DIAZEPAM INJECTION BP 10 MG / 2ML - summary of medicine characteristics

Diazepam Injection B.P. 10mg/2ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml contains 5mg of Diazepam B.P.

Excipient(s) with known effect

Benzoic acid

Dehydrated alcohol

Sodium benzoate

Benzyl alcohol

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Injection.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Diazepam Injection B.P. 10mg/2ml is indicated for

severe acute anxiety and agitation including delirium tremens.

acute muscle spasm – tetanus

acute convulsions including status epilepticus and those due to poisoning and febrile conditions

intravenous sedative cover before and during minor surgical procedures in obstetrics, surgery, dentistry, ophthalmology, endoscopy, radiology, cardiac catheterisation and cardioversion

The following points should be noted;

Benzodiazepines are indicated for the short-term relief (2 to 4 weeks only) of anxiety that is severe, disabling or subjecting the individual to unacceptable distress, occurring alone or in association with insomnia or short-term psychosomatic, organic or psychotic illness.

The use of benzodiazepines to treat short-term ‘mild anxiety’ is inappropriate and unsuitable.

Benzodiazepines should be used to treat insomnia only when it is severe, disabling or subjecting the individual to extreme distress.

4.2 Posology and method of administration

Adu

Its

Severe acute anxiety or agitation: 10mg by I.V. or I.M. injection which may be repeated after an interval of not less than 4 hours.

Delirium Tremens: 10 to 20mg I.V. or I.M. higher doses may be needed, depending on the severity of the symptoms.

Acute Muscle Spasm: 10mg by I.V. or I.M. injection which may be repeated after an interval of not less than 4 hours.

Tetanus: Initially an I.V. dose of 0.1 to 0.3mg/kg bodyweight, repeated at intervals of 1 to 4 hours. The selected dose should relate to the severity of the case and in extreme severe cases higher doses have been used.

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).

Status Epilepticus, convulsions due to poisoning: 10mg to 20mg I.V. or I.M. repeated if necessary 30–60 minutes later.

Pre-operative medication or premedication: 0.2mg/kg bodyweight. The usual adult dose is 10 to 20mg 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 to

0.3mg/kg bodyweight I.V. (or I.M.) or 1mg per year of life.

Tetanus: As for adults:

Pre-operative medication or premedication: 0.2mg/kg bodyweight.

The following points regarding dosage of benzodiazepines should be noted:

1. The lowest dose which can control the symptoms should be used.

It should not be continued beyond four weeks.

2. Long Term chronic use is not recommended.

3. Treatment should always be tapered off gradually

4. Patients who have taken benzodiazepines for a long time may require a longer period during which doses are reduced.

5. When a benzodiazepine is used as a hypnotic, treatment should, if possible, be intermittent.

In order to reduce the likelihood of untoward effects during intravenous sedation the injection should be given slowly (0.5ml of the solution per half a minute) until the patient becomes drowsy, the eyelids droop and the speech becomes slurred but the patient is still able to respond to requests.

Intravenous injection may be associated with local reactions, including thrombophlebitis. In order to reduce the likelihood of untoward effects, it is strongly recommended that the intravenous injections of diazepam should be given into a large vein of antecubital fossa, the patient having been placed in the supine position and kept there throughout the procedure.

Diazepam injection should not normally be diluted.

Diazepam injection should not be mixed with other drugs in the same syringe.

Route of administration

I.M. or

I.V.

4.3 Contraindications

Known hypersensitivity to diazepam, other benzodiazepines or propylene glycol or any of the other product excipients (see section 6.1).

Phobic or obsessional states; chronic psychosis, hyperkinesis (paradoxical reactions may occur)

Acute pulmonary insufficiency, respiratory depression, acute or chronic severe respiratory insufficiency (ventilator failure may be exacerbated).

Sleep apnoea syndrome (condition may be exacerbated).

Marked neuromuscular respiratory weakness including unstable myasthenia gravis (condition may be exacerbated).

The risk of dependence (physical or psychological) increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse, or in patients with a marked personality disorder. Therefore:

Regular monitoring of such patients is essential

Routine repeat use should be avoided

Treatment should be withdrawn gradually

Abuse of diazepam has been reported.

The duration of treatment should be as short as possible (see section 4.2).

