SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Midazolam 5mg/ml Solution for Injection/Infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1ml solution contains 5mg midazolam presented in 2ml and 10ml ampoules.

3 PHARMACEUTICAL FORM

Solution for Injection/ Infusion

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

As intravenous sedative cover before and during minor medical, dental and surgical procedures such as gastroscopy, endoscopy, cystoscopy, bronchoscopy and cardiac catheterisation.

For sedation by continuous infusion in patients in intensive care.

As an intramuscular premedication for patients with physical status ASA I-IV who are to undergo surgical procedures.

As an alternative intravenous agent for the induction of anaesthesia in high risk and elderly patients, especially where cardiovascular stability is of particular importance. Induction is more reliable when heavy opiate premedication has been administered or when midazolam is given with a narcotic analgesic such as fentanyl.

4.2 Posology and method of administration

Posology

Intravenous sedation : One or more intravenous administrations over a single operating session.

In most circumstances, the 2mg/ml formulation is more convenient for titration purposes.

Adults : An assessment should be made of the degree of sedation necessary for the planned procedure.

The dose should be titrated against the response of the patient. The desired titration end point will depend upon the procedure. Full sedation will be evident by drowsiness, slurred speech but response to commands will be maintained.

As a guide, it is recommended that 0.4ml of Midazolam 5mg/ml solution (equivalent to 2mg midazolam) be administered intravenously over 30 seconds. If after 2 minutes, sedation is not adequate, incremental doses of 0.1ml to 0.2ml of Midazolam 5mg/ml solution (0.5 to 1mg midazolam) should be given.

Usual dose range 2.5mg - 7.5mg total dose (equivalent to around 0.07mg/kg body weight).

Dosages greater than 5.0mg are not usually necessary.

Older people: OLDER PATIENTS ARE MORE SENSITIVE TO THE EFFECTS OF BENZODIAZEPINES. IN THESE PATIENTS DOSES GREATER THAN 3.5MG ARE NOT USUALLY NECESSARY AND LOW DOSES AS LITTLE AS 1MG - 2MG (0.2 - 0.4ML) MAY BE ADEQUATE. THE INITIAL DOSE SHOULD NOT EXCEED 1 - 1.5MG (0.2 - 0.3ML).

Paediatric population: Midazolam Injection has not been evaluated for use as an intravenous sedative in children.

Method of Administration : For the administration of Midazolam Injection, the patient should be placed in a supine position and remain there throughout the procedure. Resuscitation facilities should always be available and a second person fully trained in the use of such equipment should always be present. It is recommended that patients should remain under medical supervision until at least 1 hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult.

Patients who have received Midazolam Injection alone for IV sedation prior to minor procedures should be warned not to drive or operate machinery for 12 hours. Where midazolam is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.

Sedation by continuous infusion in intensive care : For sedation in the intensive care unit, dosages vary considerably and the dosage of Midazolam Injection should be individualised and titrated to the desired state of sedation according to the clinical need, physical status, age and concomitant medication.

Patients receiving Midazolam Injection for sedation by continuous infusion in the intensive care situation should receive ventilatory support.

Safety of continuous infusion of midazolam injection for periods of over fourteen days in duration has not been established in clinical trials.

Adults and children : Loading dose : For patients already sedated, a loading dose of midazolam is not required. To induce sedation, a loading dose of 0.03 -0.3mg/kg is recommended, depending on the level of sedation required. This should be administered over a five minute period.

Maintenance dose : The dosage varies considerably. A dose between 0.03 -0.2mg/kg per hour is recommended, commencing at the lower end of the range. The dosage should be reduced or the loading dose should even be omitted in hypovolaemic, vasoconstricted and hypothermic patients.

Combination therapy

Intravenous bolus sedation : Where analgesia is provided by a narcotic analgesic the latter should be administered first, the dose of midazolam should be carefully titrated and low doses 1 - 2mg (0.2 - 0.4ml) may be adequate. In the elderly, smaller doses as little as 0.5 - 1mg (0.1 - 0.2ml) may be adequate.

Sedation by continuous infusion in intensive care : Where analgesia is provided by narcotic analgesics, the rate of infusion of Midazolam Injection should be titrated carefully to the sedative needs of the patient.

Intravenous induction of anaesthesia : One or more bolus intravenous injections over a single anaesthetic session.

Adults : The dose should be titrated against the individual response of the patient. Midazolam Injection should be given by slow intravenous injection until there is a loss of eyelid reflex, response to commands and voluntary movements.

