Document: spc-doc_PL 20075-0337 change

• spc-doc_PL 12064-0077
• spc-doc_PL 20075-0337

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Midazolam Injection BP 2 mg/ml solution for injection or infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution for injection contains 2 mg midazolam as the hydrochloride.

Each 5 ml of solution for injection contains 10 mg midazolam as the hydrochloride.

Excipient with known effect:

The 5ml product contains 17.70mg (0.770mmol) of sodium per dose.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection or infusion.

Clear, colourless or slightly yellow solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Midazolam Injection BP 2 mg/ml is a short-acting sedative and sleep-inducing drug. The indications are as follows:

In adults and children

- Conscious sedation before and during diagnostic or therapeutic procedures with or without local anaesthesia,

- Premedication before induction of anaesthesia,

Sedation in Intensive Care Units.

- Induction of anaesthesia, - As an induction agent or as a sedative component in combined anaesthesia.

4.2 Posology and method of administration

STANDARD DOSAGE

Midazolam is a potent sedative that requires dose titration and slow administration. Dose titration is required tooptimise safety whilst achieving the desired level of sedation according to the clinical need, physical status, age andconcomitant medication. In adults over 60 years, debilitated or chronically ill patients and paediatric patients, the doseshould be determined with caution and risk factors related to each patient should be taken into account. Standarddosages are shown in the table below; additional details are provided in the text following the table.

Indication	Adults < 60 y	Adults _ 60 y / debilitated or chronically ill	Children
Conscious sedation	IV Initial dose: 2 - 2.5 mg Titration doses: 1 mg Total dose: 3.5 -75mg	IV Initial dose: 0.5 - 1 mg Titration doses: 0.5 -1 mg Total dose: < 3.5 mg	IV in patients 6 months - 5 years Initial dose: 0.05 -0.1 mg/kg Total dose: <6mg IV in patients 6-12 years Initial dose: 0.025 -0.05 mg/kg Total dose: < 10 mg
			rectal > 6 months 0.3 - 0.5 mg/kg
			IM 1 - 15 years 0.05 - 0.15 mg/kg
Anaesthesia premedication	i.v. 1-2mg repeated IM	i.v. Initial dose: 0.5mg Slow uptitration as	rectal > 6 months 0.3 - 0.5 mg/kg

	0.07 - 0.1 mg/kg	needed IM 0.025 - 0.05 mg/kg	IM 1 - 15 years 0.08 - 0.2 mg/kg
Anaesthesia induction	IV 0.15 - 0.2 mg/kg (0.3 0.35 mg/kg without premedication)	IV 0.05 - 0.15 mg/kg (0.15 -0.3 without premedication)
Sedative component in combined anaesthesia	IV intermittent doses of 0.03 - 0.1mg/kg or continuous infusion of 0.03 -0.1mg/kg/hr	IV lower doses than recommended for adults < 60 years
Sedation in ICU	IV Loading dose: 0.03 - 0.3 mg/kg in increments of1 - 2.5 mg Maintenance dose: 0.03 - 0.2 mg/kg/hr		IV in neonates < 32 weeks gestational age 0.03 mg/kg/hr
			IV in neonates > 32 weeks and children up to 6 months 0.06 mg/kg/hr
			IV in patients> 6 months of age Loading dose: 0.05 -0.2mg/kg Maintenance dose: 0.06 - 0.12mg/kg/h

Conscious sedation dosage

For conscious sedation prior to diagnostic or surgical intervention, midazolam is administered IV. The dose mustbe individualised and titrated, and should not be administered by rapid or single bolus injection. The onset of sedation may vary individually depending on the physical status of the patient and the detailed circumstances of dosing(e.g. speed of administration, amount of dose). If necessary, subsequent doses may be administered according to theindividual need.The onset of action is about 2 minutes after the injection.Maximum effect is obtained in about 5 to 10 minutes.

Adults

The IV injection of midazolam should be given slowly at a rate of approximately 1mg in 30 seconds. In adults belowthe age of 60 the initial dose is 2 to 2.5 mg given 5 to 10 minutes before the beginning of the procedure. Further dosesof 1mg may be given as necessary. Mean total doses have been found to range from 3.5 to 7.5 mg. A total dose greaterthan 5mg is usually not necessary. In adults over 60 years of age, debilitated or chronically ill patients, the initial dosemust be reduced to 0.5-1.0 mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0.5 to 1 mg may be given as necessary.Since in these patients the peak effect may be reached less rapidly, additional midazolam should be titrated very slowly and carefully. A total dose greater than 3.5 mg is usually notnecessary.

