4.1. Therapeutic indications

Miprosed is indicated in children aged 6 months to 14 years for:

• Sedation and anxiolysis prior to diagnostic, surgical, therapeutic or endoscopic procedures.

• Premedication before induction of general anaesthesia.

4.2. Posology and method of administration

Sedation and anxiolysis prior to diagnostic, surgical, therapeutic or endoscopic procedures:

Children (6 months to 14 years): 0.25mg/kg to 0.5mg/kg administered 15-30 minutes before the intervention. Maximum per dose: 20mg.

Premedication before induction of general anaesthesia:

Children (6 months to 14 years): 0.25mg/kg to 0.5mg/kg administered 15-30 minutes before the induction of anaesthesia. Maximum per dose: 20mg.

The dose should be adapted to the patient's weight and administered rounded to the nearest syringe graduation in millilitres. The maximum dose should not exceed 20mg of midazolam even for children weighing more than 80kg (0.25mg/kg) or 40kg (0.5mg/kg). In obese children the dose should be given according to the actual body weight up to the maximum limit of 20mg. General fasting guidelines should be respected before sedation with Miprosed.

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).

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

Children under 6 months

The safety and efficacy of midazolam in children aged 0 to 6 months for the indications listed above has not been established. Miprosed should not be used in children under 6 months of age.

Method of administration

For oral administration only.

The oral solution should be administered using the oral syringes provided.

Miprosed may be mixed with and administered in apple juice and diluted blackcurrant cordial.

Please refer to section 6.6 for any special precautions related to the manipulation or administration of the product.

4.3. Contraindications

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1

• Severe hepatic impairment

• Severe respiratory failure or acute respiratory depression

• Myasthenia gravis

• Sleep apnea

• Anatomical respiratory impairment or lung diseases

4.4. Special warnings and precautions for use

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.

Midazolam should be used with caution in patients with mild or moderate hepatic impairment, heart failure or chronic renal failure. Midazolam or its metabolite may accumulate in patients with chronic renal failure or with liver failure, and the clearance of midazolam may be decreased in patients with heart failure.

Oral midazolam should be used with caution in patients in poor general health as they are more sensitive to the effects of benzodiazepines on the central nervous system.

Risk from concomitant use of opioids:

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).

Respiratory insufficiency

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

Paediatric patients aged less than 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 children under 6 months age group cannot be excluded. Therefore, Midazolam Oral solution should not be used in children under 6 months of age.

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.

Concomitant use of alcohol/central nervous system depressants

Combined use of midazolam and alcohol and/or central nervous system depressants should be avoided. Such a combination is likely to increase the clinical effects of midazolam, which may cause deep sedation or clinically significant respiratory depression (see section 4.5).

Amnesia

Midazolam may cause anterograde amnesia. 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 (see discharge below).

Paradoxical reactions

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, hostility, rage reaction, aggression, paroxysmal excitement have been reported. Should such reactions occur, the response to midazolam and all other drugs including local anaesthetics should be evaluated before proceeding.

Discharge

It is recommended that children receiving oral midazolam are discharged post-surgery accompanied by a parent or guardian.

Excipients warning:

This medicine contains less than 1 mmol sodium (23 mg) in each ml of solution, that is to say essentially 'sodium-free'.

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

Pharmacokinetic Drug Interactions

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. 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.

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.

The effect of CYP3A4 inhibitors may be larger in infants.

Anaesthetics and narcotic analgesics

Fentanyl may reduce midazolam clearance.

Antiepileptics

After repeated administration of carbamazepine or phenytoin, the plasma concentration of oral midazolam is reduced by a whopping 90% and the terminal half-life is reduced by 60%.

Calcium-channel blockers

Diltiazem and verapamil have been shown to reduce the clearance of midazolam and other benzodiazepines and may potentiate their actions. A single dose of diltiazem increased the plasma concentrations of intravenous midazolam by about 25% and the terminal half-life was prolonged by 43%.

