Midazolam Injection Bp 2mg/Ml

Document: spc-doc_PL 12064-0077 change

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Midazolam Injection BP 2mg/ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Midazolam 100mg/50ml

3 PHARMACEUTICAL FORM

Sterile Solution for Slow Intravenous Infusion

Each vial contains 100mg of Midazolam in 50ml, at a user dilution of 2mg/ml. It is not to be used for multi-dose use.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For sedation by intravenous injection (either continuous infusion or intermittent bolus injection) in critically ill patients in intensive care.

Midazolam may also be used 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. Other presentations of Midazolam may be more suitable for this particular use.

4.2. Posology and Method of Administration

Mode of administration

For the administration of midazolam 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.

Sedation in the critically ill patient.

Midazolam can be given intravenously by two methods for this purpose, either by continuous infusion or by intermittent bolus dose. Both have their own advantages and disadvantages and the appropriate method of giving midazolam will need to be determined for each patient.

The dose of midazolam needed to sedate critically ill patients varies considerably between patients. The dose of midazolam should be titrated to the desired state of sedation. This will depend on clinical need, physical status, age and concomitant medication. If necessary a lower strength of 1mg/ml can be used, which is available at that strength (PL12064/0038,

Aurum Pharmaceuticals Ltd).

Midazolam can also be given in combination with an opioid. The opioid may be used for its analgesic effects or as an antitussive agent to help the patient tolerate the tracheal tube and ventilatory support.

Patients receiving midazolam for sedation in the intensive care situation should receive ventilatory support.

Safety of the use of midazolam for periods of over 14 days in duration has not been established in clinical trials.

Potential drug interactions

The critically ill patient is exposed to many drugs. Because of this, there is a potential for drug interactions. (See also Interactions, Contra-Indications and Special warnings below.)

After prolonged iv administration of midazolam, abrupt discontinuation may be accompanied by withdrawal symptoms, therefore a gradual reduction of midazolam is recommended.

Sedation by intermittent bolus doses in intensive care

The contents of the vial should be transferred to the administration system, eg syringe driver, for administration. Where appropriate, 2 - 7.5mg (i.e. 1 -3.75ml) may be withdrawn to administer the initial bolus doses where indicated. This presentation is not a multidose vial.

Midazolam only.

The exact dose of midazolam needs to be titrated to the individual patient response. Small doses of midazolam 1.0 - 2.0mg (0.5 - 1ml) can be given, and repeated, until the required degree of sedation is reached.

Midazolam and an opioid

When midazolam and an opioid are used together, the opioid should be given first. Both drugs need to be titrated to the individual patient’s response and to the level of sedation thought to be necessary.

The use of these two groups of drugs can increase the risk of respiratory depression. If the patient is being given ventilatory support, using a mode that depends upon some spontaneous effort by the patient, then the minute volume may decrease.

Sedation by continuous infusion in intensive care Midazolam only Adults and children

Loading dose

For patients already sedated or anaesthetised after an operation, a loading dose of midazolam is unnecessary. In other situations a loading dose of 0.03 -0.3mg/kg is recommended, depending on the level of sedation required. This should be given over a five minute period. The loading dose should be reduced or omitted in hypovolaemic, vasoconstricted or hypothermic patients.

Maintenance dose

A dose between 0.03 - 0.2mg/kg/hour is recommended, starting at the lower dose. Use of a syringe driver or other suitable volumetric infusion equipment is required.

The dose should be reduced in hypovolaemic, vasoconstricted or hypothermic patients.

Midazolam and an opioid.

When opioid analgesics are used, the rate of infusion of midazolam should be titrated carefully to the sedative needs of the patient. Low doses of midazolam 0.01 to 0.1mg/kg/hour may be used to start with, using appropriate equipment.

Whenever a continuous infusion of midazolam is used (with or without opioid analgesic), its need should be assessed on a daily basis in order to reduce the risk of accumulation and prolonged recovery. Each day the infusion of midazolam should be stopped or its rate reduced and the patient seen to recover from its effect. If recovery is prolonged (>2 hours) a lower dose should be used when it is restarted. A sedation score should be used routinely.

When midazolam has been given for a number of days and then gradually withdrawn patients may be awake but show signs of residual sedation for the next 12 to 24 hours. This can cause difficulties because patients may not cough and expectorate well if they are then weaned from ventilatory support. However, while recovering from the effects of midazolam, patients may not be sufficiently sedated to tolerate ventilatory support. In such circumstances sedation may be provided with a shorter acting agent while there is recovery from the effects of midazolam.

Intravenous induction of anaesthesia

One or more bolus intravenous injections over a single anaesthetic session.

This presentation should only be used where it is thought likely that several bolus doses would be required for the patient (see Sedation by intermittent bolus doses in intensive care above).