Children

IVadministration: midazolam should be titrated slowly to the desired clinical effect. The initial dose of midazolamshould be administered over 2 to 3 minutes. One must wait an additional 2 to 5 minutes to fully evaluatethe sedative effect before initiating a procedure or repeating a dose. If further sedation is necessary, continue to titrate with smallincrements until the appropriate level of sedation is achieved. Infants and young children less than 5 yearsof age may require substantially higher doses (mg/kg) than older children and adolescents.

•    Paediatric patients less than 6 months of age: paediatricpatients less than 6 months ofage are particularly vulnerable to airway obstruction and hypoventilation. Forthis reason,the use in conscious sedation in children less than 6 months of age is not recommended.

•    Paediatric patients 6 months to 5 years of age: initial dose 0.05 to 0.1 mg/kg. A total dose up to 0.6 mg/kg may benecessary to reach the desired endpoint, but the total dose should not exceed 6mg. Prolonged sedation and riskof hypoventilation may be associated with the higher doses.

•    Paediatric patients 6 to 12 years of age: initial dose 0.025 to 0.05 mg/kg. A total dose of up to 0.4mg/kg to amaximum of 10 mg may be necessary. Prolonged sedation and risk of hypoventilation may be associated with thehigher doses.

•    Paediatric patients 12 to 16 years of age: should be dosed as adults.

Rectal administration: the total dose of midazolam usually ranges from 0.3 to 0.5 mg/kg. Rectal administration of theampoule solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to beadministered is too small, water may be added up to a total volume of 10ml. The total dose should be administered atonce and repeated rectal administration avoided.

The use in children less than 6 months of age is not recommended, as available data in this population are limited.

IMadministration: the doses used range between 0.05 and 0.15 mg/kg. A total dose greater than 10.0mg is usually notnecessary. The IM route should only be used in exceptional cases. Rectal administration should be preferred as IM injection ispainful.

In children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1mg/ml are notrecommended. Higher concentrations should be diluted to 1mg/ml.

ANAESTHESIA DOSAGE

Premedication

Premedication with midazolam given shortly before a procedure produces sedation (induction of sleepiness or drowsiness and reliefof apprehension) and preoperative impairment of memory. Midazolam can also be administered in combination withanticholinergics. For this indication midazolam should be administered i.v. or i.m., deep into a large muscle mass 20 to 60minutes before induction of anaesthesia, or preferably via the rectal route in children (see below). Close and continuous monitoringof the patients after administration of premedication is mandatory as inter-individual sensitivity varies and symptoms ofoverdose may occur.

Adults

For preoperative sedation and to impair memory of preoperative events, the recommended dose for adults of ASAPhysical Status I & II and below 60 years is 1-2 mg i.v. repeated as needed, or 0.07 to 0.1 mg/kg administered i.m. The dose must be reduced andindividualised when midazolam is administered to adults over 60 years of age, debilitated or chronically ill patients. The recommended initial i.v. dose is 0.5 mg and should be slowly uptitrated as needed. Adose of 0.025 to 0.05 mg/kg administered i.m. is recommended. In case of concomitant administration of narcotics the midazolam dose should be reduced. The usual dose is 2 to 3 mg.

Paediatric Patients

Neonates and children up to 6 months of age:

The use in children less than 6 months of age is not recommended as available data are limited.

Children over 6 months of age

Rectal administration: The total dose of midazolam, usually ranging from 0.3 to 0.5 mg/kg should be administered 15to 30 minutes before induction of anaesthesia. Rectal administration of the ampoule solution is performed by means ofa plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be addedup to a total volume of 10 ml.

IMadministration: As IM injection is painful, this route should only be used in exceptional cases. Rectaladministration should be preferred. However, a dose range from 0.08 to 0.2 mg/kg of midazolam administered IM has beenshown to be effective and safe. In children between ages 1 and 15 years, proportionally higher doses are required thanin adults in relation to body-weight.

In children less than 15 kg of body weight, midazolam solutions with concentrations higher than 1 mg/ml are notrecommended. Higher concentrations should be diluted to 1 mg/ml.

Induction

Adults

If midazolam is used for induction of anaesthesia before other anaesthetic agents have been administered, theindividual response is variable. The dose should be titrated to the desired effect according to the patient's age andclinical status. When midazolam is used before or in combination with other i.v.or inhalation agents for induction ofanaesthesia, the initial dose of each agent should be significantly reduced, at times to as low as 25% of the usual initial dose of the individual agents.

