Midazolam parenteral
- Drugs List
- Therapeutic Indications
- Dosage
- Administration
- Contraindications
- Precautions and Warnings
- Pregnancy and Lactation
- Side Effects
- Monograph
Presentation
Solution for injection containing midazolam.
Drugs List
Therapeutic Indications
Uses
Induction of anaesthesia
Premedication - sedative
Sedation of patients receiving intensive care
Sedative cover for minor medical, dental, and surgical procedures
Sedative in combined anaesthesia
Unlicensed Uses
Convulsions in palliative care
Febrile convulsions
Restlessness and confusion in palliative care
Status epilepticus
Dosage
The dose of midazolam should be titrated to safely obtain the desired level of sedation according to clinical need, physical status, age and concomitant medication. In elderly, debilitated, or chronically ill patients and paediatric patients, dose should be determined with caution and risk factors related to each patient should be taken into account.
Adults
Conscious sedation
By slow intravenous injection (approximately 2mg/minute) 5 to 10 minutes before the procedure begins.
Initial dose: 2mg to 2.5mg. Titrate in steps of 1 mg if necessary. Total dose should be between 3.5mg to 7.5mg.
Debilitated/chronically ill patients
Initial dose: 0.5mg to 1mg. Titrate in steps of 0.5mg to 1mg if necessary in these patients. Total dose should not exceed 3.5mg.
Sedation in intensive care
Loading dose: 30microgram/kg to 300micrograms/kg given in steps of 1mg to 2.5mg every 2 minutes, by slow intravenous injection over 20 to 30 seconds. Some manufacturers suggests that a loading dose is not required for patients already sedated.
Maintenance dose: 30 to 200micrograms/kg/hour by continuous infusion or slow intravenous injection. Some manufacturers advise on intermittent intravenous bolus doses of 1mg to 2mg.
Premedication
Intravenous injection: 1mg to 2mg 5 to 30 minutes before procedure, repeated as needed.
Deep intramuscular injection: 70micrograms/kg to 100micrograms/kg 20 to 60 minutes before induction of anaesthesia.
Debilitated/chronically ill patients
Intravenous injection: Initial dose of 500micrograms slowly titrated as needed.
Deep intramuscular injection: 25micrograms/kg to 50micrograms/kg administered 20 to 60 minutes before induction. Usual total dose is between 2mg and 3mg.
Induction of anaesthesia
By slow intravenous injection over 20 to 30 seconds.
With premedication: 150micrograms/kg to 200micrograms/kg (may be given as divided doses).
Without premedication: 300micrograms/kg to 350micrograms/kg.
Increase in increments (maximum of 5mg) allowing 2 minutes between successive doses. Maximum dose of 600micrograms/kg.
Debilitated/chronically ill patients
With premedication 50micrograms/kg to 200micrograms/kg.
Without premedication 150micrograms/kg to 300micrograms/kg.
Sedative in combined anaesthesia
30micrograms/kg to 100micrograms/kg by intermittent intravenous injection, repeated as required.
Alternatively, 30 to 100micrograms/kg/hour by continuous intravenous infusion. Low total doses of 1mg to 2mg may be adequate.
Status epilepticus and febrile convulsions (unlicensed)
Buccal administration: 10mg repeated once after 10 minutes if necessary.
Convulsions (unlicensed)
20mg to 40mg over 24 hours by continuous subcutaneous infusion.
Confusion and restlessness (unlicensed)
10mg to 20mg over 24 hours by subcutaneous infusion, titrated according to individual patient response. Usual dose 20mg to 60mg over 24 hours.
Elderly
Conscious sedation
By slow intravenous injection (approximately 2mg/minute), 5 to 10 minutes before the procedure begins.
Initial dose: 0.5mg to 1mg. Titrate in steps of 0.5mg to 1mg if necessary. Total dose should not usually exceed 3.5mg. Some manufacturers recommend that the initial dose should not exceed 1mg to 1.5mg.
Sedation in intensive care
Loading dose: 30micrograms/kg to 300micrograms/kg given in steps of 1mg to 2.5mg every 2 minutes, by slow intravenous injection over 20 to 30 seconds.
