Midazolam

Drug Approvals

(British Approved Name, rINN)

Pharmacopoeias. In Europe.

European Pharmacopoeia, 6th ed. (Midazolam). A white or yellowish crystalline powder. Practically insoluble in water freely soluble in alcohol and in acetone soluble in methyl alcohol.

Drug Approvals

(BANM, US Adopted Name, rINNM)

Incompatibility.

The visual compatibility of midazolam hydrochioride with a range of drugs was studied over a period of 4 hours. A white precipitate was formed immediately with dimenhydrinate, pentobarbital sodium, perphenazine, prochlorperazine edisilate, and ranitidine hydrochioride. Similar incompatibility has been reported with furosemide, thiopental, and parenteral nutrition solutions. Other workers have reported that a precipitate is formed with midazolam hydrochioride if the resultant mixture has a pH of 5 or more.

Stability.

Ticensed product information states that solutions of midazolam hydrochioride in sodium chloride 0.9%, glucose 5%, or glucose 4% with sodium chloride 0.18% are stable at room temperature for up to 24 hours, and similar solutions containing the equivalent of 0.5 mg/mL of the base were stable for 36 days when stored in glass bottles at temperatures of 4° to 6°, 24° to 26°, and 39° to 41 °. Other workers found that a solution containing midazolam hydrochioride equivalent to 1 mg/mL of the base in sodium chloride 0.9% was stable for at least 10 days when stored in PVC bags. The product information advises against admixture with Compound Sodium Lactate Intravenous Infusion (Hartmann’s solution) as the potency of midazolam is reduced.

Drug Approvals

(BANM, US Adopted Name, rINNM)

International Nonproprietary Names (INNs) in main languages (French, Latin, and Spanish):

Dependence and Withdrawal

As for Diazepam.

Withdrawal symptoms occurred in 2 children after stopping midazolam, which had been used for sedation during mechanical ventilation.

Adverse Effects, Treatment, and Precautions

As for Diazepam. There have been reports of life-threatening adverse respiratory and cardiovascular events occurring after use of midazolam when giving midazolam the precautions given below should be observed to lessen the risk of such reactions. Pain, tenderness, and thrombophlebitis have occurred after injection of midazolam. Hiccups have been reported.

Incidence of adverse effects.

Death due to respiratory depression, hypotension, or cardiac arrest has been reported in patients given intravenous midazolam for conscious sedation. Within about 6 months of its introduction in the USA in May 1986, 13 fatalities due to cardiorespiratory depression had been reported (higher doses were used initially in the USA than those in the UK). By January 1988, 66 deaths had been reported, although in November 1987 the adult dosage recommendation had been reduced to 70 micrograms/kg and to 50 micrograms/kg for elderly patients.

Fatalities have also occurred in the UK [where the dose is 70 micrograms/kg, reduced in the elderly] with 4 deaths reported to the UK CSM by November 1987. While it appears that midazolam and diazepam produce very similar degrees of hypoventilation and oxygen desaturation when used in equivalent doses, the sedative end-point does appear to be reached more abruptly with midazolam. Appropriate precautions should therefore be taken:

• facilities for resuscitation should always be available when intravenous midazolam is used
• respiratory and cardiac function should be monitored continuously
• the dose of midazolam should be carefully titrated against the response of the patient and the product recommendations concerning dosage rate be observed
• particular care, including a reduction in midazolam dosage, is required in patients also receiving opioid analgesics, in the elderly and children, and in patients with compromised cardiorespiratory function
• similar warnings apply to the use of oral midazolam where it is available

The availability of the benzodiazepine antagonist, flumazenil, should not be an encouragement to use larger doses of midazolam.

Since endoscopy of the upper gastrointestinal tract can itself reduce oxygen saturation, some workers have advocated the prophylactic use of nasal oxygen during this procedure for those patients at particular risk as outlined above.

Breast feeding.