The desired level of anaesthesia is reachedby stepwise titration. The i.v.induction dose of midazolam should be given slowly in increments. Each increment of notmore than 5 mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments.

•    Inpremedicated adults below the age of 60 years, an i.v.dose of 0.15 to 0.2 mg/kg will usually suffice. In non-premedicated adultsbelow the age of 60 the dose may be higher (0.3 to 0.35 mg/kg i.v.). If needed to complete induction, increments ofapproximately 25% of the patient's initial dose may be used. Induction may instead be completed with inhalationalanaesthetics. In resistant cases, a total dose of up to 0.6mg/kg may be used for induction, but such larger doses mayprolong recovery.

• Inpremedicated adults over 60 years of age, debilitated or chronically ill patients, the dose should significantly be reduced, eg., down to 0.05- 0.15 mg/kg administered i.v. over 20 -30 seconds and allowing 2 minutes for effect.

•    Non-premedicated adults over 60 years of age usually require more midazolam for induction; an initial dose of 0.15 to0.3 mg/kg is recommended. Non-premedicated patients with severe systemic disease or other debilitation usuallyrequire less midazolam for induction. An initial dose of 0.15 to 0.25 mg/kg will usually suffice.

Sedative component in combined anaesthesia

Adults

Midazolam can be given as a sedative component in combined anaesthesia by either further intermittent small i.v.doses(range between 0.03 and 0.1 mg/kg) or continuous infusion of i.v.midazolam (range between 0.03 and 0.1 mg/kg/hr)typically in combination with analgesics. The dose and the intervals between doses vary according to the patient'sindividual reaction.

In adults over 60 years of age, debilitated or chronically ill patients, lower maintenance doses will be required.

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

Adults

IV loading dose: 0.03 to 0.3 mg/kg should be given slowly in increments.

Each increment of 1 to 2.5 mg should beinjected 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 potentanalgesics, the latter should be administered first so that the sedative effects of midazolam can be safely titrated on topof any sedation caused by the analgesic.

IVmaintenance dose: doses can range from 0.03 to 0.2 mg/kg/h. In hypovolaemic, vasoconstricted, or hypothermicpatients the maintenance dose should be reduced. The level of sedation should be assessed regularly. With long-termsedation, tolerance may develop and the dose may have to be increased.

Neonates and children up to 6 months of age

Midazolamshould begiven as a continuous i.v. infusion, starting at

0. 03mg/kg/h (0.5 micrograms/kg/min)in neonates with agestational age<32 weeks or0.06mg/kg/h (1 micrograms/kg/min)in neonates with agestationalage>32 weeks and children up to 6 months.

Intravenous loading doses is not recommended in premature infants, neonates and children up to 6 months, rather theinfusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusionshould be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possibleeffective dose and reduce the potential for drug accumulation.

Careful monitoring of respiratory rate and oxygen saturation is required. Children over 6 months of age

In intubated and ventilated paediatric patients, a loading dose of 0.05 to 0.2 mg/kg i.v.should be administered slowlyover at least 2 to 3 minutes to establish the desired clinical effect. Midazolam should not be administered as a rapidintravenous dose. The loading dose is followed by a continuous

1. v.infusion at 0.06 to 0.12 mg/kg/h (1 to 2pg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusionrate) as required, or supplemental i.v.doses of midazolam can be administered to increase or maintain the desired effect.

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

In premature infants, neonates and children less than 15 kg of body weight, midazolam solutions with concentrationshigher than 1 mg/ml are not recommended. Higher concentrations should be diluted to 1 mg/ml.

Use in Special Populations

Renal Impairment

In patients with renal impairment (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 a-hydroxymidazolamglucuronide. 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 knownhypersensitivity 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 themonitoring 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 havebeen reported. These have included respiratory depression, apnoea, respiratory arrest and/or cardiac arrest. Such life-threateningincidents are more likely to occur when the injection is given too rapidly or when a high dosage isadministered (see section 4.8).

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

Paediatric patients less than 6 months of age are particularly vulnerable to airway obstruction andhypoventilation, therefore titration with small increments to clinical effect and careful respiratory rateand oxygen saturation monitoringare essential.

When midazolam is used for premedication, adequate observation of the patient after administration is mandatory asinter-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

•    paediatric patients, especially those with cardiovascular instability.

These high-risk patients require lower dosages (see section 4.2) and should becontinuously 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 whenadministering midazolam to a patient with myasthenia gravis.

Tolerance

Some loss of efficacy has been reported when midazolam was used as longterm 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 onmidazolam 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 terminationof 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 andconvulsions. Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it isrecommended to decrease doses gradually.