Maintenance dose: 30 to 200micrograms/kg/hour by slow intravenous injection or continuous infusion. Some manufacturers state that for patients already sedated that a loading dose of midazolam is not required and the continuous infusion should be given over 5 minutes.
Premedication
Intravenous injection: 0.5mg, titrated as needed OR deep intramuscular injection: 25 micrograms/kg to 50 micrograms/kg administered 20 to 60 minutes before induction of anaesthesia. Usual total dose is between 2mg and 3mg.
Induction of anaesthesia
By slow intravenous injection over 20 to 30 seconds.
With premedication: 50micrograms/kg to 200micrograms/kg. Without premedication: 150micrograms/kg to 300micrograms/kg.
Increase in increments (maximum of 5mg) allowing 2 minutes between successive doses. Maximum dose of 600micrograms/kg.
Non premedicated patients with severe systemic disease or other debilitation usually require reduced doses: 150micrograms/kg to 250micrograms/kg.
Sedative in combined anaesthesia
Lower doses than for adults aged below 60 years should be administered.
Children
Not all brands are licensed for use in children.
Not licensed for use in children under 6 months for premedication and conscious sedation.
Not licensed for oral use in children. Not licensed for buccal administration for conscious sedation.
Initial dose may not be required and lower maintenance doses needed if opioid analgesics also used. Reduce dose (or reduce or limit initial dose) in hypovolaemia, vasoconstriction, or hypothermia. In children less than 15kg of body weight, concentrations higher than 1mg/ml are not recommended.
For administration by mouth, the injection solution may be diluted with apple or black currant juice, chocolate sauce, or cola.
Conscious sedation
Intravenous route Administered over 2 to 3 minutes every 2 to 5 minutes
Children aged 12 to 18 years: (See Dosage; Adult).
Children aged 6 to 12 years: Initially 25micrograms/kg to 50micrograms/kg. Total dose less than 10mg (up to 0.4mg/kg).
Children aged 6 months to 5 years: Initially 50micrograms/kg to 100micrograms/kg. Total dose should be less than 6mg.
The following alternate dosing schedule may also be suitable:
Children aged 12 to 18 years: Initial dose of 25micrograms/kg to 50micrograms/kg. Dose may be increased in small increments to a total maximum dose of 7.5mg.
Children aged 6 to 12 years: Initial dose of 25micrograms/kg to 50micrograms/kg. Dose may be increased in small increments to a total maximum dose of 10mg.
Children aged 1 month to 6 years (unlicensed in children under 6 months): Initial dose of 25micrograms/kg to 50micrograms/kg. Dose may be increased in small increments to a total maximum dose of 6mg.
Intramuscular route
Children aged 1 to 15 years: 50micrograms/kg to 150micrograms/kg.
Rectal route
Children aged 6 months to 18 years: 300micrograms/kg to 500micrograms/kg administered 15 to 30 minutes before induction of anaesthesia.
Sedation in intensive care
Children aged 6 months to 18 years
Loading dose: 50 micrograms/kg to 200 micrograms/kg by intravenous injection administered slowly over at least 2 to 3 minutes.
Maintenance dose: 60 to 120 micrograms/kg/hour by continuous infusion.
Neonates aged 32 weeks gestational age to 6 months
60 micrograms/kg/hour as a continuous infusion.
Neonates below 32 weeks gestational age
30 micrograms/kg/hour by continuous infusion.
The following alternate dosing schedule may also be suitable:
Children 12 to 18 years
Initial doss: 30 to 300 micrograms/kg by slow intravenous injection in steps of 1mg to 2.5mg every 2 minutes.
Maintenance dose: 30 to 200 micrograms/kg/hour by continuous intravenous infusion.
Children 6 months to 12 years
Initial dose: 50 micrograms/kg to 200 micrograms/kg by slow intravenous injection over at least 3 minutes.
Maintenance dose: 30 to 120 micrograms/kg/hour by continuous intravenous infusion.
Children 1 to 6 months
60 micrograms/kg/hour by continuous intravenous infusion, adjust according to individual patient response.
