Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Mercury Pharmaceuticals Ltd, Capital House, 85 King William Street, London EC4N 7BL, UK
Midazolam should be administered only by experienced physicians in a setting fully equipped for the monitoring and support of respiratory and cardiovascular function and by persons specifically trained in the recognition and management of expected adverse events including respiratory and cardiac resuscitation.
Severe cardiorespiratory adverse events have been reported. These have included respiratory depression, apnoea, respiratory arrest and/or 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 (see section 4.8).
Special caution is required for the indication of conscious sedation in patients with impaired respiratory function.
In this population, midazolam is indicated for sedation in ICU only. Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction and hypoventilation, therefore titration with small increments to clinical effect and careful respiratory rate and oxygen saturation monitoring are essential (see also section ‘Preterm infants’ below).
When midazolam is used for premedication, adequate observation of the patient after administration is mandatory as inter-individual sensitivity varies and symptoms of overdose may occur.
Special caution should be exercised when administering midazolam to high-risk patients:
These high-risk patients require lower dosages (see section 4.2) and should be continuously monitored for early signs of alterations of vital functions.
As with any substance with CNS depressant and/or muscle-relaxant properties, particular care should be taken when administering midazolam to a patient with myasthenia gravis.
Some loss of efficacy has been reported when midazolam was used as long-term sedation in intensive care units (ICU).
When midazolam is used in long-term sedation in ICU, it should be borne in mind that physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment it is also greater in patients with a medical history of alcohol and/or drug abuse (see section 4.8).
During prolonged treatment with midazolam in ICU, physical dependence may develop. Therefore, abrupt termination of the treatment will be accompanied by withdrawal symptoms. The following symptoms may occur: headaches, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.
Midazolam causes anterograde amnesia (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolonged amnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receiving midazolam parenterally, patients should be discharged from hospital or consulting room only if accompanied by an attendant.
Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reported to occur with midazolam. These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to such reactions has been reported among children and the elderly.
Midazolam elimination may be altered in patients receiving compounds that inhibit or induce CYP3A4 and the dose of midazolam may need to be adjusted accordingly (see section 4.5).
Midazolam elimination may also be delayed in patients with liver dysfunction, low cardiac output and in neonates (see section 5.2).
Due to an increased risk of apnoea, extreme caution is advised when sedating preterm and former preterm non intubated patients. Careful monitoring of respiratory rate and oxygen saturation is required.
Rapid injection should be avoided in the neonatal population.
Neonates have reduced and/or immature organ function and are also vulnerable to profound and/or prolonged respiratory effects of midazolam.
Adverse haemodynamic events have been reported in paediatric patients with cardiovascular instability; rapid intravenous administration should be avoided in this population.
The concomitant use of midazolam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of midazolam possibly including severe sedation or clinically relevant respiratory depression (see section 4.5).
Concomitant use of midazolam and opioids may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of sedative medicines such as benzodiazepines or related drugs such as midazolam with opioids should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe midazolam concomitantly with opioids, the lowest effective dose should be used, and the duration of treatment should be as short as possible (see also general dose recommendation in section 4.2).
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers (where applicable) to be aware of these symptoms (see section 4.5).
Midazolam as other benzodiazepines should be avoided in patients with a medical history of alcohol or drug abuse.
After receiving midazolam, patients should be discharged from hospital or consulting room only when recommended by treating physician and if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.
This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially 'sodium- free'
Midazolam is metabolised by CYP3A4. Inhibitors and inducers of CYP3A4 have the potential to respectively increase and decrease the plasma concentrations and, subsequently, the effects of midazolam thus requiring dose adjustments accordingly.
Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral as compared to i.v midazolam, in particular since CYP3A4 also exists in the upper gastro-intestinal tract. This is because for the oral route both systemic clearance and availability will be altered while for the parenteral route only the change in the systemic clearance becomes effective.
After a single dose of i.v midazolam the maximal clinical effect of CYP3A4 inhibition will be minor, but the duration of effect may be prolonged. However after prolonged dosing midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition.
There are no available studies on CYP3A4 modulation on the pharmacokinetics of midazolam after rectal and intramuscular administration. It is expected that these interactions will be less pronounced for the rectal than for the oral route because the gastro-intestinal tract is by-passed whereas after i.m administration the effects of CYP3A4 modulation should not substantially differ from those seen with i.v midazolam.
