Tradename
Neuril
Generic Name
Diazepam
Category
Central Nervous System
Form
Ampoule
Composition
Each 2 ml ampoule contains:
Diazepam...................2 mg
Description
Tranquilizer with anticonvulsant , sedative, and muscle relaxant properties.
Properties/Actions
Diazepam is a benzodiazepine tranquilizer with anticonvulsant, sedative, muscle relaxant and amnesic properties. It is used in the treatment of anxiety and tension sates, 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 orthopedeic 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.
  • To relieve acute muscle spasm and tetanus.
  • To manage acute convulsions, including status epilepticus; also convulsions due to poisoning and febrile convulsions.
  • As an adjunct during endoscopy, in dentistry, surgery, radiology, cardiac catheterization, and carioversion.
  • Pre-operatively to relieve anxiety, provide sedation, light anesthesia and anterograde amnesia.
Contraindications
Neuril is contraindicated in:
  • Known hypersensitivity to diazepam, other benzodiazepines or propylene glycol.
  • Acute pulmonary insufficiency or respiratory depression.
  • Sleep apnea 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 treatmetn of chronic psychosis. It should not be used alone in the treatment of depression or anxiety associated with depression due to the risk of percipitation of suicide in this patient group.

Drug Interactions
Particular attention should be paid to the potential effects of drug interactions with diazepam in the elderly.
1. 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 anesthetics.
2. 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.
3. Antidepressants:
The plasma levels of some benzodiazepines are increased by fluvoxamine. Concurrent use of selective serotonin receptor antagonists or TCAs may reduce attention and psychomotor performance and affect the ability to perform complex tasks (e.g. driving).
4. Antipsychotics:
Plasma concentrations of zotepine may be increase. 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 partenteral benzodiazepines are given with intramuscular olanzapine.
5. Sodium Oxybate:
Concomitant use of sodium oxybate (gamma hydroxybutyrate, GHB) should be avoided as benzodiazepines enhance the effects of this substance.
6. 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.
7. 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.
8. 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.
9. Gastric acid suppressants:
The metabolism of diazepam may be inhibited by cimetidine, omeprazole and esomeprazole, resulting in increased plasma concentrations.
10. Antihypertensive agents:
Enhanced hypotensive effects may occur when diazepam is given with antihypertensive agents. Increased sedation may occur with alpha-blockers or moxonidine.
11. Disulfiram:
The metabolism of diazepam is inhibited by disulfiram resulting in increased sedation.
12. Levodopa:
Benzodiazepines may antagonist the effects of levodopa.
13. Theophylline:
Theophylline may reduce the effects of benzodiazepines.
14. Skeletal Muscle Relaxants:
Increased sedation may occur with concurrent use of baclofen or tizanidine and diazepam.
Side Effects/Adverse 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.

1. Blood and Lymphatic System Disorders:
Very rare reports of thrombocytopenia, leucopenia, agranulocytosis.
2. Immune System Disorders:
Hypersensitivity reactions, including anaphylaxis.
3. Metabolism and Nutrition Disorders:
Metabolic disorders inlcuding metabolic acidosis, increased anion gap and hyperosmolality have been reproted as a consequence of propylene glycol toxicity.
4. Psychiatric Disorders:
Confusion, depression and unmasking of a depression, numbed emotions, disinhibition, euphoria, appetite changes, sleep disturbance, change in libido, dependance, suicidal ideatin/attempt.
Paradoxical reactions such as restlesness, agitation, irritability, aggressiveness, delusion, rage, insomnia, nightmares, hallucinations, psychoses, sexual arousal, and inappropriate behavior are known to occur with benzodiazepines. These are more likely to occur in children and the elderly.
5. Nervous System Disorders:
Daytime drowsiness, sedation, dizziness, ataxia, tremor, headache, reduced alertness, dysarthria/slurred speech, transient anterograde amnesia or memory impairment.
6. Eye Disorders:
Visual disturbance.
7. Ear and Labyrinth Disorders:
Veritgo.
8. 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.
9. Respiratory, Thoracic and Mediastinal Disorders:
Apnea, respiratory depression, particularly with high doses.
Worsening of sleep apnea, worsening of obstructive pulmonary disease.
10. Gastrointestinal Disorders:
Gastrointestinal disturbances (nausea, salivation changes).
11. Hepatobiliary Disorders:
Raised liver function test values, jaundice.
12. Skin and Subcutaneous Tissue Disorders:
Rash, allergic dermatitis, and urticaria.
13. Musculoskeletal Disorders:
Muscle weakness.
14. Renal and Urinary Disorders:
Urinary retention, incontinence.
15. General Disorders:
Fatigue, injection site pain or irritation.
16. Drug Withdrawal Symptoms:
Symptoms reported following discontiuation of depression, insomnia, restlesness, 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 movemens
  • Hyperreflexia
  • Tremor
  • Nausea, vomiting, diarrhea, abdominal cramps, loss of appetite
  • Agitation, palpitations, tachycardia
  • Panic attacks
  • Vertigo
  • Short-term memory loss
  • Hallucinations/delirium
  • Catactonia
  • Hyperthermia
  • Convuslions, which are more common in patients with pre-existing seizure disorders, or those taking other drugs that lower the convulsive threshold such as antidepressants.
Pregnancy & Lactation
Injections preserved with benzyl alcohol should not be administered to neonates, infants, pregnant or nursing women. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. Injection-free preservatives should be used in this patient group.
Dosage & Administration
Neuril injection may be given IV, IM or by IV infusion.
1. Adults:
a) Severe acute anxiety or agitation:
  • 10 mg IV or IM injection which may be repeated after an interval of not less than 4 hours.