If physical dependence has developed, abrupt termination of treatment results in withdrawal symptoms. These include headache, muscle pain, extreme anxiety, tension, restlessness, confusion and irritability, sleep disturbance, diarrhoea and mood changes. In severe cases the following may occur: a feeling of unreality or of being separated from the body, derealisation, depersonalisation, confusional states, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact, psychotic manifestations including hallucinations or epileptic seizures. Withdrawal symptoms will be worse in patients who have been dependent on alcohol or other narcotic drugs in the past, but can occur following abrupt cessation of treatment in patients receiving normal therapeutic doses for a short period of time.

A transient syndrome whereby the symptoms that led to treatment with a benzodiazepine recur in an enhanced form, may occur on withdrawal of treatment. It may be accompanied by other reactions including mood changes, anxiety or sleep disturbances and restlessness. Since the risk of withdrawal phenomena/rebound phenomena is greater after abrupt discontinuation of treatment, it is recommended that the dosage is decreased gradually.

Sudden discontinuation of treatment with diazepam in patients with epilepsy or other patients who have had a history of seizures can result in convulsions or epileptic status. Convulsions can also be seen following sudden discontinuation in individuals with alcohol or drug abuse.

Discontinuation should be gradual in order to minimise the risk of withdrawal symptoms.

Duration of treatment

The duration of treatment should be as short as possible (see section 4.2) depending on the indication. The patient must be evaluated after a period of no more than 4 weeks and then regularly thereafter in order to assess the need for continued treatment, especially if the patient is free of symptoms. In general, treatment must not last any longer than 8–12 weeks, including the tapering off process. Extension beyond these periods should not take place without reevaluation of the situation.

It may be useful to inform the patient when treatment is started that it will be of limited duration and to explain precisely how the dosage will be progressively decreased. Moreover it is important that the patient should be aware of the possibility of rebound phenomena, thereby minimising anxiety over such symptoms should they occur while the medicinal product is being discontinued. There are indications that, in the case of benzodiazepines with a short duration of action, withdrawal phenomena can become manifest within the dosage interval, especially when the dosage is high.

When benzodiazepines with a long duration of action are being used it is important to warn against changing to a benzodiazepine with a short duration of action, as withdrawal symptoms may develop.

Anterograde amnesia may occur even if benzodiazepines are used within the normal dose range, though this is seen in particular at high dose levels. The condition occurs most often several hours after ingesting the product and therefore to reduce the risk patients should ensure that they will be able to have an uninterrupted sleep of 7–8 hours (see also section 4.8). Amnestic effects may be associated with inappropriate behaviour.

Psychological adjustment may be inhibited by benzodiazepines.

Reactions such as restlessness, agitation, irritability, aggressiveness, excitement, confusion, delusions, rage, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects can occur.

These reactions are more likely in children and the elderly, and extreme caution should be used in prescribing benzodiazepines to patients with personality disorders. Should they occur, treatment should be discontinued.

Patients with depression

Diazepam should not be used alone to treat depression or anxiety associated with

depression as suicide may be precipitated in such patients.

Patients with a history of alcohol & drug abuse, and patients on disulfiram

Diazepam should be used with extreme caution in patients with a history of alcohol or drug abuse (risk of abuse/dependence). Diazepam should not be used concomitantly with disulfiram due to its ethanol content. A reaction may occur as long as two weeks after cessation of disulfiram (see section 4.5).

Patients with , phobias and/or chronic , psychoses

Diazepam is not recommended (inadequate evidence of efficacy and safety).

Potentially suicidal , patients

Potentially suicidal individuals should not have access to large amounts of diazepam due to the risk of overdosing.

Psychotic illness

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Paediatric , population

Benzodiazepines should not be given to children without careful assessment of the need to do so; the duration of treatment must be kept to a minimum. Safety and effectiveness of diazepam in paediatric patients below the age of 6 months have not been established.

Elderly and debilitated patients

Elderly and debilitated patients should be given a reduced dose (see section 4.2). Due to the myorelaxant effect there is a risk of falls and consequently hip fractures in the elderly.

Hepatic Impairment

Benzodiazepines are not indicated to treat patients with severe hepatic insufficiency as they may precipitate encephalopathy. In patients with chronic hepatic disease dosage may need to be reduced.

Renal Impairment

The usual precautions in treating patients with impaired renal function should be observed. In renal failure, the half-life of diazepam is not clinically significantly changed, and dose adjustment is usually not necessary.

Cardiorespiratory Impairment

A lower dose is recommended for patients with chronic respiratory insufficiency due to the risk of respiratory depression.

