Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Shire Services BVBA, rue Montoyer 47, 1000 Brussels, Belgium
Hypersensitivity to the active substance, benzodiazepines or to any of the excipients listed in section 6.1.
Myasthenia gravis.
Severe respiratory insufficiency.
Sleep apnoea syndrome.
Severe hepatic impairment.
Midazolam should be used with caution in patients with chronic respiratory insufficiency because midazolam may further depress respiration.
Given the higher metabolite to parent drug ratio in younger children, a delayed respiratory depression as a result of high active metabolite concentrations in the 3-6 months age group cannot be excluded. Therefore, the use of BUCCOLAM in the 3-6 month age group should be limited for use only under the supervision of a health care professional where resuscitation equipment is available and where respiratory function can be monitored and equipment for respiratory assistance, if needed, is available.
Midazolam should be used with caution in patients with chronic renal failure, impaired hepatic or cardiac function. Midazolam may accumulate in patients with chronic renal failure or impaired hepatic function whilst in patients with impaired cardiac function it may cause decreased clearance of midazolam.
Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required.
Midazolam should be avoided in patients with a medical history of alcohol or drug abuse.
Midazolam may cause anterograde amnesia
Midazolam is metabolized 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 oromucosal or parenteral midazolam as CYP3A4 enzymes are also present in the upper gastro-intestinal tract. After oromucosal administration, only systemic clearance will be affected. After a single dose of oromucosal midazolam, the consequence on the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged. Hence, a careful monitoring of the clinical effects and vital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a single dose.
Fentanyl may reduce midazolam clearance.
Co-administration with midazolam may cause enhanced sedation or respiratory or cardiovascular depression. Midazolam may interact with other hepatically metabolised medicinal products, e.g. phenytoin, causing potentiation.
Diltiazem and verapamil have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions.
Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions.
Metabolism of midazolam and other benzodiazepines is accelerated by xanthines.
Midazolam may cause inhibition of levodopa.
E.g. baclofen. Midazolam may cause potentiation of muscle relaxants, with increased CNS depressant effects.
Co-administration with midazolam may cause enhanced sedation or respiratory and cardiovascular depression.
Medicinal product interactions following oromucosal administration of midazolam are likely to be similar to those observed after intravenous midazolam rather than oral administration.
Grapefruit juice reduces the clearance of midazolam and potentiates its action.
Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold while the terminal half-life increased by about 3-fold.
Voriconazole increased the exposure of intravenous midazolam by 3-fold whereas its elimination halflife increased by about 3-fold.
Fluconazole and itraconazole both increased the plasma concentrations of intravenous midazolam by 2 to 3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole. Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.
Erythromycin resulted in an increase in the plasma concentrations of intravenous midazolam by about 1.6 to 2 –fold associated with an increase of the terminal half-life of midazolam by 1.5 to 1.8-fold.
Clarithromycin increased the plasma concentrations of intravenous midazolam by up to 2.5-fold associated with an increase in terminal half-life by 1.5 to 2-fold.
Co-administration with protease inhibitors (e.g. Saquinavir and other HIV protease inhibitors) may cause a large increase in the concentration of midazolam. Upon co-administration with ritonavirboosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life.
A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.
Atorvastatin showed a 1.4-fold increase in plasma concentrations of intravenous midazolam compared to control group.
7 days of 600 mg once daily decreased the plasma concentrations of intravenous midazolam by about 60%. The terminal half-life decreased by about 50-60%.
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 medicinal products and CNS depressants, including alcohol, is likely to result in enhanced sedation and respiratory depression.
Examples include opiate derivatives (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 medicinal products.
Alcohol (including alcohol-containing medicinal products 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 inhalation anaesthetics.
The effect of CYP3A4 inhibitors may be larger in infants since part of the oromucosal dose is probably swallowed and absorbed in the gastro-intestinal tract.
There are no or limited amount of data from the use of midazolam in pregnant women. Animal studies do not indicate a teratogenic effect with respect to reproductive toxicity, but foetotoxicity has been observed in humans 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 or during labour has been reported to produce maternal or foetal adverse reactions (risk of aspiration of fluids and stomach contents during labour in the mother, irregularities in the foetal heart rate, hypotonia, poor suckling, hypothermia and respiratory depression in the new-born infant).
Midazolam may be used during pregnancy if clearly necessary. The risk for new-born infants should be taken into account in the event of administration of midazolam in the third trimester of pregnancy.
Midazolam is excreted in low quantities (0.6%) in human milk. As a result it may not be necessary to stop breast feeding following a single dose of midazolam.
Animal studies did not show an impairment of fertility (see section 5.3).
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, ride a bicycle or use machines. After receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered.
Published clinical studies show that oromucosal midazolam was administered to approx 443 children with seizures. Respiratory depression occurs at a rate of up to 5%, although this is a known complication of convulsive seizures as well as being related to midazolam use. One episode of pruritus was possibly attributed to the use of buccal midazolam.
The table below lists the adverse reactions reported to occur when oromucosal midazolam was administered to children in clinical studies.
The frequency of adverse reactions is classified as follows:
Common: ≥ 1/100 to < 1/10
Uncommon: ≥ 1/1,000 to < 1/100
Very rare: < 1/10,000
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness:
Very rare: Aggression**, agitation**, anger**, confusional state**, euphoric mood**, hallucination**, hostility**, movement disorder**, physical assault**
Common: Sedation, somnolence, depressed levels of consciousness, Respiratory depression
Very rare: Anterograde amnesia**, ataxia**, dizziness**, headache**, seizure**, paradoxical reactions**
Very rare: Bradycardia**, cardiac arrest**, hypotension**, vasodilatation**
Very rare: Apnoea**, dyspnea**, laryngospasm**, respiratory arrest**
Common: Nausea and vomiting
Very rare: Constipation**, dry mouth**
Uncommon: Pruritus, rash and urticarial
Very rare: Fatigue**, hiccups**
** These adverse reactions have been reported to occur when midazolam is injected in children and/or adults, which may be of relevance to oromucosal administration.
An increased risk for falls and fractures has been recorded in elderly benzodiazepine users.
Life-threatening incidents are more likely to occur in those with pre-existing respiratory insufficiency or impaired cardiac function, particularly 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 national reporting system listed in Appendix V.
Not applicable.
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