Neonates aged 32 weeks gestational age to 1 month
60 micrograms/kg/hour by continuous intravenous infusion, adjust according to individual patient response. Duration of treatment should not exceed 4 days.
Neonates below 32 weeks gestational age
Initial dose: 60 micrograms/kg/hour over 24 hours.
Maintenance dose: 30 micrograms/kg/hour,adjust according to individual patient response. Duration of treatment should not exceed 4 days.
Premedication
Children aged 15 to 18 years: (See Dosage; Adult).
Intramuscular route
Children 1 years to 15 years: 80 micrograms/kg to 200 micrograms/kg
Rectal route
Children aged 6 months to 12 years: 300 micrograms/kg to 500 micrograms/kg, 15 to 30 minutes before procedure.
Induction of anaesthesia
Children aged 7 to 18 years
150 micrograms/kg by intravenous injection.
Alternatively, an initial dose of 150 micrograms/kg by slow intravenous injection up to a maximum of 7.5mg. Dose is administered in increments of 50 micrograms/kg up to a maximum of 2.5mg, over 2 to 5 minutes. If considered necessary, after 2 to 5 minutes, additional doses of 50 micrograms/kg up to a maximum of 2.5 mg can be given every 2 minutes. Maximum total dose should not exceed 500 micrograms/kg or 25 mg.
Status epilepticus and febrile convulsions (unlicensed)
Buccal administration: The injection solution may be given buccally, repeated once after 10 minutes if necessary.
Children aged 10 to 18 years: 10mg
Children aged 5 to 10 years: 7.5mg
Children aged 1 to 5 years: 5mg
Children aged 3 months to 1 year: 2.5mg
Children aged 1 to 3 months: 300 micrograms/kg. Maximum dose of 2.5 mg.
Intravenous route
Children 1 month to 18 years: 150 micrograms/kg to 200 micrograms/kg. Then 60 micrograms/kg/hour by continuous intravenous infusion. Dose may be increased by 60 micrograms/kg/hour every 15 minutes until seizure is controlled. Dose should not exceed 300 micrograms/kg/hour.
Neonates
In children less than 15kg of body weight solutions higher than 1mg/ml are not recommended.
Status epilepticus and febrile convulsions (unlicensed)
Buccal administration: The injection solution may be given buccally.
300micrograms/kg, repeated once after 10 minutes if necessary
Intravenous route
150 to 200micrograms/kg followed by continuous intravenous infusion of 60micrograms/kg/hour, increased by 60micrograms/kg/hour every 15 minutes until seizure controlled. Max. 300micrograms/kg/hour.
Patients with Renal Impairment
The Renal Drug Handbook advises that for patients with GFR below 10ml/minute, midazolam should be used sparingly and titrated according to response. It also suggests that only bolus doses, not continuous infusion be used.
Patients with Hepatic Impairment
Midazolam is extensively metabolised by the liver. The half-life of midazolam is prolonged in hepatic disorders resulting in a stronger/prolonged effect. Use with caution and consider dose reduction. Can precipitate hepatic coma.
Additional Dosage Information
Conscious sedation
Onset of action is approximately 2 minutes after administration and the maximum effect obtained in 5 to 10 minutes. In paediatric patients, the initial doses should be administered over 2 or 3 minutes, waiting a further 2 to 5 minutes before starting procedure or repeating the dose. Prolonged sedation and risk of hypoventilation may be associated with high doses. Younger children (less than 5 years) may require higher mg/kg doses than older children. Monitor patient as soon as sedative is given or when patient becomes drowsy and until the patient wakes up.
Sedation in intensive care
In hypovolaemic, vasoconstricted, or hypothermic adults, the loading dose should be omitted and dose reduced. The level of sedation should be assessed regularly.
Children over 6 months
When initiating an infusion with midazolam in haemodynamically compromised patients, the initial dose should be titrated in small increments and the patient monitored for haemodynamic instability, e.g. hypotension. These patients are vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.
