Midazolam 1mg/Ml Solution For Injection

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SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Midazolam 1mg/ml, solution for injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

1ml Midazolam 1mg/ml contains:

Midazolam hydrochloride 1.11mg equivalent to 1mg Midazolam

Each 2ml, 5ml and 10ml ampoule contains 2mg, 5mg and 10mg midazolam.

Each 50 ml vial contains 50 mg midazolam.

Excipient with known effect:

Midazolam 1mg/ml contains 3.47mg sodium per ml.

This should be taken into consideration for patients on a controlled sodium diet.

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Solution for injection/infusion or rectal solution The medicinal product is a clear and colourless solution. pH 2.9 - 3.7

Osmolality 275 - 305mOsmol/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Midazolam Injection is a short-acting sleep-inducing drug that is indicated:

In adults

• CONSCIOUS SEDATION before and during diagnostic or therapeutic procedures with or without local anaesthesia

• ANAESTHESIA

- Premedication before induction of anaesthesia

- Induction of anaesthesia:

- As a sedative component in combined anaesthesia.

• SEDATION IN INTENSIVE CARE UNITS In children

• CONSCIOUS SEDATION before and during diagnostic or therapeutic procedures with or without local anaesthesia

• ANAESTHESIA

- Premedication before induction of anaesthesia

• SEDATION IN INTENSIVE CARE UNITS

4.2 Posology and method of administration

Posology

STANDARD DOSAGE

Midazolam is a potent sedative agent 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 and paediatric patients, dose should be determined with caution and risk factors related to each patient should be taken into account. Standard dosages are provided in the table below. Additional details are provided in the text following the table.

Indication

Adults <60 years

Adults > 60 years / debilitated or chronically ill

Children

Conscious

sedation

Initial dose: 2-2.5mg Titration doses: 1mg Total dose : 3.5-7.5mg

Initial dose : 0.51mg

Titration doses :

0.5

1mg

Total dose : <3.5mg

IV in patients 6 months-5 years

Initial dose: 0.05-

0.1mg/kg

Total dose: <6mg

IV in patients 6-12 years

Initial dose: 0.025-0.05mg/kg Total dose: <10mg

rectal >6 months

0.3-0.5mg/kg IM 1-15 years

0.05-0.15mg/kg

Anaesthesia

premedication

1-2mg repeated IM

0.07-0.1mg/kg

Initial dose: 0.5mg Slow uptitration as needed IM

0.025-0.05mg/kg

rectal >6 months

0.3-0.5mg/kg IM 1-15 years

0.08-0.2mg/kg

Anaesthesia

induction

0.15-0.2mg/kg (0.3-0.35 without premedication)

0.05-0.15 mg/kg (0.15-0.3 without premedication)

Sedative component in combined anaesthesia

intermittent doses of 0.03-0.1mg/kg or continuous infusion of 0.03-0.1mg/kg/h

lower doses than recommended for adults <60 years

Sedation in ICU

Loading dose: 0.03-0.3mg/kg in increments of 1-2.5mg

Maintenance dose: 0.03-0.2mg/kg/h

IV in neonates <32 weeks

gestational age 0.03mg/kg/h IV in neonates >32 weeks and children up to 6 months 0.06mg/kg/h IV in patients >6 months of age

Loading dose: 0.05-0.2mg/kg

Maintenance dose: 0.06-0.12mg/kg/h

Method of administration

CONSCIOUS SEDATION DOSAGE

For conscious sedation prior to diagnostic or surgical intervention, midazolam is administered IV The dose must be 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 the individual 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 below the age of 60 the initial dose is 2 to 2.5mg given 5 to 10 minutes before the beginning of the procedure. Further doses of 1mg may be given as necessary. Mean total doses have been found to range from 3.5 to 7.5mg. A total dose greater than 5mg is usually not necessary. In adults over 60 years of age, debilitated or chronically ill patients, the initial dose must be reduced to 0.5-1.0mg and given 5-10 minutes before the beginning of the procedure. Further doses of 0.5 to 1mg 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 3.5mg is usually not necessary.

Paediatric population

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

• Paediatric patients less than 6 months of age: paediatric patients less than 6 month of age are particularly vulnerable to airway obstruction and hypoventilation. For this 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 0.1mg/kg. A total dose up to 0.6mg/kg may be necessary to reach the desired endpoint, but the total dose should not exceed 6mg. Prolonged sedation and risk of hypoventilation may be associated with the higher doses.

• Paediatric patients 6 to 12 years of age: initial dose 0.025 to 0.05mg/kg. A total dose of up to 0.4mg/kg to a maximum of 10mg may be necessary. Prolonged sedation and risk of hypoventilation may be associated with the higher 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 0.5mg/kg. Rectal administration of the ampoule/vial solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10ml. Total dose should be administered at once 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.

IM administration: the doses used range between 0.05 and 0.15mg/kg. A total dose greater than 10.0mg is usually not necessary. This route should only be used in exceptional cases. Rectal administration should be preferred as IM injection is painful.

In children less than 15kg of body weight, midazolam solutions with concentrations higher than 1mg/ml are not recommended. 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 relief of apprehension) and preoperative impairment of memory. Midazolam can also be administered in combination with anticholinergics. For this indication midazolam should be administered IV or IM, deep into a large muscle mass 20 to 60 minutes before induction of anaesthesia), or preferably via the rectal route in children (see below). Close and continuous monitoring of the patients after administration of premedication is mandatory as interindividual sensitivity varies and symptoms of overdose may occur.