Diazepam injection should be administered with caution to patients in whom a drop in blood pressure might lead to cardiovascular or cerebrovascular complications.

Benzyl alcohol poisoning

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 1mg/ml of benzoic acid and 49mg/ml of sodium benzoate which may increase the risk of jaundice in newborn babies.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium- free’.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Particular attention should be paid to the potential effects of drug interactions with diazepam in the elderly.

Alcohol

Diazepam should not be used together with alcohol (CNS inhibition enhanced sedative effects: impaired ability to drive/ operate machinery).

Sodium oxybate

Avoid concomitant use (enhanced effects of sodium oxybate)

HIV-protease inhibitors

Avoid concomitant use (increased risk of prolonged sedation) – see below for zidovudine.

Pharmacodynamic interactions

If diazepam is used with other centrally acting agents, careful consideration has to be given to the pharmacology of the agents employed, particularly with compounds that may potentiate or be potentiated by the action of diazepam, such as neuroleptics, anxiolytics/se­datives, hypnotics, antidepressants, anticonvulsants, sedating antihistamines, antipsychotics, anaesthetics for general anaesthesia and narcotic analgesics. Such concomitant use may increase sedative effects and cause depression of respiratory and cardiovascular functions. Concomitant use of narcotic analgesics may promote psychological dependency due to enhancement of euphorigenic effects.

Anti-epileptic drugs

Pharmacokinetic studies on potential interactions between diazepam and antiepileptic drugs have produced conflicting results. Both depression and elevation of drug levels, as well as no change, have been reported.

Phenobarbital taken concomitantly may result in an additive CNS effect. Increased risk of sedation and respiratory depression. Phenobarbital is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam.

Special care should be taken in adjusting the dose in the initial stages of treatment.

Side effects may be more evident with hydantoins or barbiturates.

Diazepam has been reported to be displaced from protein-binding sites by sodium valproate (increased serum levels: increased risk of drowsiness).

Narcotic analgesics

Enhancement of the euphoria may lead to increased psychological dependence.

Other drugs enhancing the sedative effect of diazepam

Cisapride, lofexidine, nabilone, disulfiram and the muscle-relaxants -baclofen, Tizanidine, suxamethonium and tubocurarine.

Compounds that affect hepatic enzymes (particularly cytochrome P450):

Inhibitors (eg cimetidine: isoniazid: erythromycin: omeprazole: esomeprazole) reduce clearance and may potentiate the action of benzodiazepines.

Itraconazole, ketoconazole, and to a lesser extent fluconazole and voriconazole are potent inhibitors of the cytochrome P450 isoenzyme CYP3A4 and may increase plasma levels of benzodiazepines. The effects of benzodiazepines may be increased and prolonged by concomitant use. A dose reduction of the benzodiazepine may be required.

Rifamycins (rifampicin)

Rifampicin is a potent inducer of CYP3A4 and substantially increases the hepatic metabolism and clearance of diazepam. In a study with healthy subjects administered 600 mg or 1.2 g rifampicin daily for 7 days, the clearance of diazepam was increased by about fourfold. Co-administration with rifampicin gives rise to substantially decreased concentrations of diazepam. Reduced effect of diazepam. The concomitant use of rifampicin and diazepam should be avoided.

Antihypertensives, vasodilators & diuretics:

Enhanced hypotensive effect with ACE inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neuron blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics.

Enhanced sedative effect with alpha-blockers or moxonidine.

Dopaminergics

Possible antagonism of the effect of levodopa.

Antiviral agents (atazanavir, ritonavir, delavirdine, efavirenz, indinavir, nelfmavir, saquinavir)

Antiviral agents may inhibit the CYP3A4 metabolic pathway for diazepam. Increased risk of sedation and respiratory depression. Therefore, concomitant use should be avoided.

Zidovudine

Increased zidovudine clearance by diazepam.

Oral contraceptives

Inhibition of oxidative metabolism of diazepam. Increased effects of diazepam.

Co-administration of diazepam and combined oral contraceptives has been known to cause breakthrough bleeding. The mechanism of this reaction is unknown. Breakthrough bleeding, but no contraceptive failures have been reported.

Theophylline

A proposed mechanism is competitive binding of theophylline to adenosine receptors in the brain. Counteraction of the pharmacodynamic effects of diazepam, e.g. reduction of sedation and psychomotor effects.