Premature infants, neonates, and children up to 6 months
Loading doses are not recommended. Instead the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be reassessed, particularly after the first 24 hours, in order to administer the lowest possible effective dose and reduce the potential for drug accumulation. Monitoring of respiratory rate and oxygen saturation is required.
Use with other agents
When midazolam is given with potent analgesics (e.g. opioids), the analgesic should be administered first to allow titration of the sedative effect of midazolam on top of any sedation caused by the analgesic. When used in combination with or before other I.V. or inhalation agents during induction, the initial dose of each agent should be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.
Administration
For slow intravenous injection, intravenous infusion, intramuscular injection, rectal or buccal administration. Not all brands/strengths are licensed for all routes of administration.
In adults for premedication the deep intramuscular injection should be given in to a large muscle mass. Premedicants can be given the night before major surgery: a smaller dose may be required before surgery OR the first dose may be given on the day of the procedure.
In children, the intramuscular route should only be used in exceptional cases. Rectal administration is preferred as it is a less painful option. Rectal administration of the injection solution in children is performed by fixing a plastic applicator to the end of the syringe. If the volume to be administered is too small, dilute with water for injection up to a total volume of 10ml.
Rapid injection should be avoided especially in neonates and in children with cardiovascular instability.
Buccal administration: Administer half of the dose between the upper lip and gum on each side of the mouth using an oral syringe. Retain in the mouth for at least 5 minutes then swallow.
Contraindications
Severe hepatic impairment
Precautions and Warnings
Children under 18 years
Chronic illness
Conscious sedation in infants under 6 months
Debilitation
Hypothermia
Patients over 60 years
Restricted sodium intake
Breastfeeding
Cardiac impairment
Children with cardiovascular impairment
Chronic renal failure
Hepatic impairment
History of alcohol abuse
History of drug misuse
Hypovolaemia
Myasthenia gravis
Peripheral vasoconstriction
Pregnancy
Renal impairment
Respiratory impairment
Sleep apnoea
Sodium content of formulation may be significant
Some formulations contain more than 1mmol (23mg) sodium per dose
Advise patient ability to drive or operate machinery may be impaired
Advise patient not to drive until they know how the medicine affects them
Advise patient this medicine may be subject to driving restrictions
Not all available brands are licensed for all age groups
Not all available brands are licensed for all indications
Not all available brands are licensed for all routes of administration
Monitor patient for at least 1 hour after administration
Resuscitation facilities must be immediately available
Treatment to be administered under the supervision of a specialist
Monitor vital functions in high risk patients
Tolerance and dependence may occur
Amnesia may occur
May cause paradoxical behaviour
Potential for withdrawal symptoms
Avoid abrupt withdrawal
Conscious sedation: Risk of overdosage with high strength formulations
Advise patient not to take St John's wort concurrently
Advise patient to avoid alcohol during treatment
Severe cardiorespiratory adverse events have been reported including respiratory depression, apnoea, respiratory arrest and cardiac arrest. Such life-threatening incidents are more likely to occur when the injection is given too rapidly or when a high dosage is administered. Adequate observation of the patient after administration is recommended (considered mandatory when used for premedication) as inter-individual sensitivity may vary and symptoms of overdose may occur. Avoid sedative premedication in patients with a compromised airway, CNS depression or a history of sleep apnoea.
Midazolam causes anterograde amnesia, the duration of which is dose dependant. As a result, patients scheduled for discharge following intervention should be assessed carefully and accompanied when leaving.
When initiating an infusion in haemodynamically compromised patients, the usual loading dose should be titrated in small increments and monitored for haemodynamic instability. These patients are vulnerable to respiratory depressant effects and require monitoring of respiratory rate and oxygen saturation.
Pregnancy and Lactation
Pregnancy
Use midazolam with caution in pregnancy.
Midazolam crosses the human placenta, but transfer appears be slower than other benzodiazepines.
Animal studies do not indicate a teratogenic effect but foetotoxicity has been observed.
There may be a small increase in the risk of congenital malformation, particularly oral cleft, with the use of benzodiazepines in the first trimester.