Amnesia

Midazolam causes anterograde amnesia (frequently this effect is very desirable in situations such as before and duringsurgical and diagnostic procedures), the duration of which is directly related to the administered dose. Prolongedamnesia can present problems in outpatients, who are scheduled for discharge following intervention. After receivingmidazolam parenterally, patients should be discharged from hospital or consulting room only if accompanied by anattendant.

Paradoxical reactions

Paradoxical reactions such as agitation, involuntary movements (including tonic/clonic convulsions and muscletremor), hyperactivity, hostility, rage reaction, aggressiveness, paroxysmal excitement and assault, have been reportedto occur with midazolam.

These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to suchreactions 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 CYP3A4and 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 (seesection 5.2).

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 prolongedrespiratory effects of midazolam.

Adverse haemodynamic events have been reported in paediatric patients with cardiovascular instability; rapidintravenous administration should be avoided in this population.

Paediatric patients less than 6 months

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' above).

•    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'.

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.

It is therefore recommended to carefully monitor the clinical effects and vital signs during the use of midazolam, taking into account that they may be stronger and last longer after co-administration of a CYP3A4 inhibitor, be it given only once. Notably, administrationof 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 andrespiratory depression, thus requiring dose adjustments.

With respect to induction, 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.

Drugs that inhibit CYP3A Azole antifungals

•    Ketoconazole increased the plasma concentrations of intravenous midazolam by 5fold while the terminal half-life increased by about 3-fold. If parenteral midazolam is co-administered with the strong CYP3A 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. The same recommendation may apply also for other azole antifungals (see further), since increased sedative effects of i.v. midazolam, although lesser, are reported.

•    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.

•    It should be kept in mind that if midazolam is given orally, its exposure will drastically be higher than the above-mentioned ones, notably with ketoconazole, itraconazole, voriconazole.

Midazolam ampoules are not indicated for oral administration.

Macrolide antibiotics

•    • 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 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: 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.

HIV Protease inhibitors

•    • Saquinavir

and other HIV 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 coadministered with HIV protease inhibitors, treatment setting should follow the description in the above section for azole antifungals, ketoconazole.

Additional information from oral midazolam

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.

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%.

Additional information from oral midazolam

•    Verapamil / diltiazem increased the plasma concentrations of oral midazolam by 3-and 4-fold, respectively. The terminal- half-life of midazolam was increased by 41% and 49% respectively.

Variousdrugs Herbs

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

Additional 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.

•    Aprepitant dose dependently increased the plasma concentrations of oral midazolam by 3.3-fold after 80 mg/day associated with an increase in terminal half-life by ca. 2-fold.

Drugs that induce CYP3A

• 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%.

Additional 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: 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.

Herbs and food

•    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 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 orsubstitutive treatments), antipsychotics, other benzodiazepines used as anxiolytics or hypnotics, barbiturates, propofol, ketamine, etomidate; sedativeantidepressants, non recent Hl-antihistamines and centrally acting antihypertensive drugs.

Alcohol may markedly enhance the sedative effect of midazolam. Alcohol intake should be strongly avoided in case ofmidazolam administration (see section 4.4).

Midazolamdecreases the minimum alveolar concentration (MAC) of inhalational anaesthetics.

4.6 Fertility, pregnancy and lactation

There are insufficient data available on midazolam to assess its safety during pregnancy. Animal studies do not indicatea teratogenic effect, but foetotoxicity was observed as with other benzodiazepines. No data on exposed pregnancies areavailable 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 aninduction 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 respiratorydepression in the neonate).

Moreover, infants born from mothers who received benzodiazepines chronically during the latter stage of pregnancymay have developed physical dependence and may be at some risk of developing withdrawal symptoms in the postnatalperiod.

Consequently, midazolam may be used during pregnancy if clearly necessary but it is preferable to avoid usingit for caesarean.

The risk for neonate should be taken into account in case of administration of midazolam for any surgery near theterm.

Midazolam passes in low quantities into breast milk. Nursing mothers should be advised to discontinue breast-feedingfor 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.

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 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 fromtheavailable data)

Immune System Disorders
frequency not known	Hypersensitivity, anaphylactic shock
Psychiatric Disorders
frequency not known	Confusional state, euphoric mood, hallucinations Agitation*, hostility*, rage*, aggressiveness*, excitement* Physical drug dependence and withdrawal syndrome
Nervous System Disorders
frequency not known	Involuntary movements (including tonic/clonic movements and muscle tremor)*, 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 have been reported in premature infants and neonates Drug withdrawal convulsions
Cardiac Disorders
frequency not known	Cardiac arrest, bradycardia
Vascular Disorders
frequency not known	Hypotension, vasodilation,

	thrombophlebitis, thrombosis
Respiratory 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	Assault1 2

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 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 drug.