Caffeine

Concurrent use may result in reduced sedative and anxiolytic effects of diazepam.

Grapefruit juice

Inhibition of CYP3A4 may increase the plasma concentration of diazepam (possible increased sedation and amnesia). Cmax is increased by 1.5 times and AUC by 3.2 times. Possible increased effect of diazepam.

This interaction may have little significance in healthy individuals, but it is not clear is if other factors such as old age or liver cirrhosis increase the risk of adverse effects with concurrent use.

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.

Pharmacokinetic interactions

Diazepam is mainly metabolised to the pharmacologically active metabolites N-desmethyldiazepam, temazepam and oxazepam. The oxidative metabolism of diazepam is mediated by CYP3A4 and CYP2C19 isoenzymes. Oxazepam and temazepam are further conjugated to glucuronic acid. Inhibitors of CYP3A4 and/or CYP2C19 can give rise to increased concentrations of diazepam while enzyme inducing drugs such as rifampicin, hypericum perforatum and certain antiepileptics can result in substantially decreased plasma concentrations of diazepam.

Carbamazepine

Carbamazepine is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. This can result in up to three-fold greater plasma clearance and a shorter half-life of diazepam. Reduced effect of diazepam.

Phenytoin

Phenytoin is a known inducer of CYP3A4 and increases hepatic metabolism of diazepam. Reduced effect of diazepam. The metabolism of phenytoin may be increased or decreased or remain unaltered by diazepam in an unpredictable way. Increased or decreased serum concentration of phenytoin. Phenytoin concentrations should be monitored more closely when diazepam is added or discontinued.

Azoles (fluconazole, itraconazole, ketoconazole, voriconazole)

Increased plasma concentration of benzodiazepines, due to inhibition of the CYP3A4 and/or CYP2C19 metabolic pathway.

Fluconazole

Co-administration with 400 mg fluconazole on the first day and 200 mg on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.5-fold and prolonged the half-life from 31 hours to 73 hours.

Voriconazole

A study with healthy subjects found that 400 mg voriconazole twice daily on the first day and 200 mg twice daily on the second day increased the AUC of a single 5 mg oral dose of diazepam 2.2-fold and prolonged the half-life from 31 hours to 61 hours.

Increased risk of undesired effects and toxicity of benzodiazepine. Concomitant use should be avoided or the dose of diazepam reduced.

Fluvoxamine

Fluvoxamine inhibits both CYP3A4 and CYP2C19 which leads to inhibition of the oxidative metabolism of diazepam. Co-administration with fluvoxamine results in an increased half-life and an approximately 190% increased plasma concentrations (AUC) of diazepam. Drowsiness, reduced psychomotor performance and memory impairment may result. Preferably, benzodiazepines that are metabolised via a nonoxidative pathway should be used instead.

Corticosteroids

Chronic use of corticosteroids may cause increased metabolism of diazepam due to induction of cytochrome P450 isoenzyme CYP3A4, or of enzymes responsible for glucuronidation. Reduced effects of diazepam.

Cimetidine

Cimetidine inhibits the hepatic metabolism of diazepam, reducing its clearance and prolonging its half-life. In one study where 300 mg cimetidine was administered four times daily for 2 weeks, the combined plasma level of diazepam and its active metabolite, desmethyldiazepam, was found to be increased by 57%, but reaction times and other motor and intellectual tests remained unaffected. Increased action of diazepam and increased risk of drowsiness. Reduction of the diazepam dose may be necessary.

Omeprazole

Omeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Omeprazole prolongs the elimination half-life of diazepam and increases the plasma concentrations (AUC) of diazepam approximately between 30% –120%. The effect is seen in CYP2C19 extensive metabolisers but not in slow metabolisers, with a low clearance of diazepam. Increased action of diazepam. Reduction of the diazepam dose may be necessary.

Esomeprazole

Esomeprazole inhibits the CYP2C19 metabolic pathway for diazepam. Coadministration with esomeprazole results in an extended half-life and an increase in plasma concentrations (AUC) of diazepam by approximately 80%. Increased effect of diazepam. Reduction of the diazepam dose may be necessary.

Isoniazid

Isoniazid inhibits the CYP2C19 and CYP3A4 metabolic pathway for diazepam. Co-administration with 90 mg isoniazid twice daily for 3 days resulted in a prolonged elimination half-life of diazepam and in a 35% increased plasma concentration (AUC) of diazepam. Increased effect of diazepam.

