This information is intended for use by health professionals

1. Name of the medicinal product

Midazolam 2 mg/ml solution for injection/infusion in pre-filled syringe

2. Qualitative and quantitative composition

Each ml of the solution for injection/infusion contains 2 mg midazolam.

Each pre-filled syringe of 50 ml contains 100 mg midazolam.

Excipient with known effect:

A 50 ml pre-filled syringe contains 157.36 mg (6.84 mmol) of sodium. Each ml contains 3.15 mg (0.14 mmol) of sodium.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Solution for injection/infusion

Clear, colourless to viscous solution, with pH between 2.9 and 3.7, and osmolality between 230 and 290 mOsm/kg.

4. Clinical particulars
4.1 Therapeutic indications

Midazolam is a short-acting sleep-inducing active substance that is indicated in adults for sedation in intensive care units.

4.2 Posology and method of administration

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.

Standard posology

Midazolam is a potent sedative active substance that requires titration and slow administration. Titration is strongly recommended to safely obtain the desired level of sedation according to the clinical need, physical status, age and concomitant medication. In adults over 60 years, debilitated or chronically ill patients, dose should be determined with caution and risk factors related to each patient should be taken into account. Standard doses are provided in the table below. Additional details are provided in the text following the table.

Indication

Adults

Sedation in ICU

i.v.

Loading dose: 0.03 - 0.3mg/kg in increments of

1 - 2.5 mg

Maintenance dose: 0.03 - 0.2 mg/kg/h

Sedation in intensive care units

The desired level of sedation is reached by stepwise titration of midazolam followed by continuous infusion, according to the clinical need, physical status, age and concomitant medication (see section 4.5).

Adults

I.V. loading dose: 0.03 to 0.3 mg/kg should be given slowly in increments. Each increment of 1 to 2.5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments. In hypovolaemic, vasoconstricted or hypothermic patients the loading dose should be reduced or omitted. When midazolam is given with potent analgesics, the latter should be administered first so that the sedative effects of midazolam can be safely titrated on top of any sedation caused by the analgesic.

I.V. maintenance dose: doses can range from 0.03 to 0.2 mg/kg/h. In hypovolaemic, vasoconstricted or hypothermic patients the maintenance dose should be reduced. The level of sedation should be assessed regularly. With long-term sedation, tolerance may develop and the dose may have to be increased. Midazolam 2 mg/ml should be used if higher doses are required.

When initiating an infusion with midazolam in haemodynamically compromised patients, the usual loading dose should be titrated in small increments and the patient monitored for haemodynamic instability, e.g., hypotension. These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

Special population

Renal Impairment

In patients with severe renal impairment (creatinine clearance below 30 ml/min) midazolam may be accompanied by more pronounced and prolonged sedation possibly including clinically relevant respiratory and cardiovascular depression. Midazolam should therefore be dosed carefully in this patient population and titrated for the desired effect (see section 4.4). In patients with renal failure (creatinine clearance < 10 ml/min) the pharmacokinetics of unbound midazolam following a single i.v. dose is similar to that reported in healthy volunteers. However, after prolonged infusion in intensive care unit (ICU) patients, the mean duration of the sedative effect in the renal failure population was considerably increased most likely due to accumulation of 1'-hydroxymidazolam glucuronide (see sections 4.4 and 5.2).

Hepatic Impairment

Hepatic impairment reduces the clearance of i.v. midazolam with a subsequent increase in terminal half-life. Therefore the clinical effects in patients with hepatic impairment may be stronger and prolonged. The required dose of midazolam may have to be reduced and proper monitoring of vital signs should be established (See section 4.4).

Paediatric population

Midazolam is not recommended for the use in children due to the total amount of midazolam contained in the pre-filled syringes.

Method of administration

Midazolam is for intravenous use.

The solution should be examined visually before administration. Only solutions without visible particles should be used.

One pre-filled syringe must be used for one patient only.

When Midazolam is used to maintain anaesthesia, it is recommended that equipment such as syringe pumps or volumetric infusion pumps should always be used to control infusion rates.

When the pre-filled syringe presentation is used in a syringe pump appropriate compatibility should be ensured. In particular, the pump should be designed to prevent syphoning and should have an occlusion alarm.

Users must be familiar with the infusion pump users' manual and with the correct use of the syringe identification system.

4.3 Contraindications

- 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.

4.4 Special warnings and precautions for use

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 dose is administered (see section 4.8).

Benzodiazepines are not recommended for the primary treatment of psychotic illness.

Special caution should be exercised when administering midazolam to high-risk patients:

- adults over 60 years of age

- chronically ill or debilitated patients, e.g.