The American Academy of Pediatrics considers that, although the effect of midazolam on breast-fed infants is unknown its use by mothers during breast feeding may be of concern since psychotropic drugs do appear in breast milk and thus could conceivably alter CNS function in the infant both in the short and long term.

Midazolam could not be detected in breast milk from 11 mothers the morning after either the first or the fifth nightly 15-mg oral dose. Additional study of 2 mothers found that midazolam and its hydroxy-metabolite disappeared rapidly from milk with undetectable concentrations at 4 hours. The mean milk to plasma ratio for midazolam was 0.15 in 6 paired samples.

Children.

An intravenous bolus injection of midazolam in children already receiving intravenous morphine after cardiac surgery produced an undesirable transient fall in cardiac output. It was suggested that for patients already receiving other drugs that provide sedation the use of midazolam in the early postoperative period should be limited to a continuous infusion. Similarly, it has been recommended that bolus intravenous doses of midazolam should be avoided in neonates due to the occurrence of hypotension.

The initial dosage of midazolam used for continuous intravenous sedation may need to be reduced in critically ill children under 3 years of age since the plasma clearance of midazolam appears to be reduced in these patients.

Effects on mental function.

For discussion of the adverse effects of benzodiazepines on mental function, including reports of sexual fantasies in women sedated with intravenous midazolam, see Diazepam.

Effects on the nervous system.

For reference to acute dystonia associated with use of midazolam, see Diazepam.

ENCEPHALOPATHY.

For a report of prolonged use of midazolam with fentanyl being associated with encephalopathy in infants sedated under intensive care, see Diazepam.

MYOCLONUS.

Myoclonic twitching of all four limbs was noted in 6 of 102 neonates who received a continuous intravenous infusion of midazolam at a rate of 30 to 60 micrograms/kg per hour. Myoclonus ceased a few hours after stopping the infusion and never recurred. No ictal activity was detected in EEGs recorded during the myoclonus.

The elderly.

Sedation with midazolam in elderly subjects needed only about half the dose necessary to produce comparable effects in younger subjects. Pharmacodynamic differences due to age suggested an increase in sensitivity of the CNS to midazolam in the elderly subjects.

Hepatic impairment.

For the precautions to be observed in patients with impaired liver function, see under Pharmacokinetics, below.

Renal impairment.

Five patients with severe renal impairment experienced prolonged sedation when given midazolam this was attributed to accumulation of conjugated metabolites.

Interactions

As for Diazepam.

Pharmacokinetics

Absorption of midazolam is rapid, peak plasma concentrations being achieved within 20 to 60 minutes of a dose, depending on the route. Extensive first-pass metabolism results in a low systemic bioavailability after oral doses. Bioavailability is higher, but variable, after intramuscular injection figures of more than 90% are often cited.

Midazolam is lipophilic at physiological pH. It crosses the placenta and is distributed into breast milk (but see above). Midazolam is about 96% bound to plasma proteins.

Midazolam usually has a short elimination half-life of about 2 hours although half-lives longer than 7 hours have been reported in some patients. The half-life of midazolam is also prolonged in neonates, in the elderly, and in patients with liver disorders. Midazolam is metabolised in the liver via the cytochrome P450 isoenzyme CYP3A4. The major metabolite, 1-hydroxymidazolam (alpha-hydroxymidazolam) has some activity its half-life is less than 1 hour. Midazolam metabolites are excreted in the urine, mainly as glucuronide conjugates.

Children.

In a study of the pharmacokinetics of midazolam in children the bioavailability of a dose of 0.15 mg/kg was 100, 87, 27, and 18% when given by the intravenous, intramuscular, oral, and rectal routes, respectively. The oral bioavailability was reduced to 16 and 15% after increasing the dose to 0.45 and 1 mg/kg, respectively. There was bioequivalence between the 0.15 mg/kg intramuscular dose and the 0.45 mg/kg oral dose from 45 to 120 minutes after dosage. Absorption from the rectal route gave lower serum-midazolam concentrations than the oral route at the 0.15 mg/kg dose.