The administration of midazolam in the last trimester of pregnancy, during labour, or before caesarean section, has been reported to produce maternal or foetal adverse effects. These include inhalation risk in the mother, irregularities in the foetal heart rate, hypotonia, poor sucking, hypothermia, and respiratory depression in the neonate. The risk for the neonate should be considered when administering midazolam near delivery. Observation of the neonate for respiratory depression, withdrawal symptoms or adaption problems is recommended when benzodiazepines have been used up to delivery.
Infants born from mothers whom received benzodiazepines chronically during the later stage of pregnancy may have developed physical dependence and may be at risk of withdrawal symptoms in the post-natal period. A small number of children exposed in utero to benzodiazepines have shown slow development in the early years but by 4 years have developed normally.
The use of all medication in pregnancy should be avoided whenever possible; particularly in the first trimester. Non-drug treatments should also be considered. When essential, a medication with the best safety record over time should be chosen, employing the lowest effective dose for the shortest possible time. Polypharmacy should be avoided. Teratogens taken in the pre-embryonic period, often quoted as lasting until 14 to 17 days post-conception, are believed to have an all-or-nothing effect. Where drugs have a short half-life, and when the date of conception is certain, this may allow women to be reassured where drug exposure has occurred within this time frame. Further advice may be available from the UK National Teratology Information Service (NTIS) and through ToxBase, available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Lactation
Use midazolam with caution in breastfeeding.
Low quantities of midazolam pass into breast milk. The amount of midazolam transferred to an infant is minimal, especially if the baby is breastfed more than 4 hours after administration (LactMed). Some manufacturers advise that breastfeeding is discontinued for 24 hours following administration. Information published on LactMed states that no waiting period or discarding of milk is required before resuming breastfeeding after a single dose of midazolam in mothers of infants over 2 months of age. After general anaesthesia, breastfeeding can be resumed as soon as the mother has recovered sufficiently.
Neonates, infants born prematurely, those with low birth weight, those with an unstable gastrointestinal function or who have serious illnesses may require special consideration. For any infant, if a drug is prescribed to the nursing mother, it should be at the lowest practical dose and for the shortest time. When drug administration is unavoidable and breastfeeding is to continue, minimisation of exposure of the infant to the drug may sometimes be achieved by timing the maternal doses to just after a feeding episode. Infants exposed to drugs via breast milk should be monitored for unusual signs or symptoms. Interactions between the drug received by the infant from the mother's milk and medication prescribed for the infant should also be considered, for example, when the drug given to the infant may prevent metabolism of the drug received via breast milk.
Specialist advice is available from the UK Drugs in Lactation Advisory Service at https://www.midlandsmedicines.nhs.uk/content.asp?section=6&subsection=17&pageIdx=1
Effects on Ability to Drive and Operate Machinery
This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988 (England and Wales). When prescribing this medicine: Advise patient the medicine can affect cognitive function and is likely to affect ability to drive. Advise patient not to drive until they know how the medicine affects them.
Side Effects
Aggressive reaction
Agitation
Amnesia
Anaphylactic shock
Anaphylaxis
Angioedema
Anterograde amnesia
Apnoea
Ataxia
Blood disorders
Bradycardia
Bronchospasm
Cardiac arrest
Changes in libido
Confusion
Constipation
Convulsions
Decreased cardiac output
Decreased stroke volume
Decreased systemic vascular resistance
Delirium
Dependence
Disorientation
Disturbances of gastrointestinal function
Dizziness
Drowsiness
Dry mouth
Dysarthria
Dyspnoea
Erythema at injection site
Euphoria
Excitement (paradoxical)
Falls
Fatigue
Hallucinations
Headache
Hiccough
Hostility
Hyperactivity
Hypersensitivity reactions
Hypotension
Incontinence
Increased appetite
Increased risk of fractures
Injection site reactions
Involuntary movement disorders
Jaundice
Laryngospasm
Local pain (injection site)
Muscle weakness
Nausea
Paradoxical reactions
Pruritus
Rages
Rash
Reduced alertness
Respiratory arrest
Respiratory depression
Restlessness
Salivation changes
Sedation
Skin reactions
Thrombophlebitis
Thrombosis
Tolerance
Tonic-clonic seizures (generalised)
Tremor
Urinary retention
Urticaria
Variation in heart rate
Vasodilation
Vertigo
Visual disturbances
Vomiting
Withdrawal symptoms
Overdosage
It is strongly recommended that the UK National Poisons Information Service be consulted on cases of suspected or actual overdose where there is doubt over the degree of risk or about appropriate management.
