4.1. Therapeutic indications

Treatment of prolonged, acute, convulsive seizures in infants, toddlers, children, and adolescents (from 3 months to < 18 years).

Midazolam must only be used by parents/carers where the patient has been diagnosed to have epilepsy.

For infants between 3-6 months of age treatment should be in a hospital setting where monitoring is possible and resuscitation equipment is available. See section 4.2.

4.2. Posology and method of administration

Posology

Standard doses are indicated below:

Age range

Dose

Label colour

3 to 6 months hospital setting

2.5 mg

Yellow

> 6 months to < 1 year

2.5 mg

Yellow

Carers should only administer a single dose of midazolam. If the seizure has not stopped within 10 minutes after administration of midazolam, emergency medical assistance must be sought, and the empty syringe given to the healthcare professional to provide information on the dose received by the patient.

A second or repeat dose when seizures re-occur after an initial response should not be given without prior medical advice (see section 5.2).

Special populations

Renal impairment

No dose adjustment is required; however, Midazolam should be used with caution in patients with chronic renal failure as elimination of midazolam may be delayed and the effects prolonged. (see section 4.4)

Hepatic impairment

Hepatic impairment reduces the clearance of midazolam with a subsequent increase in terminal half- life. Therefore, the clinical effects may be stronger and prolonged, hence careful monitoring of the clinical effects and vital signs is recommended following administration of midazolam in patients with hepatic impairment (see section 4.4).

Midazolam is contraindicated in patients with severe hepatic impairment (see section 4.3).

Paediatric population

The safety and efficacy of midazolam in children aged 0 to 3 months has not been established. No data are available.

Method of administration

Midazolam is for oromucosal use. The full amount of solution should be inserted slowly into the space between the gum and the cheek. Laryngo-tracheal insertion should be avoided to prevent accidental aspiration of the solution. If necessary (for larger volumes and/or smaller patients), approximately half the dose should be given slowly into one side of the mouth, then the other half given slowly into the other side.

For detailed instructions on how to administer the medicinal product, see section 6.6.

Precautions to be taken before handling or administering the medicinal product

No needle, intravenous tubing or any other device for parenteral administration should be attached to the oral syringe.

Midazolam is not for intravenous use.

The oral syringe cap should be removed before use to avoid risk of choking.

4.3. Contraindications

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.

4.4. Special warnings and precautions for use

Respiratory insufficiency

Midazolam should be used with caution in patients with chronic respiratory insufficiency because midazolam may further depress respiration.

Paediatric patients aged 3 to 6 months

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 Midazolam 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.

Altered elimination of midazolam

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.

Concomitant use with other benzodiazepines

Debilitated patients are more prone to the central nervous system (CNS) effects of benzodiazepines and, therefore, lower doses may be required.

Medical history of alcohol or drug abuse

Midazolam should be avoided in patients with a medical history of alcohol or drug abuse.

Amnesia

Midazolam may cause anterograde amnesia.

4.5. Interaction with other medicinal products and other forms of interaction

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.

Anaesthetics and narcotic analgesics

Fentanyl may reduce midazolam clearance.

Antiepileptics

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.

Calcium-channel blockers

Diltiazem and verapamil have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions.

Ulcer-healing medicinal products

Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions.

Xanthines

Metabolism of midazolam and other benzodiazepines is accelerated by xanthines.

Dopaminergic medicinal products

Midazolam may cause inhibition of levodopa.

Muscle relaxants

E.g. baclofen. Midazolam may cause potentiation of muscle relaxants, with increased CNS depressant effects.

Nabilone

Co-administration with midazolam may cause enhanced sedation or respiratory and cardiovascular depression.

Medicinal products that inhibit CYP3A4

Medicinal product interactions following oromucosal administration of midazolam are likely to be similar to those observed after intravenous midazolam rather than oral administration.

Food

Grapefruit juice reduces the clearance of midazolam and potentiates its action.

Azole antifungals

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 half- life 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.

Macrolide antibiotics

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.

HIV Protease inhibitors

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 ritonavir- boosted lopinavir, the plasma concentrations of intravenous midazolam increased by 5.4-fold, associated with a similar increase in terminal half-life.

Calcium-channel blockers

A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.

Various medicinal products

Atorvastatin showed a 1.4-fold increase in plasma concentrations of intravenous midazolam compared to control group.

Medicinal products that induce CYP3A4

Rifampicin

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%.

Herbs

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.

Pharmacodynamic Drug-Drug Interactions (DDI)

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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

Animal studies did not show an impairment of fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

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.

Tabulated list of adverse reactions

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:

System Organ Class

Frequency: Adverse Drug Reaction

Psychiatric disorders

Very rare:

Aggression**, agitation**, anger**, confusional state**, euphoric mood**, hallucination**, hostility**, movement disorder**, physical assault**

Nervous system disorders

Common:

Sedation, somnolence, depressed levels of consciousness Respiratory depression

Very rare:

Anterograde amnesia**, ataxia**, dizziness**, headache**, seizure**, paradoxical reactions**

Cardiac disorders

Very rare:

Bradycardia**, cardiac arrest**, hypotension**, vasodilatation**

Respiratory, thoracic and mediastinal disorders

Very rare:

Apnoea**, dyspnea**, laryngospasm**, respiratory arrest**

Gastrointestinal disorders

Common:

Nausea and vomiting

Very rare:

Constipation**, dry mouth**

Skin and subcutaneous tissue disorders

Uncommon:

Pruritus, rash and urticarial

General disorders and administration site conditions

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.

Description of selected adverse reactions

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 of suspected adverse reactions

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.

4.9. Overdose

Symptoms

Midazolam overdose can present a threat to life if the patient has pre-existing respiratory or cardiac insufficiency, or when combined with other CNS depressants (including alcohol).

Overdose of benzodiazepines is usually manifested by degrees of central nervous system depression ranging from drowsiness to coma. In mild cases, symptoms include drowsiness, mental confusion and lethargy, in more serious cases, symptoms may include ataxia, hypotonia, hypotension, respiratory depression, rarely coma and very rarely death.

Management

In the management of overdose with any medicinal product, it should be borne in mind that multiple agents may have been taken.

Following overdose with oral midazolam, vomiting should be induced (within one hour) if the patient is conscious or gastric lavage undertaken with the airway protected if the patient is unconscious. If there is no advantage in emptying the stomach, activated charcoal should be given to reduce absorption. Special attention should be paid to respiratory and cardiovascular functions in intensive care.

Flumazenil may be useful as an antidote.