In anticipating the required dose of midazolam, both the premedication already given and the age of the patient are important. Young, fit unpremedicated patients may require at least 0.3mg/kg body-weight, whereas patients premedicated with an opiate usually require only 0.2mg/kg body-weight.

Older people : OLDER PATIENTS ARE MORE SENSITIVE TO THE EFFECTS OF BENZODIAZEPINES. INDUCTION MAY BE ADEQUATE WITH 0.1MG/KG BODY-WEIGHT IN PREMEDICATED PATIENTS AND 0.2MG/KG BODY-WEIGHT IN UNPREMEDICATED PATIENTS.

Paediatric population : Midazolam Injection has been shown to be an effective agent for induction of anaesthesia in children over 7 years of age, at a dose of 0.15mg/kg body-weight.

Intramuscular premedication : Adults : A single intramuscular injection of 0.07 -0.1mg/kg body-weight, administered 30 - 60 minutes pre-operatively, has been shown to be adequate in most cases. The usual dose is about 5mg.

Atropine or hyoscine hydrobromide may be given concomitantly, bearing in mind that hyoscine hydrobromide will enhance and prolong the sedative and amnesic effects of midazolam.

Midazolam Injection can be combined with atropine or hyoscine hydrobromide in the same syringe to be given as a single intramuscular injection.

Older people : OLDER PATIENTS ARE MORE SENSITIVE TO THE EFFECTS OF BENZODIAZEPINES AND IN THESE PATIENTS A LOWER DOSE OF 2.5MG MAY BE ADEQUATE.

Paediatric population: Midazolam Injection has not been evaluated for use as an intramuscular premedicant in children.

Use in Special Populations:

Renal Impairment:

In patients with renal impairment (creatinine clearance <10ml/min) the pharmacokinetics of unbound midazolam following a single IV 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 a-hydroxymidazolam glucuronide.

There is no specific data in patients with severe renal impairment (creatinine clearance below 30 ml/min) receiving midazolam for induction of anaesthesia.

Hepatic Impairment

Hepatic impairment reduces the clearance of i.v. midazolam with a subsequent increase in terminal half-life. Therefore the clinical effects may be stronger and

prolonged. The required dose of midazolam may be reduced and proper monitoring of vital signs should be established. (See section 4.4).

Paediatric population See above and section 4.4

4.3    Contraindications

Use of this drug in patients with known hypersensitivity to benzodiazepines or to any excipient of the product.

Use of this drug for conscious sedation in patients with severe respiratory failure, or acute respiratory depression.

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.

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 dosage is administered (see section 4.8).

Special caution is required for the indication of conscious sedation in patients with impaired respiratory function.

Paediatric 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' below).

When midazolam is used for premedication, adequate observation of the patient after administration is mandatory as inter-individual sensitivity varies and symptoms of overdose may occur.

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, impaired hepatic function or with impaired cardiac function

-    pediatric patients specially those with cardiovascular instability.

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.

Tolerance

Some loss of efficacy has been reported when midazolam was used as long-term sedation in intensive care units (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, muscle pain, anxiety, tension, restlessness, confusion, irritability, rebound insomnia, mood changes, hallucinations and convulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.

Amnesia

Midazolam causes anterograde amnesia (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. 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 agitation, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, rage reaction, aggressiveness, 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.

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, low cardiac output and in neonates.

Preterm infants and neonates

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.

Rapid injection should be avoided in the neonatal population.

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.

Concomitant use of alcohol / CNS depressants

The concomitant use of midazolam with alcohol or/and CNS depressants should be avoided. Such concomitant use has the potential to increase the clinical effects of midazolam possibly

including severe sedation 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 less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially 'sodium- free'

Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Interactions

Midazolam is metabolised 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.

Inhibition

• After a single dose of IV midazolam, the maximal clinical effect due to CYP3A4 inhibition will be minor while the duration of effect may be prolonged.

•    After prolonged dosing of midazolam, both the magnitude and duration of effect will be increased in the presence of CYP3A4 inhibition since increased plasma concentrations cause increased sedation

•    It takes several days for both inductions to reach its maximum effect and to dissipate. However, for strong inducers a relevant induction even after shortterm treatment cannot be excluded.

•    Carefully monitoring of the clinical effects and vital signs is recommended during the use of midazolam with a CYP3A4 inhibitor even after a single dose.