Midazolam appears to be absorbed rapidly when given intranasally to children with mean maximum plasma concentrations being achieved within about 12 minutes values of 30% and 55% have been reported for the bioavailability but methods to optimise nasal delivery have resulted in higher bioavailability in studies in adults (see below). A study comparing intranasal, intravenous, and rectal dosage of midazolam in children found that plasma concentrations from 45 minutes after intranasal and intravenous doses were similar those after rectal doses were consistently less than after these other 2 routes. Possible reasons suggested by the authors for this included the effect that the wide interindividual variations in rectal pH may have had on the absorption of midazolam.

Another study has investigated the relationship between intravenous dose and plasma-midazolam concentrations in children. See also Children under Precautions, above.

NEONATES.

References to the pharmacokinetics of midazolam in neonates. See also Children under Precautions, above.

Half-life.

Data collected from 7 studies involving 90 subjects has suggested that the prolonged midazolam half-lives reported in a small number of patients are secondary to increases in the volume of distribution and not a result of alterations in clearance and metabolism. Prolongation of the half-life of midazolam has been reported in 2 patients after sustained infusion for status epileptic us.

Intranasal administration.

Plasma concentrations of midazolam sufficient to induce conscious sedation are rapidly attained after intranasal doses. Although bioavailability of up to 55% had previously been obtained in children after intranasal use (see above), slow administration and other methods to optimise nasal delivery had resulted in a bioavailability of 83% in adults.

Liver disorders.

The pharmacokinetics of midazolam in patients with advanced cirrhosis of the liver were characterised by an increase in oral systemic bioavailability and by a decrease in clearance with consequent prolongation of elimination half-life. Dosage may need to be reduced. However, metabolism of midazolam has been found in the anhepatic period of liver transplantation indicating extrahepatic metabolism (see below).

Metabolism.

For a discussion of the metabolism of benzodiazepines, see Diazepam. Midazolam appears to be metabolised by at least 3 different cytochrome P450 isoenzymes found in the liver and in the kidney. Variations in the activity of these enzymes might accountfor some of the interindividual differences in pharmacokinetics and pharmacodynamics seen with midazolam. However, a study in patients undergoing liver transplantation has indicated that the small intestine is a significant site for the first-pass metabolism of midazolam, metabolism presumably being catalysed by the cytochrome P450 isoenzyme CYP3A4 found in intestinal mucosa.

Sublingual administration.

High bioavailability (about 75%) and reliable plasma concentrations have been achieved after sub-lingual doses of midazolam.

Uses and Administration

Midazolam is a short-acting benzodiazepine with general properties similar to those of diazepam, except that it has a more potent amnestic action. It is mainly used for sedation in minor surgical or investigative procedures and in intensive care, for pre-medication, and for induction of general anaesthesia. It is also used as a hypnotic in the short-term management of insomnia. When midazolam is used as a pre-medicant or for conscious sedation, onset of sedation occurs at about 15 minutes after intramuscular injection reaching a peak at 30 to 60 minutes, and within about 3 to 5 minutes after intravenous injection. When given intravenously as an anaesthetic induction agent, anaesthesia is induced in about 2 to 2.5 minutes onset of action is more rapid when premedication with an opioid analgesic has been given.

Since the sedative end-point is reached abruptly with midazolam, dosage must be titrated carefully against the response of the patient, lower doses of midazolam are required when it is used with opioid analgesics. Respiratory and cardiac function should be monitored continuously, and facilities for resuscitation should always be available. It is advisable to keep the patient supine during intravenous use and throughout the procedure. The doses given below are, except where specified, the usual adult doses: midazolam should be given in reduced doses to elderly or debilitated patients. Midazolam is used as the hydrochloride for oral, parenteral, and rectal dosage the maleate may also be given orally. All doses are given in terms of the base midazolam hydrochloride 8.3 mg or midazolam maleate 10.2mgarebothequivalenttoabout7.5 mgof midazolam.

