardioversion, used pre-operatively to relieve anxiety, provide sedation, light anaesthesia and anterograde amnesia. DOSAGE AND ADMINISTRATION: Neuril Injection may be given IV, IM or by IV infusion. Adults: Severe acute anxiety or agitation: 10 mg IV or IM injection which may be repeated after an interval of not less than 4 hours. Delirium Tremens: 10 – 20 mg IV or IM. Higher doses may be needed depending on severity of symptoms. Acute Muscle Spasm: 10 mg IV or IM injection which may be repeated after an interval of not less than 4 hours. Tetanus: Initially an IV dose of 0.1 - 0.3 mg/kg body weight, repeated at intervals of 1 - 4 hours. Continuous IV infusion of 3 – 10 mg/kg body weight per 24 hours can also be used. The chosen dose should be related to the severity of the case and in extremely severe cases higher doses have been used. Status epilepticus, convulsions due to poisoning: 10 – 20 mg IV or IM, repeated if necessary 30 - 60 minutes later. If indicated, this may be followed by slow intravenous infusion (maximum dose 3 mg/kg body weight over 24 hours). Pre-operative medication or premedication: 0.2 mg/kg body weight. The usual adult dose is 10 – 20 mg but higher doses may be necessary according to the clinical response. Elderly or Debilitated Patients: Doses should not exceed half those normally recommended. Children: Status epilepticus, convulsions due to poisoning, febrile convulsions: 0.2 - 0.3 mg/kg body weight IV (or IM) or 1 mg per year of life. Tetanus: As for adults. Pre-operative medication or premedication: 0.2 mg/kg body weight. The injection should be given slowly (0.5 ml per minute). Neuril injection should be given into a large vein of the antecubital fossa, the patient in a supine position throughout the procedure to reduce the possibility of hypotension or apnoea occurring. CONTRAINDICATIONS: • Known hypersensitivity to diazepam, other benzodiazepines or propylene glycol. • Acute pulmonary insufficiency or respiratory depression. • Sleep apnoea syndrome. • Marked neuromuscular respiratory weakness including unstable myasthenia gravis. • This product contains propylene glycol so it is contraindicated in case of kidney insufficiency or renal impairment. • Severe hepatic impairment. • Neuril Injection should not be used for the primary treatment of chronic psychosis. It should not be used alone in the treatment of depression or anxiety associated with depression due to the risk of precipitation of suicide in this patient group. • Pregnancy , nursing mothers & pediatric use Do not administer injections preserved with benzyl alcohol to premature infants, neonates, infants below 13 years, pregnant women or nursing mothers. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients (it may cause Gasping syndrome). Injections preservative free should be used in these populations. SIDE EFFECTS: Most frequently reported adverse reactions associated with benzodiazepines include daytime drowsiness, sedation, unsteadiness and ataxia; these are dose-related and may persist to the following day. Blood and lymphatic system disorders: Very rare reports of thrombocytopenia, leucopenia, agranulocytosis Immune system disorders: Hypersensitivity reactions, including anaphylaxis Metabolism and nutrition disorders: Metabolic disorders including metabolic acidosis, increased anion gap and hyperosmolality have been reported as a consequence of propylene glycol toxicity. Psychiatric disorders: Confusion, depression and unmasking of depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, dependence, suicidal ideation/attempt. Paradoxical reactions such as restlessness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behaviour are known to occur with benzodiazepines including diazepam. These are more likely to occur in children and the elderly. Nervous system disorders: Daytime drowsiness, sedation, dizziness, ataxia, tremor, headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment. Eye disorders: Visual disturbance. Ear and labyrinth disorders: Vertigo. Vascular disorders: Hypotension may occur. The incidence of hypotension may be reduced by not exceeding the recommended rate of administration. Patients should be managed in the supine position and kept there throughout the procedure. Intravenous injections of diazepam may be associated with local reactions and thrombophlebitis and venous thrombosis may occur. Respiratory thoracic and mediastinal disorders: Apnoea, respiratory depression, particularly with high doses. Worsening