Adults

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

Paediatric population

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 0.5mg/kg should be administered 15 to 30 minutes before induction of anaesthesia. Rectal administration of the ampoule solution is performed by means of a plastic applicator fixed on the end of the syringe. If the volume to be administered is too small, water may be added up to a total volume of 10ml.

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

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

INDUCTION

Adults

If midazolam is used for induction of anaesthesia before other anaesthetic

agents have been administered, the individual response is variable. The dose should be titrated to the desired effect according to the patient's age and clinical status. When midazolam is used before or in combination with other IV or inhalation agents for induction of anaesthesia, 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 reached by stepwise titration. The IV induction dose of midazolam should be given slowly in increments. Each increment of not more than 5mg should be injected over 20 to 30 seconds allowing 2 minutes between successive increments.

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

• In premedicated adults over 60 years of age, debilitated or chronically ill patients, the dose should be significantly reduced, e.g., down to 0.05-0.15mg/kg administered IV 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 to 0.3mg/kg is recommended. Non-premedicated patients with severe systemic disease or other debilitation usually require less midazolam for induction. An initial dose of 0.15 to 0.25mg/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 IV doses (range between 0.03 and 0.1mg/kg) or continuous infusion of IV midazolam (range between 0.03 and 0.1mg/kg/h) typically in combination with analgesics. The dose and the intervals between doses vary according to the patient's individual reaction.

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

SEDATION IN INTENSIVE CARE UNITS

The desired level of sedation is reached by stepwise titration of midazolam followed by either continuous infusion or intermittent 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 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.

IV 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.

Paediatric population

Neonates and children up to 6 months of age:

Midazolam should be given as a continuous IV infusion, starting at 0.03 mg/kg/h (0.5 pg/kg/min) in neonates with a gestational age <32 weeks, or 0.06 mg/kg/h (1 pg/kg/min) in neonates with a gestational age >32 weeks and children up to 6 months.

Intravenous loading doses are not recommended in premature infants, neonates and children up to 6 months, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels. The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective 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 IV should be administered slowly over at least 2 to 3 minutes to establish the desired clinical effect. Midazolam should not be administered as a rapid intravenous dose. The loading dose is followed by a continuous IV infusion at 0.06 to 0.12 mg/kg/h (1 to 2 pg/kg/min). The rate of infusion can be increased or decreased (generally by 25% of the initial or subsequent infusion rate) as required or supplemental IV 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 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.

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

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 (shown after prolonged infusion in intensive care unit (ICU) patients) 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 30ml/min) receiving midazolam for induction of anaesthesia.

Hepatic Impairment

Hepatic impairment reduces the clearance of IV 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

Hypersensitivity to benzodiazepines or to any of the excipients listed in section 6.1.

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

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.

When midazolam is used for premedication, adequate observation of the patient after administration is mandatory as interindividual 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 be continuously monitored for early signs of alterations of vital functions.

Benzodiazepines should be used with caution in patients with a history of alcohol or drug abuse.

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 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 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 the 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 have 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 (see section 5.2).

Paediatric population

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.

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.

Criteria for discharge:

After receiving midazolam, patients should be discharged from the hospital or consulting room only when recommended by the treating physician and only if accompanied by an attendant. It is recommended that the patient is accompanied when returning home after discharge.

Midazolam 1mg/ml contains 3.47mg sodium per ml.

Midazolam 2mg/ml contains 3.39mg sodium per ml.

Midazolam 5mg/ml contains 3.16mg sodium per ml.

This should be taken into consideration for patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Pharmacokinetic Interactions

Midazolam is metabolized by CYP3A4. Inhibitors and inducers of CYP3A have the potential to respectively increase and decrease the plasma concentrations and, subsequently, the effects of midazolam requiring dose adjustments accordingly. Pharmacokinetic interactions with CYP3A4 inhibitors or inducers are more pronounced for oral than for IV midazolam, as CYP3A4 is also present in the upper gastro-intestinal tract. For the oral route both systemic clearance and availability will be altered while for the parenteral route only the change in the systemic clearance is affected. After a single dose of IV midazolam, the impact 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 of 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 IM administration the effects of CYP3A4 modulation should not substantially differ from those seen with IV midazolam.

It is therefore recommended to carefully monitor 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, even if given only once. Notably, administration of high doses or long-term infusions of midazolam to patients receiving potent CYP3A4 inhibitors, e.g. during intensive care, may result in long-lasting hypnotic effects, delayed recovery and respiratory 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. Short term treatment with an inducer (unlike treatment of several days with an inducer) is expected to result in less apparent DDI with midazolam. However, for strong potent inducers a relevant induction even after short-term treatment cannot be excluded.

Midazolam is not known to alter the pharmacokinetics of other drugs.

Drugs that inhibit CYP3A

Azole antifungals

• Ketoconazole increased the plasma concentrations of intravenous midazolam by 5-fold 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 IV dose of midazolam is administered. The same recommendation may apply also for other azole antifungals (see further), since increased sedative effects of IV midazolam, although lesser, are reported.

• Voriconazole increased the exposure (plasma concentration) 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 be significantly higher than discussed above, notably with ketoconazole, itraconazole and voriconazole.

Midazolam ampoules/vials 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.