A usual total sedative dose for dental and minor surgical and other procedures ranges from 2.5 to 7.5 mg (about 70 micrograms/kg) intravenously an initial dose of 2 mg over 30 seconds has been suggested, with further incremental doses of 0.5 to 1 mg at intervals of 2 minutes if required until the desired end-point is reached. In the USA a suggested initial dose of up to 2.5 mg is given intravenously over at least 2 minutes and repeated if necessary after an additional 2 minutes or more to a usual maximum total dose of 5 mg.

Sedation in children aged 6 months and over may be achieved orally. A single oral dose of 250 to 500 micrograms/kg, up to a maximum of 20 mg, is recommended although younger patients (6 months to less than 6 years) may require up to 1 mg/kg. If the intravenous route is more suitable, doses of 50 to 100 micrograms/kg up to a total dose of 600 micrograms/kg (but not exceeding 6 mg) are recommended in children aged 6 months to 5 years children aged 6 to 12 years may be given 25 to 50 micrograms/kg up to a total dose of 400 micrograms/kg (or a maximum of 10 mg).

Initial doses should be given over 2 to 3 minutes and an additional interval of at least 2 minutes is recommended before giving further doses. In some countries including the UK, the injection may be used rectally for sedation in children over 6 months of age doses range from 300 to 500 micrograms/kg as a single dose. The injection solution may be diluted with Water for Injections up to a total volume of 10 niL if the volume is too small. The intramuscular route should only be used in children in exceptional cases as such injections are painful usual doses ranging from 50 to 150 micrograms/kg have been suggested for intramuscular use in children aged 1 to 15 years.

In the UK, although midazolam is not licensed for sedation of children under 6 months of age, the BNFC suggests that it may be given orally or intravenously to those aged 1 month and over in doses similar to those used in children aged 6 months and over (see above). Although also unlicensed, it further suggests that midazolam may be given buccally to children 6 months to 10 years of age in doses of 200 to 300 micrograms/kg (maximum of 5 mg) those aged 10 to 18 years may be given 6 to 7 mg (maximum of 8 mg if weighing 70 kg or over). The injection solution has been given intranasally to children aged 1 month and over however, severe irritation of the nasal mucosa may occur (see Administration, below) and use of this route is not recommended in the BNFC.

Patients in intensive care who require continuous sedation can be given midazolam by intravenous infusion. An initial loading dose of 30 to 300 micrograms/kg may be given by intravenous infusion over 5 minutes to induce sedation in the USA a lower dose of 10 to 50 micrograms/kg is recommended. The maintenance dose required varies considerably but a dose of between 20 and 200 micrograms/kg per hour has been suggested. The loading dose should be reduced or omitted, and the maintenance dose reduced, for patients with hypovolaemia, vasoconstriction, or hypothermia. The need for continuous infusion should be reassessed on a daily basis to reduce the risk of accumulation and prolonged recovery. Sedation can also be achieved by giving intermittent intravenous bolus injections of midazolam doses of 1 to 2 mg may be given, and repeated, until the desired level of sedation has been reached.

Midazolam is also used in children in intensive care who require sedation. In those aged over 6 months, an initial loading dose of 50 to 200 micrograms/kg is given by slow intravenous injection maintenance doses are given as an intravenous infusion and range from 60 to 120 micrograms/kg per hour. Neonates with a gestational age of greater than 32 weeks and infants aged up to 6 months may be given midazolam by intravenous infusion in a dose of 60 micrograms/kg per hour neonates with a gestational age of less than 32 weeks should be started on 30 micrograms/kg per hour. Loading doses are not recommended in infants aged under 6 months.

Abrupt withdrawal should be avoided after prolonged use.

