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

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

Each 5 ml ampoule contains 5mg midazolam.

3. Pharmaceutical Form

Solution for injection.

Clear colourless or slightly yellow sterile solution.

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.

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.

As a sedative in intensive care units.

4.2 Posology and method of administration

Posology

Intravenous sedation: One or more intravenous administrations over a single operating session. Severe cardio respiratory events have been reported and are most likely to occur when injection is given too rapidly or when too high dose is used(see section 4.4 and 4.8).

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.

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 2ml of Midazolam 1mg/1ml solution (equivalent to 2mg midazolam) be administered intravenously over 30 seconds. If after 2 minutes, sedation is not adequate, incremental doses of 0.5ml to 1ml of midazolam 1mg/1ml 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 (1.0 -2ML) MAY BE ADEQUATE. THE INITIAL DOSE SHOULD NOT EXCEED 1 -1.5MG (1 - 1.5ML).

Paediatric population:

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 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 i.v. 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 i.v. doses of midazolam can be administered to increase or maintain the desired effect.

Neonates and children up to 6 months of age

Midazolam should be given as a continuous i.v. infusion, starting at 0.03 mg/kg/h (0.5 qg/kg/min) in neonates with a gestational age <32 weeks or 0.06 mg/kg/h (1 qg/kg/min) in neonates with a gestational age >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 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.

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

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.

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 (1.0- 2.0ml) may be adequate. In the elderly, smaller doses as little as 0.5 -1mg (0.5 - 1.0ml) 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 0.15 mg/kg body-weight.

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, acute respiratory depression or unstable myasthenia gravis

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 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' 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

- 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.

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 (see section 5.2)

Preterm infants and neonates

Due to an increased risk of apnoea, extreme caution is advised when sedating pre-term and former pre-term 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'

4.5 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.

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.

Inhibition

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

• After prolonged dosing of midazolam, both the magnitude and duration of effect will be increased (increased plasma concentrations: increased sedation).

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

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

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 IM administration the effects of CYP3A4 modulation should not substantially differ from those seen with IV midazolam.

Notably, administration of high doses or long-term infusions of midazolam to patients receiving strong CYP3A4 inhibitors, e.g. during intensive care, may result in long-lasting hypnotic effects, delayed recovery and respiratory depression, thus requiring dose adjustments.

Contrary to a treatment of several days with an inducer, a short term-treatment is expected to result in less apparent DDI with midazolam.

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

Drugs that inhibit CYP3A4 Azole antifungals

If parenteral midazolam is coadministered it should be done in an intensive care unit (ICU) or similar setting with 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 i.v 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 i.v. 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 of i.v midazolam by 3-fold whereas its elimination half-life increased by about 3-fold.

• Fluconazole and itraconazole both increased the plasma concentrations of i.v. 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 i.v. 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-mentionned ones, notably with ketoconazole, itraconazole, voriconazole.

Midazolam ampoules are not indicated for oral administration.

Macrolide antibiotics • Erythromycin increases the plasma concentrations of i.v. midazolam by about

1.6 - 2-fold associated with an increase in terminal half-life of midazolam of 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.