Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2016 Publisher: Wockhardt UK Ltd, Ash Road North, Wrexham, LL13 9UF, UK
Known sensitivity to benzodiazepines or any of the ingredients.
Severe or acute respiratory insufficiency/depression.
Sleep apnoea syndrome.
Severe hepatic insufficiency.
Avoid injection in neonates (contains benzyl alcohol).
Diazepam injection should not be used in phobic or obsessional states nor be used alone in the treatment of depression or anxiety associated with depression due to the risk of suicide being precipitated in this patient group. Diazepam Injection should not be used for the primary treatment of psychotic illness. In common with other benzodiazepines the use of diazepam may be associated with amnesia and Diazepam Injection should not be used in cases of loss or bereavement as psychological adjustment may be inhibited.
Diazepam injection should be used with caution in patients with renal or hepatic dysfunction (see 4.2 Posology and Method of Administration), chronic pulmonary insufficiency, porphyria, muscle weakness, myasthenia gravis, coma, a known history of drug or alcohol abuse, or organic brain changes, particularly arteriosclerosis.
Diazepam may enhance the effects of other CNS depressants; their concurrent use should be avoided.
Elderly and debilitated patients are more prone to the CNS effects of benzodiazepines and, therefore, lower doses are required (see section 4.2 Posology and Method of Administration). Benzodiazepines should be used with caution in the elderly as long term use is associated with an increased risk of developing dementia.
The dependence potential of diazepam increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse (see 4.8 Undesirable Effects). It is low when limited to short term use. 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 (see Section 4.8 Withdrawal symptoms). This should be considered when treating patients for more than a few days; abrupt discontinuation should be avoided and the dose reduced gradually.
Benzodiazepines may induce anterograde amnesia (see 4.8 Undesirable Effects). The condition occurs most often several hours after administration. To reduce the risk, where appropriate and possible, patients should be able to have an uninterrupted sleep of 7-8 hours after administration.
As with other benzodiazepines, extreme caution should be used if prescribing diazepam for patients with personality disorders. The disinhibiting effects of benzodiazepines may be manifested as the precipitation of suicide in patients who are depressed or show aggressive behaviour towards self and others.
This medicinal product contains 15mg/ml of benzyl alcohol. There is a risk of benzyl alcohol poisoning with prolonged use of high-dose intravenous infusions of diazepam injection containing benzyl alcohol.
Benzyl alcohol may cause toxic reactions and anaphylactoid reactions in infants and children up to three years old. Must not be given to premature babies or neonates.
This medicinal product contains benzoic acid and sodium benzoate which may increase the risk of jaundice in newborn babies.
This medicinal product contains 0.34mmol sodium per ml. To be taken into consideration by patients on a controlled sodium diet.
This medicinal product contains 12.5 vol % ethanol (alcohol), i.e. 100mg per ml.
Harmful for those suffering from alcoholism.
To be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.
Enhanced sedation or respiratory or CNS depression with concomitant administration of diazepam. Concomitant use should be avoided.
Enhanced sedation or respiratory and cardiovascular depression. If such centrally acting depressant drugs are given parenterally in conjunction with intravenous diazepam, severe respiratory and cardiovascular depression may occur; careful monitoring is required. When intravenous diazepam is to be administered concurrently with a narcotic analgesic agent (e.g. fentanyl), it is recommended that diazepam be given after the analgesic and that the dose be carefully titrated to meet the patient’s needs. Premedication with diazepam may decrease the dose of fentanyl derivatives required for induction of anaesthesia.
Agents that interfere with metabolism by hepatic enzymes (isoniazid and to a lesser extent erythromycin) may reduce the clearance of diazepam and potentiate its action. Known inducers of hepatic enzymes, for example, rifampicin, may increase the clearance of benzodiazepines diazepam.
Enhanced sedation or respiratory or CNS depression with concomitant administration of mirtazapine or tricyclic antidepressants. Diazepam plasma levels increased by concomitant fluvoxamine or fluoxetine.
Enhanced sedaion or respiratory and cardiovascular depression. Known inducers of hepatic enzymes, for example, carbamazepine, phenobarbital and phenytoin, may increase the clearance of benzodiazepines, however, despite enzyme stimulation, the net effect of adding these antiepileptics can be augmentation of benzodiazepine-induced sedation. Serum phenytoin levels may rise, fall or remain unaltered. In addition, phenytoin may cause diazepam serum levels to fall. Concomitant sodium valproate may increase serum levels of diazepam, with associated drowsiness.
Enhanced sedation or respiratory and cardiovascular depression with sedative antihistamines.
Enhanced hypotensive effect with concomitant administration of ACE inhibitors or beta-blockers or calcium-channel blockers or hydralazine. Enhanced sedative effect with alpha blockers and possibly moxonidine.
Enhanced sedation or respiratory and cardiovascular depression. Increased plasma concentrations of zotepine. Severe hypotension, collapse, respiratory depression, potentially fatal respiratory arrest and unconsciousness have been reported in a few patients on benzodiazepines and clozapine. Caution is advised when initiating clozapine therapy in patients taking benzodiazepines. Increased risk of hypotension, bradycardia and respiratory depression with concomitant administration of parenteral benzodiazepines with intramuscular olanzapine.
Amprenavir, ritonavir and saquinavir have been shown to reduce the clearance of diazepam and may potentiate its actions, with risk of extreme sedation and respiratory depression – avoid concomitant use.