Itraconazole

Increased plasma concentration of diazepam due to inhibition of the CYP3A4 metabolic pathway. In a study with healthy subject given 200 mg itraconazole daily for 4 days increased the AUC of a single 5 mg oral dose of diazepam by about 15%, but there was no clinically significant interaction as determined by psychomotor performance tests. Possible increased effect of diazepam.

Fluoxetine

Fluoxetine inhibits the metabolism of diazepam via CYP2C19 and other pathways, resulting in elevated plasma concentrations and decreased clearance of diazepam. Increased effect of diazepam. Concomitant use should be monitored closely.

Disulfiram

Reduced metabolism of diazepam leading to prolonged half-life and increased plasma concentration of diazepam. The elimination of the N-desmethyl metabolites of diazepam is slowed down which can give rise to marked sedative effects. Increased risk of CNS inhibition such as sedation.

Cisapride

Accelerated absorption of diazepam. Temporary increase of the sedative effects of orally administered diazepam.

Levodopa

Concomitant use with diazepam resulted in reduced effects of levodopa in a small number of case reports.

Ketamine

Due to similar oxidative processes, diazepam competitively inhibits ketamine metabolism. Pre-medication with diazepam leads to prolonged half-life of ketamine with enhanced effect as a result. Increased sedation.

4.6 Fertility, Pregnancy and lactation

Pregnancy

There is no evidence regarding the safety of diazepam in human pregnancy, nor is there evidence from animal studies, that it is free from hazard.

Do not use during pregnancy, especially during the first and last trimesters unless there are compelling reasons.

If diazepam is prescribed to a woman of childbearing potential, she should be warned to contact her physician regarding discontinuance of diazepam if she intends to become, or suspects that she is pregnant.

Results of retrospective studies suggest an increased risk of congenital malformation in infants or mothers who received diazepam during the first trimester of pregnancy.

Infants born to mothers who take benzodiazepines chronically during the later stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

An increase in foetal heart rate has occurred after diazepam use during labour.

Hypoactivity, hypotonia, hypothermia, apnoea, feeding problems, hyperbilirubinaemia and kernicterus have been reported in neonates born to mothers who receive large doses of diazepam (generally greater than 30 mg) shortly before delivery.

Breast-feeding:

Diazepam has been detected in breast milk. If possible diazepam should

avoided during breast feeding.

Fertility:

Studies in animals have shown a decrease in pregnancy rate and reduced number of surviving offspring in rats at high doses. There are no human data.

4.7 Effects on ability to drive and use machines

Sedation, amnesia and impaired muscular function may adversely affect the ability to drive or use machines. If insufficient sleep occurs, the likelihood of impaired alertness may be increased (See section 4.5). Patients should be warned that effects on the central nervous system may persist into the day after administration even after a single dose.

Details regarding a new driving offence concerning driving after drugs have been taken in the UK may be found here: https://www.gov.uk/…-driving-law

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 Traffic Act 1988. When prescribing this medicine, patients should be told:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

o It was not affecting your ability to drive safely.

4.8 Undesirable effects

Drowsiness, numbed emotions, reduced alertness, confusion, fatigue, headache, dizziness, muscle weakness, ataxia or double vision predominantly occur at the start of therapy but usually disappear with repeated administration. Among elderly patients there may be confusion conditions at high dose levels. There is an increased risk of falls and associated fractures in elderly patients using benzodiazepines.

Increased salivary and bronchial secretion has been reported, in particular in children.

Amnesia

Anterograde amnesia may occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

Dependence

Chronic use (even at therapeutic doses) may lead to the development of physical and psychological dependence: discontinuation of the therapy may result in withdrawal or rebound phenomena (see section 4.4). Abuse of benzodiazepines has been reported.

The frequencies of adverse events are ranked according to the following:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data).

a Known to occur when using benzodiazepines or benzodiazepine-like agents. These reactions may be quite severe. They are more likely to occur in children and the elderly. Diazepam should be discontinued if such symptoms occur (see section 4.4).

b Pre-existing depression may be unmasked during benzodiazepine use.

c May occur using therapeutic dosages, the risk increasing at higher dosages. Amnestic effects may be associated with inappropriate behaviour (see section 4.4).

d The likelihood and degree of severity of withdrawal symptoms is dependent on the duration of treatment, dose level and degree of dependency. 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.