Midazolam is given intramuscularly as a premedicant about 20 to 60 minutes before surgery. The usual dose is about 5 mg doses range from 70 to 100 micrograms/kg. Children aged 6 months and over may be premedicated with oral midazolam in similar doses to those used for sedation (see above). The rectal route is used for premedication in some countries total doses recommended in the UK in children aged over 6 months range from 300 to 500 micrograms/kg. The intramuscular route is also licensed in children aged 1 to 15 years in doses of 80 to 200 micrograms/kg however, as before, this route should only be used in exceptional circumstances.

The usual dose of midazolam for induction of anaesthesia is about 150 to 200 micrograms/kg by slow intravenous injection in premedicated patients and at least 300 micrograms/kg in those who have not received a premedicant. Additional doses may be needed to complete induction up to 600 micrograms/kg has been used in resistant cases. Further incremental doses of midazolam of about 25% of the induction dose have also been given as a component of the regimens used for the maintenance of anaesthesia during short surgical procedures. A dose of 150 micrograms/kg has been recommended for the induction of anaesthesia in children over 7 years of age however, the BNFC notes that such use is rare and suggests a maximum total dose of 500 micrograms/kg (not exceeding 25 mg) in those aged up to 18 years. Midazolam is also given for sedation in combined anaesthesia by intravenous injection in a dose of 30 to 100 micrograms/kg repeated as required or by intravenous infusion in a dose of 30 to 100 micrograms/kg every hour.

Midazolam maleate is also given orally for the short-term management of insomnia the usual dose is the equivalent of midazolam 7.5 to 15 mg at night.

Administration.

The rectal, intranasal, buccal, and sublingual routes have all been proposed as alternatives to parenteral use of midazolam.

Intranasal midazolam has caused intense burning, irritation, and lachrymation on instillation, and use of a lidocaine nasal spray has been advocated before giving midazolam to children. The use of midazolam spray intranasally in adults would be impractical and uncomfortable because of the large volume required. It has therefore been tried as a nebulised solution.

INTRATHECAL

See Pain, below.

Conversion and dissociative disorders.

For reference to the use of midazolam in the diagnosis of conversion disorders, such as hysterical paralysis.

Convulsions.

Benzodiazepines such as diazepam or lorazepam given parenterally are often tried first to control status epilepticus. Midazolam has been used as an alternative. It may be of value when intravenous access is difficult as effective concentrations of midazolam can be obtained after intramuscular injection. The BNF considers it to be the benzodiazepine of choice when a continuous subcutaneous infusion is required for the control of convulsions, such as in palliative care, and states that it may be given in an initial dose of 20 to 40 mg every 24 hours. Intravenous midazolam has been used in some centres for status epilepticus refractory to diazepam, lorazepam, or phenytoin but reviews of the literature reveal that evidence of efficacy is limited mainly to uncontrolled studies and anecdotal reports.

The intranasal and buccal routes have also been used for the management of seizures, and UK guidelines consider buccal midazolam an alternative to rectal diazepam for initial management of status epilepticus in the home setting or where intravenous access is not possible. In addition, a recent study found that buccal midazolam was more effective than rectal diazepam for treatment of children with seizures in the hospital setting and did not appear to increase the risk of respiratory depression. The BNF states that a dose of midazolam 10 mg, repeated once if necessary, may be given by the buccal route to adults and children aged over 10 years.

The BNFC suggests giving a single buccal dose of 300 micrograms/kg to neonates. It suggests giving the following buccal doses, which may be repeated once if necessary, according to age: 1 to 6 months, 300 micrograms/kg (maximum of 2.5 mg) 6 months to 1 year, 2.5 mg 1 to 5 years, 5 mg 5 to 10 years, 7.5 mg. Alternatively, 1 microgram/kg per minute by continuous intravenous infusion may be given to neonates, children, and adolescents after an initial loading dose of 150 to 200 micrograms/kg. This may be increased by 1 microgram/kg per minute every 15 minutes until the seizure is controlled or until a maximum of 5 micrograms/kg per minute is reached.

Disturbed behaviour.