Enhanced sedation or respiratory and cardiovascular depression with other anxiolytics.
Reduced clearance of digoxin.
Has been shown to reduce clearance and may potentiate actions of benzodiazepines.
nhanced hypotensive effect when benzodiazepines and diuretics are used concomitantly.
Diazepam may cause inhibition of levodopa.
Enhanced sedation or respiratory and cardiovascular depression.
Enhanced sedation or respiratory and cardiovascular depression.
Increased CNS depressant effects with baclofen and tizanidine.
Enhanced sedation or respiratory and cardiovascular depression.
Diazepam metabolism is accelerated by smoking.
Enhanced hypotensive effect when benzodiazepines and nitrates are used concomitantly.
May reduce the clearance of diazepam and may potentiate its actions.
Enhanced sedation or respiratory and cardiovascular depression.
Enhanced CNS depressant effects of sodium oxybate with concomitant benzodiazepines.
Cimetidine, omeprazole and esomeprazole have been shown to reduce the clearance of diazepam and may potentiate its actions.
Diazepam metabolism is accelerated by theophylline. Sedative effects of diazepam reduced by caffeine. Sedative effects of diazepam reversed with concomitant administration of aminophylline
There is no evidence regarding the safety of diazepam in pregnancy, however, diazepam and its metabolite desmethyldiazepam freely cross the placenta and accumulate in the fetal circulation. It should not be used, especially in the first and third trimesters, unless the benefit is considered to outweigh the risk.
If the product is prescribed to a woman of childbearing potential she should be warned to contact her physician regarding the discontinuance of the product if she intends to become or suspects that she is pregnant.
There may be a small increase in the risk of congenital malformation, particularly oral cleft, with the use of benzodiazepines in the first trimester.
In labour, high single doses or repeated low doses have been reported to produce effects on the neonate, such as hyperbilirubinaemia, hypothermia, hypotonia, respiratory depression and poor suckling (floppy infant syndrome) in the neonate and irregularities in the foetal heart.
Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period. A small number of children exposed in utero to benzodiazepines have shown slow development in the early years but by four years of age had developed normally.
Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast feeding mothers.
Patients treated with Diazepam Injection should not drive or use machinery.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road of Traffic Act 1988. When prescribing this medicine, patients should be told:
The side effects of diazepam are usually mild and infrequent.
Blood and lymphatic system disorders: Blood dyscrasias including thrombocytopenia and agranulocytosis have been reported with diazepam.
Immune system disorders: Hypersensitivity reactions, including anaphylaxis, are rare.
Psychiatric disorders: Numbed emotions. In susceptible patients, an unnoticed depression may become evident. Paradoxical reactions (including aggression, rage, hostility, hallucinations, nightmares, disinhibition, euphoria, excitation, irritability, restlessness, increased anxiety, agitation, inappropriate behaviour and insomnia) are known to occur with benzodiazepines and may be quite severe with diazepam. They are more likely to occur in children and the elderly.
Nervous system disorders: Elderly or debilitated patients are particularly susceptible to the CNS effects of benzodiazepines. It is recommended that dosage be limited to the smallest effective dose and increased gradually, if necessary, to decrease the possibility of development of ataxia, dizziness, and oversedation, which may lead to falls and other accidents (see 4.2 Posology and method of administration). Long term use of benzodiazepines in the elderly may be associated with an increased risk of dementia. Headaches, confusion, slurred speech, tremor, reduced alertness and drowsiness. Anterograde amnesia may occur using therapeutic doses, the risk increasing at higher doses (see 4.4 Special Warnings and Special Precautions for Use). Amnestic effects may be associated with inappropriate behaviour. Extrapyramidal effects and convulsions have occurred rarely with diazepam.
Eye disorders: Visual disturbances.
Ear and labyrinth disorders: Rarely, vertigo
Cardiac disorders: Hypotension, particularly with high dosage, bradycardia, chest pain. Cardiac arrest may occur with diazepam injection.
Vascular disorders: Diazepam injection may be associated with thrombophlebitis and venous thrombosis.
Respiratory, thoracic and mediastinal disorders: Rarely, respiratory depression and apnoea, particularly with high dosage.
Gastrointestinal disorders: Rarely, salivation changes, including dry mouth or excessive salivation and gastrointestinal disturbances including nausea.
Hepatobiliary disorders: Raised liver enzymes, jaundice and cholestasis.
Skin and subcutaneous tissue disorders: Skin reactions such as Steven-Johnson syndrome, urticaria, rash.
Musculoskeletal and connective tissue disorders: Muscle weakness.
Renal and urinary disorders: Urinary retention, incontinence.
Reproductive system and breast disorders: Inhibition of female orgasm, changes in libido, gynaecomastia and rarely, increased prolactin levels and galactorrhoea. Plasma testosterone concentrations may be increased in men taking diazepam.
General disorders and administration site conditions: Fatigue and a hangover effect. Diazepam injection may be associated with pain. Inadvertent intra-arterial administration of diazepam has resulted in ischaemia and tissue necrosis.
Withdrawal symptoms: Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation may be associated with withdrawal symptoms or rebound phenomena (see 4.4 Special Warnings and Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, muscle aches/cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension. Rare and more serious withdrawal symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme www.mhra.gov.uk/yellowcard.
Diazepam Injection should not be mixed with other drugs in the same infusion solution or the same syringe.
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