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 at: www.mhra.gov.uk/yellowcard.

4.9 OverdoseSymptoms

The symptoms of diazepam overdose are mainly an intensification of the therapeutic effects (ataxia, drowsiness, dysarthria, sedation, muscle weakness, profound sleep, hypotension, bradycardia, nystagmus) or paradoxical excitation. In most cases only observation of vital functions is required.

Extreme overdosage may lead to coma, areflexia, cardiorespiratory depression and apnoea, requiring appropriate countermeasures (ventilation, cardiovascular support). Benzodiazepine respiratory depressant effects are more serious in patients with severe chronic obstructive airways disease. Severe effects in overdose also include rhabdomyolysis and hypothermia.

Rarely, propylene glycol toxicity has been reported following higher than recommended doses (see section 4.4).

Management

Maintain a clear airway and adequate ventilation.

Monitor level of consciousness, respiratory rate, pulse oximetry and blood pressure in symptomatic patients.

Consider arterial blood gas analysis in patients who have a reduced level of consciousness (GCS < 8; AVPU scale P or U) or have reduced oxygen saturations on pulse oximetry.

Correct hypotension by raising the foot of the bed and by giving an appropriate fluid challenge. Where hypotension is thought mainly due to decreased systemic vascular resistance, drugs with alpha-adrenergic activity such as noradrenaline or high dose dopamine (10–30 micrograms/kg/min) may be beneficial. The dose of inotrope should be titrated against blood pressure.

If severe hypotension persists despite the above measures, then central venous pressure monitoring should be considered.

Supportive measures are indicated depending on the patient's cli­nical state.

Benzodiazepines are poorly dialysable.

Flumazenil, a benzodiazepine antagonist, is not advised as a routine diagnostic test in patients with reduced conscious level. It may sometimes be used as an alternative to ventilation in children who are naive to benzodiazepines, or in patients with COPD to avoid the need for ventilation. It is not necessary or appropriate in cases of poisoning to fully reverse the benzodiazepine effect. Flumazenil has a short half-life (about an hour) and in this situation an infusion may therefore be required. Flumazenil is contraindicated when patients have ingested multiple medicines, especially after co-ingestion of a benzodiazepine and a tricyclic antidepressant or any other drug that causes seizures. This is because the benzodiazepine may suppress seizures induced by the second drug; its antagonism by flumazenil can reveal severe status epilepticus that is very difficult to control.

The use of flumazenil is not recommended in epileptic patients who have been receiving benzodiazepine treatment for a prolonged period. Although flumazenil exerts a slight intrinsic anticonvulsant effect, the abrupt suppression of the protective effect of a benzodiazepine agonist can give rise to convulsions in epileptic patients.

Contraindications to the use of flumazenil include features suggestive of a tricyclic antidepressant ingestion including a wide QRS, or large pupils. Use in patients postcardiac arrest is also contraindicated.

It should be used with caution in patients with a history of seizures, head injury, or chronic benzodiazepine use.

Occasionally a respirator may be required but generally few problems are encountered, although behavioral changes are likely in children.

If excitation occurs, barbiturates should not be used.

Effects of overdose are more severe when taken with centrally-acting drugs, especially alcohol, and in the absence of supportive measures, may prove fatal.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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.

5.2 Pharmacokinetic properties

Diazepam is metabolised to two active metabolites, one of which, desmethyldiazepam, has an extended half-life. Diazepam is therefore a long acting benzodiazepine and repeated doses may lead to accumulation.

Diazepam is metabolised in the liver and excreted via the kidney. Impaired hepatic or renal function may prolong the duration of action of diazepam. It is recommended that elderly and debilitated patients receive initially one half the normal recommended dose.

During prolonged administration, for example in the treatment of tetanus, the dosage should generally be reduced after 6–7 days, to reduce the likelihood of accumulation and prolonged CNS depression.

5.3 Preclinical safety data

None available.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzoic acid, dehydrated alcohol, propylene glycol, sodium benzoate, benzyl alcohol and water.

6.2 Incompatibilities

The injection should not be diluted or mixed with other drugs in the same syringe.

6.3 Shelf life

24 months.

6.4 Special precautions for storage

Store below 25°C and protect from light.

6.5 Nature and contents of container

Colourless glass ampoules in boxes of 10.

6.6 Special precautions for disposal

Not applicable.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited

Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford

DA1 5BS

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 40147/0021