It is therefore recommended to carefully monitor the clinical effects and vital signs during the use of midazolam, taking into account that they may be stronger and longer after co-administration of a CYP3A4 inhibitor, be it given only once. Notably, administration of high doses or long-term infusions of midazolam to patients receiving strong CYP3A4 inhibitors, e.g. during intensive care, may result in long-lasting hypnotic effects, delayed recovery and respiratory depression, thus requiring dose adjustments.
With respect to induction, it should be considered that the inducing process needs several days to reach its maximum effect and also several days to dissipate. Contrary to a treatment of several days with an inducer, a short-term treatment is expected to result in less apparent DDI with midazolam. However, for strong inducers a relevant induction even after short-term treatment cannot be excluded.
Midazolam is not known to change the pharmacokinetics of other drugs.
Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is coadministered with the strong CYP3A4 inhibitor ketoconazole, it should be done in an intensive care unit (ICU) or similar setting which ensures close clinical monitoring and appropriate medical management in case of respiratory depression and/or prolonged sedation. Staggered dosing and dosage adjustment should be considered, especially if more than a single i.v. dose of midazolam is administered.
Voriconazole increased the exposure of intravenous midazolam by 3-fold whereas its elimination half-life increased by about 3-fold.
Fluconazole and itraconazole both increased the plasma concentrations of intravenous midazolam by 2 – 3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole, respectively.
Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
It should be kept in mind that if midazolam is given orally, its exposure will drastically be higher than the above-mentioned ones, notably with ketoconazole, itraconazole, voriconazole.
Midazolam ampoules are not indicated for oral administration.
Erythromycin increases the plasma concentrations of intravenous midazolam by about 1.6 – 2-fold associated with an increase of the terminal half-life of midazolam by 1.5 – 1.8-fold.
Clarithromycin increased the plasma concentrations of midazolam by up to 2.5-fold associated with an increase in terminal half-life by 1.5 – 2-fold.
Roxithromycin: There is no information on roxithromycin with i.v midazolam but the mild effect on the terminal half-life of oral midazolam increase of 30%, indicates that the effects on i.v midazolam may be minor.
Quinupristin/ dalfopristin and telithomycin may increase plasma concentration of midazolam
Saquinavir and other HIV protease inhibitors: Co-administration with protease inhibitors may cause a large increase in the concentration of midazolam. Upon coadministration with ritonavir-boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life. If parenteral midazolam is co-administered with HIV protease inhibitors, treatment setting should follow the description in the above section for azole antifungals, ketoconazole.
Based on data for other CYP3A4 inhibitors, plasma concentrations of midazolam are expected to be significantly higher when midazolam is given orally. Therefore protease inhibitors should not be co-administered with orally administered midazolam
Diltiazem: A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.
Verapamil/diltiazem increased the plasma concentrations of oral midazolam by 3- and 4-fold, respectively. The terminal half-life of midazolam was increased by 41% and 49% respectively
Atorvastatin showed a 1.4-fold increase in plasma concentrations of IV midazolam compared to control group.
Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold with an increase of its terminal half-life by 1.6-fold.
Aprepitant dose dependently increased the plasma concentrations of oral midazolam by 3.3-fold after 80 mg/day associated with an increase in terminal half-life by ca. 2-fold. therefore increasing the risk of prolonged sedation.
Rifampicin decreased the plasma concentrations of intravenous midazolam by about 60% after 7 days of rifampicin 600mg o.d. The terminal half-life decreased by about 50-60%.
Rifampicin decreased the plasma concentrations of oral midazolam by 96% in healthy subjects and its psychomotor effects were almost totally lost.
Carbamazepine / phenytoin: Repeat dosages of carbamezepine or phenytoin resulted in a decrease in plasma concentrations of oral midazolam by up to 90% and a shortening of the terminal half-life by 60%.
Efavirenz: The 5-fold increase in the ratio of the CYP3A4 generated metabolite α-hydroxymidazolam to midazolam confirms its CYP3A4-inducing effect.
St. John’s Wort decreased plasma concentrations of midazolam by about 20 – 40 % associated with a decrease in terminal half life of about 15 – 17%. Depending on the specific St John’s Wort extract, the CYP3A4-inducing effect may vary.
The co-administration of midazolam with other sedative/hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and respiratory depression.
Examples include opiate derivatives (be they used as analgesics, antitussives or substitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedative antidepressants, non recent H1-antihistamines, sodiumoxybate, and centrally acting antihypertensive drugs.