For a discussion of the palliative treatment of terminal restlessness with benzodiazepines such as midazolam.

Dyspnoea.

Midazolam has been suggested as an alternative to chlorpromazine in patients with advanced cancer and intractable dyspnoea to relieve air hunger and to sedate dying patients who have unrelieved distress. Suggested initial doses are 2.5 to 5 mg subcutaneously or 10 mg given by infusion over a period of 24 hours, increased as necessary. It may be combined successfully with morphine.

Hiccup.

For the management of intractable hiccups see under Chlorpromazine. Midazolam given intravenously or subcutaneously has been reported to have been effective in 2 patients with metastatic cancer who had hiccups unresponsive to conventional treatment. However, it has been noted’ that benzodiazepines such as midazolam may exacerbate or precipitate hiccups.

Insomnia.

For discussion of the management of insomnia including limitations on the use of benzodiazepines and a recommendation that the period of treatment with midazolam should be limited to 2 weeks.

Pain.

The conventional use of benzodiazepines in pain management is as muscle relaxants to relieve pain associated with skeletal muscle spasm (see under Choice of Analgesic). Midazolam has been studied for use as an intrathecal analgesic but efficacy has been inconsistent.

Premedication and sedation.

Midazolam is used as a pre-medicant and as a sedative for therapeutic and investigative procedures such as dental treatment and endoscopy (see below). It is also used to provide continuous sedation in patients in intensive care although a systematic review has raised concerns about such use in neonates.

ENDOSCOPY.

Intravenous benzodiazepines such as diazepam or midazolam are often the preferred drugs for sedation in patients undergoing endoscopy. They are sometimes used with opioid analgesics for sedation. A reduced dose of midazolam was required for endoscopy when it was given as a bolus intravenous inj ection rather than as a slow intravenous titration. A study in 788 patients undergoing endoscopy found that a mean dose of 4.65 mg of midazolam given as a bolus intravenous injection was safe and effective in patients under 70 years of age whereas a mean dose of 1.89 mg was sufficient for patients over 70 years of age.

Furthermore, topical pharyngeal anaesthesia was not required with these doses of midazolam. Intravenous boluses were also easier to give and associated with less oxygen desaturation than titrating the dose. Another study found that even lower doses of midazolam (35 micrograms/kg) were effective as premedication before gas-troscopy, and were associated with fewer complications than higher doses (70 micrograms/kg).

Intranasal and oral midazolam have also been tried for sedation before endoscopy, particularly in children.

Preparations

British Pharmacopoeia 2008: Midazolam Injection.

Proprietary Preparations

Argentina: Dalam Dormicum Dormid Drimnorth Gobbizolam Ormir Rem Ukel

Australia: Hypnovel

Austria: Dormicum

Belgium: Dormicum

Brazil: Dormire Dormium Dormonid Hipnazolam Zolidan

Canada: Versed

Chile: Dormonid Noctura Terap Zolmid

Czech Republic: Dormicum Fulsed

Denmark: Dormicum

Finland: Dormicum

France: Hypnovel Versed

Germany: Dormicum Midaselect

Greece: Damizol Dormicum Dormixal

Hong Kong: Dormicum

Hungary: Dormicum

India: Fulsed

Indonesia: Dormicum Fortanest Miloz

Ireland: Hypnovel

Israel: Dormicum Midazol Midolam

Italy: Ipnovel

Malaysia: Dormicum Fulsed Mizolam

Mexico: Dormicum

Norway: Dormicum

New Zealand: Hypnovel

Philippines: Dormicum

Poland: Dormicum Midanium Sopodorm

Portugal: Dormicum Zolamid

South Africa: Dormicum Midacum Midanium

Singapore: Dormicum Fulsed

Spain: Dormicum

Sweden: Dormicum

Switzerland: Dormicum

Thailand: Dormicum Midazol

Turkey: Dormicum

UK: Hypnovel

USA: Versed

Venezuela: Benzosed Doricum Midazepin