b) Delirium treatments:

  • 10-20 mg IV or IM.
  • Higher doses may be needed depending on severity of symptoms.

c) Acute muscle spasm:

  • 10 mg IV or IM injection which may be repeated after an interval of not less than 4 hours.

d) 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.

e) 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 IV infusion (maximum dose 3 mg/kg body weight over 24 hours).

f) 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.

g) Elderly or debilitated patients:

  • Doses should not exceed half those normally recommended.

2. Children:
a) 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.

b) Tetaus:

  • As for adults.

c) Pre-operative medication or premedication:

  • 0.2 mg/kg body weight.
  • 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 apnea occurring.

Overdosage
Symptoms
The symptoms of a mild overdose may include confusion, somnolence, lethargy, impairment of consciusness, diminished reflexes or paradoxical excitation. In more serious cases, and especially when other CNS-depressant drugs or alcohol are ingested, symptoms may incluce ataxia, hypotension, hypotonia, respiratory depression, coma and, very rarely, death.
Rarely, propylene glycol toxicity has been reported following higher than recommended doses.

Treatment
Treatment is symptomatic. Respiration, heart rate, blood pressure and body temperature should be monitored and supportive measures taking to maintain cardiovascular and respiratory function. Hypotension may be controlled if necessary by IV administration of adrenaline (epinephrine).
Benzodiazepines are poorly dialysable.
The benzodiazepine antagonist, flumazenil, may be useful in hospitalised patients for the management of benzodiazepine overdose. The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts or slight intrinsic anticonvulsant effect, the abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.
Warnings
Except in emergencies, a second person should always be present during the intravenous use of Neuril and facilities for resuscitation should always be available. Patients should ideally remain under medical supervision until at least one hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult, with a warning not to drive or operate machinery for 24 hours. The IM use of Neuril injection can lead to a rise in serum creatinine phosphokinase activity, with a maximum level occurring between 12 and 24 hours after injection. This fact should be taken into account in the differential diagnosis of myocardial infarction. The absorption from IM injection of Neuril may be variable, particularly for the gluteal muscles. This route of administration should only be used if IV administration is not possible.
Neuril injection contains propylene glycol. They have been rare reports of propylene glycol toxicity (e.g. increased anion gap, metabolic acidosis, hyperosmolalit, renal impairment) with the potential for organ system failure and cardiocirculatory shock, in patients treated with continuous infusions of Neuril. Central nervous system toxicity, including seizures, as well as, unresponsiveness, tachypnea, tachycardia and diaphoresis have also been associated with propylene glycol toxicity.
Symptoms may be more likely to develop in patients with renal or hepatic impairment and in pediatric patients.
The elderly, and patients with impaired renal and/or hepatic function may be particularly susceptible to the adverse effects of Neuril listed. Dose reduction may be required.
Extreme care must be taken when administering Neuril injection to very ill patients and to those with limited pulmonary reserve, because of the possiblity of respiratory depression or apnea.
Use with caution in patients with myasthenia gravis, porphyria, known history of drug or aclohol abuse, or organic brain changes, particularly arteriosclerosis. Neuril injection should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications. The dependence potential of Neuril increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse. Withdrawal symptoms may occur with benzodiazepines following normal use of therapeutic doses for only short periods and may be associated with physiological and psychological sequelae. The potential for withdrawal symptoms should be considered when treating patients for more than a few days; abrupt discontinuation should be avoided and the dose reduced gradually. Abuse of Neuril has been reported. Neuril may induce anterograde amnesia. This occurs most often several hours after administration. In cases of loss or bereavement, psychological adjustment may be inhibited by benzodiazepines.
Paradoxical reactions and disinhibition have been occasionally reported during benzodiazepine use. Such reactions may be more likely to occur in children and the elderly. Should these occur, use of the drug should be discontinued. Extreme caution should be used in prescribing Neuril for patients with personality disorders. Suicide may be precipitated in patients who are depressed, as may aggressive behavior towards self and others.
This product contains benzyl alcohol which is potentially toxic when administered locally to neural tissue. This product is contraindicated for use in premature infants because the formulation contains benzyl alcohol.
Neuril injection should not be mixed with other drugs or IV fluids and should not normally be diluted except when given slowly in large intravenous infusions of normal saline or dextrose. not more than 40 mg of Neuril should be added to 500 ml infusion solution. The solution should freshly made up and used within 6 hours.
Notes
Storage
Store at a temperature not exceeding 30°C.
Packaging
Box containing 5 ampoules of 2 ml each.
Manufacturer
Memphis Co. for Pharm. and Chemical Ind.
Date Added/Updated
13th May 2013 8:38am

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