- patients with chronic respiratory insufficiency

- patients with chronic renal failure

- patients with impaired hepatic function (benzodiazepines may precipitate or exacerbate encephalopathy in patients with severe hepatic impairment)

- patients with impaired cardiac function.

These high-risk patients require lower doses (see section 4.2) and should be continuously monitored for early signs of alterations of vital functions.

Particular care should be taken when administering midazolam to a patient with myasthenia gravis.

Tolerance

Some loss of efficacy has been reported when midazolam was used as long-term sedation in ICU.

Dependence

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).

Withdrawal symptoms

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.

Amnesia

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

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 the elderly. In the event of these reactions, discontinuation of the drug should be considered.

Altered elimination of midazolam

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 or low cardiac output (see section 5.2).

Sleep apnoea

Midazolam should be used with extreme caution in patients with sleep apnoea syndrome and patients should be regularly monitored.

Concomitant use of alcohol/CNS depressants

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).

Medical history of alcohol or drug abuse

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

Discharging criteria

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 6.84 mmol (or 157.36 mg) sodium per pre-filled syringe, equivalent to 7.9% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Midazolam is not indicated for oral use.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic interactions

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, itraconzaole

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 is 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 inhibitors are more pronounced for oral as compared to i.v. midazolam. Midazolam is not indicated for oral administration.

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 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

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 should not be used during pregnancy unless clearly necessary and it is preferable to avoid using it for caesarean section.

The risk for neonates should be taken into account in case of administration of midazolam for any surgery near the term.

Breast-feeding

Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feeding for 24 hours following administration of midazolam.

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 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. When prescribing this medicine, patients should be told:

- the medicine is likely to affect your ability to drive

- do not drive until you know how the medicine affects you

- it is an offence to drive while under the influence of this medicine, unless:

- the medicine has been prescribed to treat a medical or dental problem and

- you have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

- it was not affecting your ability to drive safely.

4.8 Undesirable effects

Adverse reactions listed below are classified according to frequency and System Organ Class (SOC). Frequency groupings are defined according to the following convention: 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)

The following undesirable effects have been reported to occur when midazolam is injected:

Immune system disorders

frequency not known

Hypersensitivity, angioedema, anaphylactic shock

Psychiatric disorders

frequency not known

Confusional state, euphoric mood, hallucinations

Agitation*, hostility*, rage*, aggressiveness*, excitement*

Physical drug dependence and withdrawal syndrome

Abuse

Nervous system 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

Cardiac disorders

frequency not known

Cardiac arrest, bradycardia

Vascular disorders

frequency not known

Hypotension, vasodilation, thrombophlebitis, thrombosis

Respiratory, thoracic and mediastinal 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 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 cardiorespiratory 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 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 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 commonly causes drowsiness, ataxia, dysarthria and nystagmus. Overdose of midazolam is seldom life-threatening if the medicinal product is taken alone, but may lead to areflexia, apnoea, hypotension, cardiorespiratory depression and in rare cases to coma. Coma, if it occurs, usually lasts a few hours but it may be more protracted and cyclical, particularly in elderly patients. Benzodiazepine respiratory depressant effects are more serious in patients with respiratory disease.

Benzodiazepines increase the effects of other central nervous system depressants, including alcohol.

Management

The patient's vital signs should be monitored and supportive measures should be instituted as indicated by the patient's clinical state. In particular, patients may require symptomatic treatment for cardiorespiratory effects or central nervous system effects.

If taken orally further absorption should be prevented using an appropriate method e.g. treatment within 1-2 hours with activated charcoal. If activated charcoal is used airway protection is imperative for drowsy patients. In case of mixed ingestion gastric lavage may be considered, however not as a routine measure.

If CNS depression is severe consider the use of flumazenil, a benzodiazepine antagonist. This should only be administered under closely monitored conditions. It has a short half-life (about an hour), therefore patients administered flumazenil will require monitoring after its effects have worn off. Flumazenil is to be used with extreme caution in the presence of drugs that reduce seizure threshold (e.g. tricyclic antidepressants). Refer to the prescribing information for flumazenil, for further information on the correct use of this medicinal product.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics; hypnotics and sedatives; benzodiazepine derivatives,

ATC code: N05CD08.

Mechanism of action

The central actions of benzodiazepines are mediated through an enhancement of the GABAergic neurotransmission at inhibitory synapses. In the presence of benzodiazepines the affinity of the GABA receptor for the neurotransmitter is enhanced through positive allosteric modulation resulting in an increased action of released GABA on the postsynaptic transmembrane chloride ion flux.