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.ori.v.administrationanterograde amnesia of short duration occurs (the patient does not rememberevents 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 30minutes. The absolute bioavailability after i.m.injection is over 90%.

Absorption after rectal administration

After rectal administration midazolam is absorbed quickly. Maximum plasma concentration is reached in about 30minutes. The absolute bioavailability is about 50%.

Distribution

When midazolam is injected i.v., the plasma concentration-time curve shows one or two distinct phases ofdistribution. The volume of distribution at steady state is 0.7 - 1.2 l/kg. 96 - 98% of midazolam is bound toplasma proteins. The major fraction of plasma protein binding is due to albumin. There is a slow and insignificant passage of midazolam into the cerebrospinalfluid. In humans, midazolam has been shown to cross the placenta slowly and to enter foetal circulation. Smallquantities 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 beenestimated to be 30 - 60%. Midazolam is hydroxylated by the cytochrome P4503A4 isozyme and the major urinaryand plasma metabolite is alpha-hydroxymidazolam. Plasma concentrations of alpha-hydroxymidazolam are 12% ofthose of the parent compound. Alpha-hydroxymidazolam is pharmacologically active, but contributes only minimally (about10%) 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 therange of 300 - 500ml/min. Midazolam is excreted mainly by renal route (60 - 80% of the injected dose) and recoveredas glucuroconjugated alpha-hydroxymidazolam. Less than 1% of the dose is recovered in urine as unchanged drug. Theelimination half-life of alpha-hydroxy-midazolam is shorter than 1 hour. When midazolam is given by i.v.infusion, itselimination 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 rate of rectal absorption in children is similar to that in adults but the bioavailability is lower (5 - 18%).Theelimination half-life after i.v.and rectal administration is shorter in children 3 - 10 years old (1 - 1.5 hours) as comparedwith 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 isreduced (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 approximately50% in the volume of distribution corrected for total body weight. The clearance is not significantly different in obeseand 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 healthyvolunteers (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 (seesection 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.

6.1 List of excipients

Sodium Chloride, Hydrochloric Acid, Sodium Hydroxide, Water for Injections.

6.2 Incompatibilities

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

6.3    Shelf life

Unopened: 36 months Diluted: 24 hours

Chemical and physical in-use stability of the diluted product has been demonstrated for 24 hours at 21°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storagetimes and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2to 8°C, unless reconstitution/dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage

Do not store above 25°C.

Keep the container in the outer carton in order to protect from light.

For storage conditions of the diluted product, refer to section 6.3 and 6.6.

Nature and contents of container

For 1 mL

1    mL clear maroon OPC with two white ring glass ampoule For 2 mL

2    mL clear blue OPC with two red ring glass ampoule For 5 mL

5 mL red snap off green band glass ampoule

1 ml, 2 ml, and 5 ml glass ampoules in packs of 10’s and 20’s. Not all pack sizes may be marketed.

6.6 Special precautions for disposal

Midazolam Injection BP is for single use only.

Discard any unused contents.

The product should be used immediately after opening.

Midazolam Injection BP 2 mg/ml is stable, both physically and chemically, for up to 24 hours at 2°C - 8°C when mixed aseptically with 500 ml infusion fluids containing Dextrose 4 % with Sodium Chloride 0.18 %, Dextrose 5 % or Sodium Chloride 0.9 %. Diluted product should be discarded if not used within 24 hours.

Do not use the product if the solution is discoloured (see 3. Pharmaceutical Form).

7 MARKETING AUTHORISATION HOLDER

Accord Healthcare Limited,

Sage House, 319 Pinner Road,

North Harrow, Middlesex HA1 4HF,

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 20075/0337

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

31/08/2012

10    DATE OF REVISION OF THE TEXT

21/05/2014

1

Such paradoxical drug reactions have been reported, particularly among children and the elderly (see section 4.4).

2

Anterograde amnesia may still be present at the endof the procedure and in few 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 i.v.administration, discontinuation, especially abrupt discontinuation of the product, may be accompanied by withdrawal symptoms including withdrawalconvulsions (see section 4.4).

Severecardiorespiratory adverse events have occurred. Life-threatening incidents are more likely to occur in adults over 60 years of age and those with pre-existing respiratoryinsufficiency or impaired cardiac function, particularly when the injection is given too rapidly or when a high dosage isadministered (see section 4.4).

4.9 Overdose

Symptoms