H2-receptor antagonists and 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. Cimetidine has been shown to increase the diazepam and metabolite plasma concentration by 57%.

Substance P antagonists

Aprepitant causes a dose dependent increase in the plasma concentrations of oral Midazolam. The plasma concentration of oral Midazolam increased by 3.3-fold after 80mg/day dose of aprepitant on day 5 and the terminal half-life increased by approximately 2-fold.

Xanthines

Metabolism of midazolam and other benzodiazepines is accelerated by xanthines.

Dopaminergic medicinal products

Midazolam may cause inhibition of levodopa.

Muscle relaxants

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

Nabilone

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

Food

Grapefruit juice and caffeine 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.

When bolus doses of midazolam (given for short term sedation) were administered to patients receiving itraconazole or fluconazole the effect of midazolam was not enhanced to a clinically significant degree and dosage reduction is not required. High doses of midazolam may require dosage adjustments.

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.

Anticholinergics

Propiverine reduce the hepatic and intestinal CYP3A4 activity by 0.89-fold and to 0.80-fold, respectively, and with the combined effect resulting in a 1.46-fold increase in AUC of oral midazolam.

Selective serotonin reuptake inhibitors

Fluvoxamine has been shown to possess CYP3A4 inhibitory properties, therefore increase the midazolam AUC and Cmax by approximately 60% and decrease clearance by 30%.

Nefazodone

Treatment with nefazodone increased the AUC0-∞ of midazolam by about four times and doubled the Cmax.

Glucocorticoids (GCs)

Use of GCs decreased the mean AUC of Midazolam (63.9%), whereas total clearance of midazolam was increased to a mean of 125.7%. Terminal t1/2 and AUC0-∞ of the metabolite 1'-OH midazolam significantly declined in the patients taking GCs.

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.

Reverse transcriptase inhibitors:

Efavirenz: the ratio of α-hydroxymidazolam (metabolite that is generated by CYP3A4) increases by a factor of five compared to midazolam, confirming the induction effect of efavirenz on CYP3A4.

Various medicinal products

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

Pharmacodynamic Drug Interactions

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.

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

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

Opioids

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).

4.6. Fertility, pregnancy and lactation

Pregnancy

No data on the use of midazolam in women during the first two trimesters of pregnancy are available.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). 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 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

The safety of orally administered Midazolam Oral Solution in conscious sedation in children has been evaluated from the results of 32 clinical studies in which 4148 patients participated. The frequency of adverse reactions is classified 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) and

Not known (cannot be estimated from the available data).

System Organ Class

Frequency

Common

Uncommon

Rare

Not known

Cardiac disorders

Kounis syndrome*

Eye disorders

Diplopia

Gastrointestinal disorders

Nausea

Vomiting

Injury, poisoning, procedural complication

Sedation complication

Nervous system disorders

Agitation

Somnolence

Dyskinesia

Ataxia

Dizziness

Headache

Compulsive lip biting

Excessive/prolonged sedation

Aphasia

Psychiatric disorders

Paradoxical reactions

Crying

Gait disorders

Anger

Hallucination

Mood swings

Aggression

Screaming

Irritability

Respiratory

Hiccups

Respiratory disorder

Oxygen saturation decreased

Surgical and medical procedures

Endotracheal intubation

Vascular disorders

Hypotension

*particularly after parenteral administration

From the available clinical studies reporting the use of oral midazolam as a premedicant before induction of anaesthesia, it has not been possible to estimate the frequency of adverse events. The adverse events that have been reported in these clinical studies in patients receiving oral midazolam include: nausea, vomiting, salivation, hypoxia, hypertension, tachycardia, agitation, vertigo, euphoria, excitation, restlessness and nocturnal enuresis.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.

In most cases, monitoring of vital signs is necessary. Special attention should be paid to respiratory and cardiovascular functions in intensive care.

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.