Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: Neon Healthcare Ltd., 8 The Chase, John Tate Road, Hertford, SG13 7NN, United Kingdom
Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section 6.1. Conscious sedation in patients with severe respiratory failure or acute respiratory depression.
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 cardio-respiratory 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).
Benzodiazepines are not recommended for the primary treatment of psychotic illness.
Special caution is required for the indication of conscious sedation in patients with impaired respiratory function.
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.
When midazolam is used for premedication, adequate observation of the patient after administration is mandatory as interindividual 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 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, diarrhoea, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability, sleep disturbances, mood changes, hallucinations and convulsions. In severe cases, the following symptoms may occur: depersonalisation, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.
Anterograde amnesia may occur with therapeutic doses (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, with the risk increasing at higher dosages. 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 restlessness, agitation, irritability, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, delusion, anger, aggressiveness, anxiety, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, 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. In the event of these reactions discontinuation of the drug should be considered.
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).
Midazolam ampoules should be used with extreme caution in patients with sleep apnoea syndrome and patients should be regularly monitored.
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.
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.
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 and neonates’ above).
The concomitant use of midazolam with alcohol and/or CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of midazolam possibly including severe sedation that could result in coma or death, or clinically relevant respiratory depression (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 CYP3A 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 consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. However, after prolonged dosing of 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.
When co-administered with a CYP3A4 inhibitor the clinical effects of midazolam may be stronger and longer lasting, and a lower dose may be required. 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. It is recommended to carefully monitor the clinical effects and vital signs during the use of midazolam with a CYP3A4 inhibitor. Interactions between midazolam and medicinal products that inhibit CYP3A4 are listed in Table 2.
The effect of midazolam may be weaker and shorter lasting when co-administered with a CYP3A inducer and a higher dose may be required. Interactions between midazolam and medicinal products that induce CYP3A4 are listed in Table 3.
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.
Table 2. Interactions between midazolam and medicinal products that inhibit CYP3A:
| Medicinal product | Interaction with Intravenous Midazolama |
|---|---|
| Azole antifungalsb | |
| Ketoconazole, Voriconazole | Ketoconazole and voriconazole increased the plasma concentrations of intravenous midazolam by 5-fold and 3-4-fold respectively, while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with these strong CYP3A inhibitors, it should be done in an 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. The same recommendation may apply also for other azole antifungals, since increased sedative effects of i.v. midazolam, although lesser, are reported. |
| Fluconazole, Itraconazole | 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. |
| Posaconazole | Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold. |
| Macrolide antibiotics | |
| Erythromycin | Erythromycin resulted in an increase in 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 | 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. |
| Telithromycin, Roxithromycin | Information from oral midazolam Telithromycin increased the plasma levels of oral midazolam 6-fold. While no information on roxithromycin with i.v. midazolam is available, the mild effect on the terminal half-life of oral midazolam tablet, increasing by 30%, indicates that the effects of roxithromycin on intravenous midazolam may be minor. |
| Intravenous anaesthetics | |
| Propofol | Intravenous propofol increased the AUC and half-life of intravenous midazolam by 1.6-fold. |
| Protease inhibitorsc | |
| Saquinavir and other HIV (human immunodeficiency virus) protease inhibitors | Co-administration with protease inhibitors may cause a large increase in the concentration of midazolam. Upon co-administration 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, the advice given above for the azole antifungals, ketoconazole and voriconazole should be followed. |
| Hepatitis C virus (HCV) protease inhibitors | Boceprevir and telaprevir reduce midazolam clearance. This effect resulted in a 3.4-fold increase of midazolam AUC after i.v. administration and prolonged its elimination half-life 4-fold. |
| Calcium channel blockers | |
| Diltiazem | A single dose of diltiazem given to patients undergoing coronary artery bypass grafting increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%. This was less than the 4-fold increase seen after oral administration of midazolam. |
| Verapamil | Information from oral midazolam Verapamil increased the plasma concentrations of oral midazolam by 3-fold. The terminal half-life of midazolam was increased by 41%. |
| Various drugs/herbs | |
| Atorvastatin | Atorvastatin resulted in a 1.4-fold increase in plasma concentrations of i.v. midazolam compared to control group. |
| Fentanyl | Intravenous fentanyl is a weak inhibitor of midazolam elimination: AUC and half-life of i.v. midazolam were increased by 1.5-fold in the presence of fentanyl. |
| Nefazodone | Information from oral midazolam Nefazodone increased the plasma concentrations of oral midazolam by 4.6-fold with an increase of its terminal half-life by 1.6-fold. |
| Tyrosine kinase inhibitors | Information from oral midazolam Tyrosine kinase inhibitors have been shown to be potent inhibitors of CYP3A4 in vitro (imatinib, lapatinib) or in vivo (idelalisib). After concomitant administration of idelalisib, oral midazolam exposure was increased on average 5.4-fold. |
| NK1 receptor antagonists | Information from oral midazolam NK1 receptor antagonists (aprepitant, netupitant, casoprepitant) dose dependently increased the plasma concentrations of oral midazolam up to about 2.5-3.5-fold and increased terminal half-life by approximately 1.5-2-fold. |
| Other | Information from oral midazolam For a number of drugs or herbal medicines, a weak interaction with midazolam’s elimination was observed with concomitant changes in its exposure (<2-fold change in AUC) (everolimus, cyclosporine, simeprevir, propiverine). These weak interactions are expected to be further attenuated after i.v. administration. |
a For some interactions, additional information using orally administered midazolam is provided. Interactions with CYP3A inhibitors are more pronounced for oral as compared to i.v. midazolam. Midazolam ampoules are not indicated for oral administration.
b If midazolam is given orally with an azole antifungal (particularly ketoconazole, itraconazole or voriconazole), its exposure will be drastically higher compared to intravenous administration.
c 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.