Drugs that inhibit CYP3A4 Azole antifungals

If parenteral midazolam is coadministered with the strong CYP3A4 inhibitor ketoconazole, it should be done in an intensive care unit (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.

•    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 - 3-fold associated with an increase in terminal half-life by 2.4-fold for itraconazole and 1.5-fold for fluconazole, respectively.

•    Posaconazole increased the plasma concentrations of intravenous midazolam by about 2-fold.

Midazolam ampoules are not indicated for oral administration.

Macrolide antibiotics

•    Erythromycin increases 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 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.

•    Roxithromycin: There is no information on roxithromycin with i.v midazolam but the mild effect on the terminal half-life of oral midazolam increase of 30%, indicates that the effects on i.v midazolam may be minor.

•    Quinupristin/ dalfopristin and telithomycin may increase plasma concentration of midazolam

HIV Protease inhibitors

Coadministration with protease inhibitors may cause a large increase in the concentration of midazolam. If parenteral midazolam is co-administered with HIV protease inhibitors, treatment setting should follow the description in the above section for azole antifungals, ketoconazole.

Upon coadministration 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

•    Diltiazem: 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 drugs/Herbs

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

Aprepitant dose dependently increased the plasma concentrations of midazolam therefore increasing the risk of prolonged sedation.

Drugs that induce CYP3A4

•    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%.

•    Carbamazepine / phenytoin: Repeat dosages of carbamezepine 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%.

•    Efavirenz: The 5-fold increase in the ratio of the CYP3A4 generated metabolite a-hydroxymidazolam to midazolam confirms its CYP3A4-inducing effect.

•    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)

Sedative and hypnotics

The co-administration of midazolam with other sedative/hypnotic agents and CNS depressants, including alcohol, is likely to result in enhanced sedation and 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, sodiumoxybate, and centrally acting antihypertensive drugs.

Alcohol

Alcohol may markedly enhance the sedative effect of midazolam, so concurrent intake should be strongly avoided (see section 4.4).

Muscle relaxants

Increased sedative effect with baclofen and tizanidine.

Inhalation anaesthetics

Midazolam decreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.

Antihypertensives, vasodilators & diuretics:

Enhanced hypotensive effect with ACE-inhibitors, alpha-blockers, angiotensin-II receptor antagonists, calcium channel blockers, adrenergic neurone blockers, beta-blockers, moxonidine, nitrates, hydralazine, minoxidil, sodium nitroprusside and diuretics.

Anti-epileptics

Carbamazepine    reduces the    plasma concentrations of    midazolam.

Benzodiazepines may alter ie. Either increase or decrease the plasma concentrations of phenytoin.

Others

Nilotinib and Nabilone may increase plasma concentration of midazolam.

4.6    Fertility, Pregnancy and lactation

Pregnancy

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

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. 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, 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 post-natal period.

The risk for neonate 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

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.

Where midazolam is used concurrently with other central nervous system depressants (e.g. potent analgesics) recovery may be prolonged. Patients should therefore be assessed carefully before being allowed to go home or resume normal activities.

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:

•    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

• However, you would not be committing an offence (called ‘statutory defence’) if:

o The medicine has been prescribed to treat a medical or dental problem and

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

o It was not affecting your ability to drive safely

4.8 Undesirable effects

The following undesirable effects 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)

Immune system disorders
Frequency not known	Hypersensitivity, anaphylactic shock, angioedema
Psychiatric disorders
Frequency not known	Confusional state, euphoric mood, hallucination Agitation*, hostility*, rage*, hyperactivity, aggressiveness*, excitement* Physical drug dependence and withdrawal syndrome Abuse
Nervous system disorders
Frequency not known	Involuntary movements (including tonic/clonic movements and muscle tremor)*, psychomotor 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 local have been reported in premature infants

	and neonates Drug withdrawal convulsions
Cardiac disorders
Frequency not known	Cardiac arrest, bradycardia, cardiovascular disorder
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, bronchospasm
Gastrointestinal disorders
Frequency not known	Nausea, vomiting, constipation, dry mouth
Skin and subcutaneous tissue disorders
Frequency not known	Rash, urticaria, pruritus, skin reactions,
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, fractures1
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 isolated cases prolonged amnesia has been reported (see section 4.4).

Dependence: Use of midazolam even in therapeutic doses may lead to the development of physical dependence. After prolonged IV 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 of suspected adverse reactions

Reporting suspected adverse reactions is an important way to gather more information to continuously monitor the benefit/risk balance of the medicinal product. Any suspected adverse reactions should be reported via the internet at: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Like other benzodiazepines, midazolam commonly causes drowsiness, ataxia, dysarthria and nystagmus. Overdose of midazolam is seldom life-threatening if the drug 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.

