Special Warning : אזהרת שימוש

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 cardio-respiratory 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).

Benzodiazepines are not recommended for the primary treatment of psychotic illness.
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 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
- patients with impaired hepatic function (benzodiazepines may precipitate or exacerbate encephalopathy in patients with severe hepatic impairment)
- patients 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 ICU.

Dependence
When midazolam is used in long-term sedation in ICU, it should be borne in mind that physical dependence on midazolam may develop. The risk of dependence increases with dose and duration of treatment; it is also greater in patients with a medical history of alcohol and/or drug abuse (see section 4.8).

Withdrawal symptoms
During prolonged treatment with midazolam in ICU, physical dependence may develop.
Therefore, abrupt termination of the treatment will be accompanied by withdrawal symptoms.
The following symptoms may occur: headaches, diarrhoea, muscle pain, extreme anxiety, tension, restlessness, confusion, irritability, sleep disturbances, mood changes, hallucinations and convulsions. In severe cases, the following symptoms may occur: depersonalisation, numbness and tingling of the extremities, hypersensitivity to light, noise and physical contact.
Since the risk of withdrawal symptoms is greater after abrupt discontinuation of treatment, it is recommended to decrease doses gradually.

Amnesia
Anterograde amnesia may occur with therapeutic doses (frequently this effect is very desirable in situations such as before and during surgical and diagnostic procedures) the duration of which is directly related to the administered dose, with the risk increasing at higher dosages.
Prolonged amnesia can present problems in outpatients,who are scheduled for discharge following intervention. After receiving midazolam parenterally, patients should be discharged from hospital or consulting room only if accompanied by an attendant.

Paradoxical reactions
Paradoxical reactions such as restlessness, agitation, irritability, involuntary movements (including tonic/clonic convulsions and muscle tremor), hyperactivity, hostility, delusion, anger, aggressiveness, anxiety, nightmares, hallucinations, psychoses, inappropriate behaviour and other adverse behavioural effects, paroxysmal excitement and assault, have been reported to occur with midazolam. These reactions may occur with high doses and/or when the injection is given rapidly. The highest incidence to such reactions has been reported among children and the elderly. In the event of these reactions discontinuation of the drug should be considered.

Altered elimination of midazolam
Midazolam elimination may be altered in patients receiving compounds that inhibit or induce CYP3A4 and the dose of midazolam may need to be adjusted accordingly (see section 4.5).
Midazolam elimination may also be delayed in patients with liver dysfunction, low cardiac output and in neonates (see section 5.2).

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

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 and neonates’ above).

Concomitant use of alcohol / CNS depressants
The concomitant use of midazolam with alcohol and/or CNS depressants should be avoided.
Such concomitant use has the potential to increase the clinical effects of midazolam possibly including severe sedation that could result in coma or death, or clinically relevant respiratory depression (see section 4.5).

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

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

Excipients

Midazolam Kalceks 1 mg/ml
In daily dose up to 6.5 ml this medicinal product contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’. If daily dose 6.6 ml or more is administered (equivalent to more than 1 mmol sodium) the following should be taken into account: This medicinal product contains 3.5 mg sodium per ml of solution, equivalent to 0.18 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.
Midazolam Kalceks 5 mg/ml

In daily dose up to 7.3 ml this medicinal product contains less than 1 mmol sodium (23 mg), that is to say essentially ‘sodium-free’. If daily dose 7.4 ml or more is administered (equivalent to more than 1 mmol sodium) the following should be taken into account: This medicinal product contains 3.15 mg sodium per ml of solution, equivalent to 0.16 % of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7   Effects on ability to drive and use machines

Midazolam has a major influence on the ability to drive and use machines.
Sedation, amnesia, impaired attention and impaired muscular function may adversely affect the ability to drive or use machines. Prior to receiving midazolam, the patient should be warned not to drive a vehicle or operate a machine until completely recovered. The physician should decide when these activities may be resumed. It is recommended that the patient is accompanied when returning home after discharge.
If insufficient sleep occurs or alcohol is consumed, the likelihood of impaired alertness may be increased (see section 4.5).
This medicine can impair cognitive function and can affect a patient's ability to drive safely.
When prescribing this medicine, patients should be told:
•      The medicine is likely to affect your ability to drive
•      Do not drive until you know how the medicine affects you