Chemically midazolam is a derivative of the imidazobenzodiazepine group, the basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of midazolam to form water-soluble salts with acids, producing a stable and well tolerated injection solution. At physiological pH the diazepine ring closes and the free base is formed resulting in a lipophilic substance with rapid onset of action. Rapid metabolic transformation and redistribution are key reasons for the short duration of effects.

Pharmacodynamic effects

Midazolam has hypnotic and sedative effects characterised by a rapid onset and short duration. It also exerts anxiolytic, anticonvulsant and muscle-relaxant effects. Midazolam impairs psychomotor function after single and/or multiple doses but causes minimal haemodynamic changes.

After i.m. or i.v. administration anterograde amnesia of short duration occurs (the patient does not remember events that occurred during the maximal activity of the compound).

5.2 Pharmacokinetic properties

Distribution

When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct disposition phases. The volume of distribution at steady state is 0.7 - 1.2 l/kg. 96 - 98% of midazolam is bound to plasma proteins. The major binding protein is albumin. There is a slow and insignificant passage of midazolam into the cerebrospinal fluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Small quantities of midazolam are found in human milk. Midazolam is not a substrate for any of the drug transporters tested so far (cellular efflux transporter: P-glycoprotein; cellular uptake transporters: OAT1, OAT2, OAT3, OCT1, OCT2, OATP1A2, OATP1B1, OATP1B3.1, OATP1B3.2, OATP2B1 and rOatp1b2, which is found in rats only).

Biotransformation

Midazolam is almost entirely eliminated by biotransformation. The fraction of the dose extracted by the liver has been estimated to be 30 - 60%. Midazolam is hydroxylated by the cytochrome P450 CYP3A4 isozyme and the major urinary and plasma metabolite is 1'-hydroxymidazolam (also known as alpha-hydroxymidazolam). Plasma concentrations of 1'-hydroxymidazolamare 12% of those of the parent compound. 1'-hydroxymidazolamis pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.

Elimination

In young healthy volunteers, the elimination half-life of midazolam ranges from 1.5 to 2.5 hours. The elimination half-life of the metabolite is shorter than 1 hour; therefore after midazolam administration the concentration of the parent compound and the main metabolite declines in parallel. Plasma clearance of midazolam is in the range of 300 – 500 ml/min. Midazolam's metabolites are excreted mainly by the renal route (60 - 80% of the injected dose) and recovered as glucuroconjugated 1'-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged active substance. When midazolam is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection. Repeated administration of midazolam does not induce drug metabolising enzymes.

Pharmacokinetics in special populations

Elderly

In adults over 60 years of age, the elimination half-life may be prolonged up to four times.

Obese

The mean half-life is greater in obese than in non-obese patients (5.9 vs 2.3 hours). This is due to an increase of approximately 50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obese and non-obese patients.

Patients with hepatic impairment

The clearance in cirrhotic patients may be reduced and the elimination may be longer when compared to those in healthy volunteers (see section 4.4).

Patients with renal impairment

The pharmacokinetics of unbound midazolam are not altered in patients with severe renal impairment. The pharmacologically mildly active major midazolam metabolite, 1'-hydroxymidazolam glucuronide, which is excreted through the kidney, accumulates in patients with severe renal impairment. This accumulation may produces a prolonged sedation. Midazolam should therefore be administered carefully and titrated to the desired effect (see section 4.4).

Critically ill patients

The elimination half-life of midazolam is prolonged up to six times in the critically ill.

Patients with cardiac insufficiency

The elimination half-life is longer in patients with congestive heart failure compared with that in healthy subjects (see section 4.4).

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6. Pharmaceutical particulars
6.1 List of excipients

Sodium chloride

Hydrochloric acid 0.5% (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for injection

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

The use of PVC extension sets should be avoided. Where the use of PVC extension sets is unavoidable, their use should be limited to 24 hours.

6.3 Shelf life

2 years.

6.4 Special precautions for storage

Keep the pre-filled syringe in the outer carton in order to protect from light.

6.5 Nature and contents of container

One 50 ml pre-filled syringe made of cyclic olefin copolymer (COP) fitted with a chlorobutyl elastomer screw cap along with a bromobutyl plunger stopper, containing 50 ml of solution for injection.

One oxygen scavenger pouch (proprietary iron based blend) is included in pack.

Each carton contains one blister containing one pre-filled syringe.

6.6 Special precautions for disposal and other handling

No special requirement for disposal.

7. Marketing authorisation holder

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 87

2132 JH Hoofddorp

The Netherlands

8. Marketing authorisation number(s)

PL 31750/0151

9. Date of first authorisation/renewal of the authorisation

09/05/2019

10. Date of revision of the text

10/06/2021