The concomitant use of sedative medicines such as benzodiazepines or related drugs such as midazolam with opioids increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dosage and duration of concomitant use should be limited (see section 4.4).
Alcohol may markedly enhance the sedative effect of midazolam, so concurrent intake should be strongly avoided (see section 4.4).
Increased sedative effect with baclofen and tizanidine.
Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.
Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics.
Carbamazepine reduces the plasma concentrations of midazolam. Benzodiazepines may alter ie. Either increase or decrease the plasma concentrations of phenytoin.
Nilotinib and Nabilone may increase plasma concentration of midazolam.
Midazolam should not be used during pregnancy unless clearly necessary. It is preferable to avoid using it for caesarean.
Insufficient data are available on midazolam to assess its safety during pregnancy. Animal studies do not indicate a teratogenic effect, but foetotoxicity was observed as with other benzodiazepines. No data on exposed pregnancies are available for the first two trimesters of pregnancy.
The administration of high doses of midazolam in the last trimester of pregnancy, during labour or when used as an induction agent of anaesthesia for caesarean section has been reported to produce maternal or foetal adverse effects (inhalation risk in mother, irregularities in the foetal heart rate, hypotonia, poor sucking, hypothermia and respiratory depression in the neonate).
Moreover, infants born from mothers who received benzodiazepines chronically during the latter stage of pregnancy may have developed physical dependence and may be at some risk of developing withdrawal symptoms in the post-natal period.
The risk for neonate should be taken into account in case of administration of midazolam for any surgery near the term.
Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of midazolam.
Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive or use machines.
Prior to receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed. It is recommended that the patient is accompanied when returning home after discharge.
Where midazolam is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.
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 following undesirable effects have been reported to occur when midazolam is injected:
Frequency categories are as follows:
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)
Not known: Hypersensitivity, anaphylactic shock, angioedema
Not known: Confusional state, euphoric mood, hallucination. Agitation*, hostility*, rage*, hyperactivity, aggressiveness*, excitement*, Assault*. Physical drug dependence and withdrawal syndrome, Abuse
Not known: Sedation (prolonged and postoperative), alertness decreased, somnolence, headache, dizziness, ataxia, anterograde amnesia**, the duration of which is directly related to the administered dose. Convulsions local have been reported in premature infants and neonates. Involuntary movements (including tonic/clonic movements and muscle tremor), psychomotor hyperactivity. Drug withdrawal convulsions
Not known: Cardiac arrest, bradycardia, cardiovascular disorder, Hypotension, vasodilation
Not known: Respiratory depression, apnoea, respiratory arrest, dyspnea, laryngospasm, hiccups, bronchospasm
Not known: Nausea, vomiting, constipation, dry mouth
Not known: Rash, urticaria, pruritus, skin reactions,
Not known: Fatigue, injection site erythema, injection site pain, thrombophlebitis, thrombosis
Not known: Falls, fractures***
* Such paradoxical drug reactions have been reported particularly among children and the elderly (see section 4.4).
** Anterograde amnesia may still be present at the end of the procedure and in isolated cases prolonged amnesia has been reported (see section 4.4).
*** The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Dependence: Use of midazolam even in therapeutic doses may lead to the development of physical dependence. After prolonged i.v administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawal convulsions (see section 4.4). Cases of abuse have been reported.
Severe cardio-respiratory adverse events have occurred. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratory insufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage is administered (see section 4.4).
η2. Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Midazolam Injection is stable, both physically and chemically, for up to 1 hour at room temperature when mixed in the same syringe with Atropine Sulphate Injection BP or Hyoscine Hydrobromide Injection 0.4mg/ml. There is no evidence of the adsorption of midazolam onto the plastic of infusion apparatus or syringes.
Midazolam Injection when mixed with 500ml infusion fluids containing dextrose 4% with sodium chloride 0.18%, dextrose 5% or sodium chloride 0.9% is chemically and physically stable for up to 24 hours at 25°C and up to 72 hours at 2 to 8°C. However, for pharmaceutical microbiological reasons, the product should be used immediately after dilution. When aseptically prepared, the diluted solution may be kept for not more than 24 hours if stored under refrigeration at a temperature between 2-8°C.
Admixture with Hartmann’s solution is not recommended, as the potency of midazolam decreases.
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