Treatment

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

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 drug.

The correct information for using Flumazenil can also be obtained from the UK National Poison Information Service by calling on the following telephone number.

Tel: 0844-892-0111 (directs caller to relevant local centre.)

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:

Hypnotics and sedatives (benzodiazepine derivatives), ATC code: N05CD08.

Midazolam is a derivative of the imidazobenzodiazepine group. The free base is a lipophilic substance with low solubility in water.

The basic nitrogen in position 2 of the imidazobenzodiazepine ring system enables the active ingredient of midazolam to form water-soluble salts with acids. These produce a stable and well tolerated injection solution.

The pharmacological action of midazolam is characterised by short duration because of rapid metabolic transformation. Midazolam has a sedative and sleep-inducing effect of pronounced intensity. It also exerts an anxiolytic, an anticonvulsant and a muscle-relaxant effect.

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

Absorption after i.m. injection

Absorption of midazolam from the muscle tissue is rapid and complete. Maximum plasma concentrations are reached within 30 minutes. The absolute bioavailability after i.m. injection is over 90%.

Distribution

When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct phases of distribution. 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 fraction of plasma protein binding is due to 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.

Metabolism

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 P4503A4 isozyme and the major urinary and plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% of those of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (about 10%) to the effects of intravenous midazolam.

Elimination

In healthy volunteers, the elimination half-life of midazolam is between 1.5 - 2.5 hours. Plasma clearance is in the range of 300 - 500ml/min. Midazolam is excreted mainly by renal route (60 - 80% of the injected dose) and recovered as glucuroconjugated alpha-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged drug. The elimination half-life of alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given by i.v. infusion, its elimination kinetics do not differ from those following bolus injection.

Pharmacokinetics in special populations

Elderly

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

Children

The elimination half-life after i.v. administration is shorter in children 3 - 10 years old (1 - 1.5 hours) as compared with that in adults. The difference is consistent with an increased metabolic clearance in children.

Neonates

In neonates the elimination half-life is on average 6 - 12 hours, probably due to liver immaturity and the clearance is reduced (see section 4.4).

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 elimination half-life in cirrhotic patients may be longer and the clearance smaller as compared to those in healthy volunteers (see section 4.4).

Patients with renal impairment

The elimination half-life in patients with chronic renal failure is similar to that in healthy volunteers.

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 Sodium hydroxide Water for injections

6.2 Incompatibilities

Midazolam Injection is stable, both physically and chemically, for up to 1 hour at room temperature when mixed in the same syringe with Atropine Sulphate Injection BP or Hyoscine Hydrobromide Injection 0.4mg/ml. There is no evidence of the adsorption of midazolam onto the plastic of infusion apparatus or syringes.

Midazolam Injection when mixed with 500ml infusion fluids containing dextrose 4% with sodium chloride 0.18%, dextrose 5% or sodium chloride 0.9% is chemically and physically stable for up to 24 hours at 25°C and up to 72 hours at 2 to 8°C. However, for pharmaceutical microbiological reasons, the product should be used immediately after dilution. When aseptically prepared, the diluted solution may be kept for not more than 24 hours if stored under refrigeration at a temperature between 2-8°C.

Admixture with Hartmann's solution is not recommended, as the potency of midazolam decreases.

Shelf life

Unopened: 3 years.

After reconstitution: not applicable After first opening: not applicable

6.4    Special precautions for storage

Protect from light.

Store below 25°C.

6.5    Nature and contents of container

Clear One Point Cut (OPC) 2ml & 10ml glass ampoules, glass type I, Ph. Eur. Pack sizes: 5 x 2ml ampoules; 10 x 2ml ampoules.

5 x 10ml ampoules; 10 x 10ml ampoules

6.6    Special precautions for disposal and other handling

If only part used, discard the remaining solution.

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7    MARKETING AUTHORISATION HOLDER

Mercury Pharma International Ltd 4045, Kingswood Road,

City West Business Park,

Co Dublin, Ireland

8    MARKETING AUTHORISATION NUMBER(S)

PL 02848/0203

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

20/12/2005

10    DATE OF REVISION OF THE TEXT

12/05/2015

1

The risk of falls and fractures is increased in those taking concomitant sedatives (including alcoholic beverages) and in the elderly.