Table 3. Interactions between midazolam and medicinal products that induce CYP3A:
| Medicinal product | Interaction with Intravenous Midazolama |
|---|---|
| Rifampicin | 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%. Information from oral midazolam Rifampicin decreased the plasma concentrations of oral midazolam by 96% in healthy subjects and its psychomotor effects were almost totally lost. |
| Carbamazepine, phenytoin | Information from oral midazolam Repeat dosages of carbamazepine 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%. |
| Mitotane, enzalutamide | Information from oral midazolam The very strong CYP3A4 induction seen after mitotane or enzalutamide resulted in a profound and long-lasting decrease of midazolam levels in cancer patients. AUC of orally administered midazolam was reduced to 5% and 14% of normal values respectively. |
| Ticagrelor | Ticagrelor is a weak CYP3A inducer and has only small effects on intravenously administered midazolam (-12%) and 4-hydroxymidazolam (-23%) exposures. |
| Clobazam, efavirenz | Information from oral midazolam Clobazam and Efavirenz are weak inducers of midazolam metabolism and reduce the AUC of the parent compound by approximately 30%. There is a resulting 4-5-fold increase in the ratio of the active metabolite (1'-hydroxymidazolam) to the parent compound but the clinical significance of this is unknown. |
| Vemurafenib | Information from oral midazolam Vemurafenib modulates CYP isozymes and induces CYP3A4 mildly: Repeat-dose administration resulted in a mean decrease of oral midazolam exposure of 39% (up to 80% in individuals). |
| Herbs and food | |
| St John’s Wort | 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. |
| Quercetin | Information from oral midazolam Quercetin (also contained in ginkgo biloba) and panax ginseng both have weak enzyme inducing effects and reduced exposure to midazolam after its oral administration by approximately 20-30%. |
a For some interactions, additional information using orally administered midazolam is provided. Interactions with CYP3A inducers are more pronounced for oral as compared to i.v. midazolam. Midazolam ampoules are not indicated for oral administration.
The co-administration of midazolam with other sedative/hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and cardio-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 and centrally acting antihypertensive drugs.
Alcohol may markedly enhance the sedative effect of midazolam. Alcohol intake should be strongly avoided in case of midazolam administration (see section 4.4).
Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.
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.
An increased risk of congenital malformation associated with the use of benzodiazepines during the first trimester of pregnancy has been suggested.
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 postnatal period.
Consequently, midazolam may be used during pregnancy if clearly necessary but it is preferable to avoid using it for caesarean.
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.
Midazolam has a major influence on the ability to drive and use machines.
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.
If insufficient sleep occurs or alcohol is consumed, the likelihood of impaired alertness may be increased (see section 4.5).
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:
Table 4 summarises the undesirable effects which have been reported (frequency not known, cannot be estimated from the available data) 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).
Table 4. Summary of adverse reactions:
| Immune System Disorders | |
| frequency not known | Hypersensitivity, angioedema, anaphylactic shock |
| Psychiatric Disorders | |
| frequency not known | Confusional state, disorientation, emotional and mood disturbances, changes in libido Physical drug dependence and withdrawal syndrome Abuse Paradoxical reactions* including; restlessness, agitation, irritability, nervousness, hostility, anger, aggressiveness, anxiety, nightmares, abnormal dreams, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, paroxysmal excitement |
| Nervous System Disorders | |
| frequency not known | Involuntary movements* (including tonic/clonic movements and muscle tremor), hyperactivity* Sedation (prolonged and postoperative), alertness decreased, somnolence, headache, dizziness, ataxia, anterograde amnesia**, the duration of which is directly related to the administered dose Convulsions have been reported in premature infants and neonates Drug withdrawal convulsions |
| Cardiac Disorders | |
| frequency not known | Cardiac arrest, bradycardia |
| Vascular Disorders | |
| frequency not known | Hypotension, vasodilation, thrombophlebitis, thrombosis |
| Respiratory Disorders | |
| frequency not known | Respiratory depression, apnoea, respiratory arrest, dyspnea, laryngospasm, hiccups |
| Gastrointestinal Disorders | |
| frequency not known | Nausea, vomiting, constipation, dry mouth |
| Skin and Subcutaneous Tissue Disorders | |
| frequency not known | Rash, urticaria, pruritus |
| General Disorders and Administration Site Conditions | |
| frequency not known | Fatigue, injection site erythema, injection site pain |
| Injury, Poisoning and Procedural Complications | |
| frequency not known | Falls, fractures*** |
| Social Circumstances | |
| frequency not known | Assault* |
* 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 few cases prolonged amnesia has been reported (see section 4.4).
*** There have been reports of falls and fractures in benzodiazepine users. The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.
Renal impairment: There is a greater likelihood of adverse drug reactions in patients with severe renal impairment (see section 4.2).
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).
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 website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Admixture with Hartmann’s solution is not recommended, as the potency of midazolam decreases.
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