of sleep apnoea, worsening of obstructive pulmonary disease. Gastrointestinal disorders: Gastrointestinal disturbances (nausea, salivation changes). Hepatobiliary disorders: Raised liver function test values, jaundice. Skin and subcutaneous tissue disorders: Rash, allergic dermatitis, urticaria. Musculoskeletal disorders: Muscle weakness. Renal and urinary disorders: Urinary retention, incontinence General disorders: Fatigue, injection site pain or irritation Drug withdrawal symptoms: Symptoms reported following discontinuation of benzodiazepines include headaches, muscle pain, anxiety, depression, insomnia, restlessness, confusion, irritability, sweating, and the occurrence of rebound phenomena. In severe cases the following symptoms may occur: derealisation, depersonalisation, tinnitus, numbness and tingling of the extremities, hypersensitivity to light, noise, and physical contact, involuntary movements, hyperreflexia, tremor, nausea, vomiting, diarrhoea, abdominal cramps, loss of appetite, agitation, palpitations, tachycardia, panic attacks, vertigo, short-term memory loss, hallucinations/delirium, catatonia, hyperthermia, convulsions. Convulsions may be more common in patients with pre-existing seizure disorders, or those taking other drugs that lower the convulsive threshold such as antidepressants. DRUG INTERACTIONS: Particular attention should be paid to the potential effects of drug interactions with diazepam in the elderly. CNS depressants: Enhanced sedation, or respiratory or cardiovascular depression may occur when diazepam is administered concomitantly with other CNS depressants including other anticonvulsants, anxiolytics/hypnotics, sedative antihistamines, alcohol, neuroleptics, antidepressants, analgesics and anaesthetics. Anticonvulsants: Diazepam may increase or decrease plasma concentrations of phenytoin. Patients should be monitored for signs of increased phenytoin toxicity. Phenytoin and carbamazepine may reduce plasma levels of diazepam. Increased sedation or respiratory depression may occur with concurrent use of barbiturates. Concomitant sodium valproate may increase plasma levels of diazepam, with associated sedation. Antidepressants: The plasma levels of some benzodiazepines are increased by fluvoxamine. Concurrent use of selective serotonin receptor antagonists or tricyclic antidepressants may reduce attention and psychomotor performance and affect the ability to perform complex tasks (e.g. driving). Antipsychotics: Plasma concentrations of zotepine may be increased. Severe hypotension, collapse, loss of consciousness, respiratory depression, and potentially fatal respiratory arrest have been reported in a few patients taking benzodiazepines and clozapine. Salivary hypersecretion has also occurred. Caution is advised when initiating clozapine therapy in patients taking diazepam. There is an increased risk of hypotension, bradycardia and respiratory depression when parenteral benzodiazepines are given with intramuscular olanzapine. Sodium oxybate Concomitant use of sodium oxybate (gamma hydroxybutyrate, GHB) should be avoided as benzodiazepines enhance the effects of this substance. Antibacterials: The metabolism of diazepam is inhibited by isoniazid, and to a lesser extent, by erythromycin. The effect of diazepam may be increased and prolonged. Known inducers of hepatic enzymes such as rifampicin may increase the clearance of diazepam. Antivirals: Concomitant use of amprenavir and ritonavir should be avoided, as they have been shown to reduce the clearance of benzodiazepines and may prolong their actions, with risk of extreme sedation and respiratory depression. Alcohol: The sedative effects of Neuril may be enhanced when the product is used in combination with alcohol. This affects the ability to drive or use machines. Gastric acid suppressants: The metabolism of diazepam may be inhibited by cimetidine, omeprazole and esomeprazole, resulting in increased plasma concentrations. Antihypertensive agents: Enhanced hypotensive effects may occur when diazepam is given with antihypertensive agents. Increased sedation may occur with alpha-blockers or moxonidine. Disulfiram: The metabolism of diazepam is inhibited by disulfiram resulting in increased sedation. Levodopa: Benzodiazepines may antagonise the effects of levodopa. Theophylline: Theophylline may reduce the effects of benzodiazepines. Skeletal muscle relaxants: Increased sedation may occur with concurrent use of baclofen or tizanidine and diazepam.