The following number will direct the caller to the relevant local centre (0844) 892 0111
Information may be obtained if you have access to ToxBase the primary clinical toxicology database of the National Poisons Information Service. This is available via password on the internet ( www.toxbase.org ) or if this is unavailable at the backup site ( www.toxbasebackup.org ).
Further Information
Last Full Review Date: September 2015
Reference Sources
Drugs During Pregnancy and Lactation: Treatment Options and Risk Assessment, 2nd edition (2007) ed. Schaefer, C., Peters, P. and Miller, R. Elsevier, London.
Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, 9th edition (2011) ed. Briggs, G., Freeman, R. and Yaffe, S. Lippincott Williams & Wilkins, Philadelphia.
Medications and Mothers' Milk, Sixteenth Edition (2014) Hale, T and Rowe, H, Hale Publishing, Plano, Texas.
The Renal Drug Handbook. 3rd edition. (2009) ed. Ashley, C and Currie, Radcliffe Publishing Ltd, Abingdon.
Summaries of Product Characteristics: Hypnovel 10mg/2ml solution for injection. Roche Products Ltd. Revised January 2015.
Summaries of Product Characteristics: Midazolam 1mg/ml solution for injection or infusion. Accord Healthcare Ltd. Revised March 2015.
Summaries of Product Characteristics: Midazolam Injection BP 5mg/ml solution for injection or infusion. Accord Healthcare Ltd. Revised September 2014.
Summaries of Product Characteristics: Midazolam 5mg/ml solution for injection or infusion. Accord Healthcare Ltd. Revised March 2015.
Summaries of Product Characteristics: Midazolam 1mg in 1ml injection. Amdipharm Mercury Company Ltd. Revised March 2015.
Summaries of Product Characteristics: Midazolam 2mg in 1ml injection. Amdipharm Mercury Company Ltd. Revised May 2015.
Summaries of Product Characteristics: Midazolam 5mg in 1ml injection. Amdipharm Mercury Company Ltd. Revised May 2015.
Summaries of Product Characteristics: Midazolam 1mg/ml solution for injection. hameln pharmaceuticals ltd. Revised March 2014.
Summaries of Product Characteristics: Midazolam 2mg/ml solution for injection. hameln pharmaceuticals ltd. Revised November 2014.
Summaries of Product Characteristics: Midazolam 5mg/ml solution for injection. hameln pharmaceuticals ltd. Revised November 2014.
Summaries of Product Characteristics: Midazolam Injection 1mg/1ml. Martindale Pharmaceuticals Ltd. Revised March 2014.
Summaries of Product Characteristics: Midazolam Injection BP 2mg/ml. Martindale Pharmaceuticals Ltd. Revised March 2014.
Summaries of Product Characteristics: Midazolam 2mg/ml solution for injection/infusion in pre-filled syringe. Sun Pharmaceuticals Company. Revised April 2019.
NPSA: Reducing risk of overdose with midazolam injection in adults. 9 December 2008.
Available at: https://www.nrls.npsa.nhs.uk/resources/?EntryId45=59896
US National Library of Medicine. Toxicology Data Network. Drugs and Lactation Database (LactMed).
Available at: https://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT
Midazolam. Last revised: 8 July 2014.
Last accessed: 9 September 2015.
Gov.uk. Government departments. Department for Transport. Publications. Drug driving and medicine: advice for healthcare professionals. Drug driving: Guidance for healthcare professionals on drug driving. Available at: https://www.gov.uk Last accessed: 9 September 2015 New drug driving offence implications for medicines packaging. Medicines Regulatory News. 10 December 2013. Available at: https://www.mhra.gov.uk Last accessed: 6 January 2015
NICE Evidence Services Available at: www.nice.org.uk Last accessed: 14 September 2017
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