Adults

The dose should be titrated against the individual response of the patient. Midazolam 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 need at least 0.3mg/kg bodyweight, whereas patients premedicated with an opiate usually need only 0.2mg/kg bodyweight.

Use in the elderly

The elderly are more sensitive to the effects of benzodiazepines. Induction may be adequate with 0.1mg/kg bodyweight in premedicated patients and 0.2mg/kg bodyweight in unpremedicated patients.

Children over 7 years

Midazolam has been shown to be an effective agent for induction of anaesthesia in children over 7 years of age, at a dose of 0.15mg/kg bodyweight.

4.3. Contra-indications

Benzodiazepine sensitivity. Myasthenia Gravis.

Severe respiratory insufficiency.

4.4 Special warnings and precautions for use

Midazolam should be given with caution with acute pulmonary insufficiency, impairment of renal or hepatic function, cardiac disease, respiratory disease and to children (particularly with cardiovascular impairment), to the elderly or debilitated patients. Patients with renal impairment are advised to initiate treatment with small doses to avoid increased cerebral sensitivity. In patients with hepatic impairment there can be a significant prolongation of the elimination half-life of midazolam. During bolus sedation for operative procedures, extreme caution should be exercised in patients with acute pulmonary insufficiency or respiratory depression. Disinhibiting effects have been noted, even after a single dose. This possibility should therefore be borne in mind if treating patients with a history of personality disorders.

Midazolam should be used with caution in patients with a history of alcohol and drug abuse.

After prolonged iv administration of midazolam, abrupt discontinuation may be accompanied by withdrawal symptoms. Therefore a gradual reduction of midazolam is recommended.

4.5 Interaction with other medicinal products and other forms of interaction

When midazolam is given along with central nervous system depressants, such as potent analgesics, the sedative effect may be intensified and the possibility of severe respiratory or cardiovascular depression should be considered.

There is an increased risk of prolonged sedation and respiratory depression when midazolam is given with amprenavir. Prolonged sedation may also occur with efavirenz, indinavir or nelfinavir; concomitant use should therefore be avoided. The plasma concentration of midazolam may be increased by ritonavir and there is a risk of extreme sedation and respiratory depression. Again concomitant use should be avoided. An increase in plasma concentration and prolonged sedation may occur when midazolam is given with saquinavir.

There is potentially relevant interaction between midazolam and compounds which inhibit certain hepatic enzymes (particularly cytochrome p450 IIIA). Data clearly indicate that these compounds influence the pharmacokinetics of midazolam and may lead to prolonged sedation. At present this interaction is known to occur with cimetidine, erythromycin, clarithromycin, telithromycin, quinupristin/dalfopristin, diltiazem, verapamil, ketoconazole, and itraconazole and fluconazole. There is also a theoretical possibility that by competitive inhibition of p450 IIIA, midazolam could potentiate the effects of other drugs which are metabolised by this isoenzyme, e.g. cyclosporin, nifedipine. Therefore patients receiving these compounds or others which inhibit p450 IIIA together with midazolam should be monitored carefully for the first few hours after administration of midazolam. (Studies have shown than ranitidine has no influence on the pharmacokinetics of parenterally given midazolam).

Midazolam increases the absorption of lercanidipine.

The sedative effects may be enhanced when Midazolam Injection is used in combination with alcohol. This affects the ability to drive or use machines. Concomitant use with alcohol is therefore not recommended.

4.6. Pregnancy and Lactation

Animal experiments have not indicated any teratogenic risk with midazolam but evaluation in human pregnancy has not been undertaken. Therefore midazolam should not be used during pregnancy unless this is considered essential by the physician. The administration of high single doses of benzodiazepines in the last trimester of pregnancy has been reported to produce irregularities in the foetal heart rate, and hypotonia, poor sucking and hypothermia in the neonate. Midazolam should not therefore be used during the last trimester.

Midazolam may pass into breast milk and caution should be exercised with its use in lactating mothers.

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

Changes in cardiovascular parameters are slight, but can include a decrease in mean arterial pressure, cardiac output, stroke volume and systemic vascular resistance. Such changes may be important in patients with impaired myocardial oxygen delivery capacity and hypovolaemia. Following intravenous administration of midazolam, laryngospasm, bronchospasm, respiratory depression and respiratory (or cardiac) arrest have occurred. These life-threatening incidents may occur especially in elderly patients or patients with pre-existing respiratory insufficiency, particularly if excessive or too rapidly injected doses are administered.

Other side effects include gastro-intestinal disturbances, increased appetite, jaundice, anaphylaxis, thrombosis, drowsiness, confusion, ataxia, euphoria, fatigue, vertigo and involuntary movements.

Paradoxical reactions, e.g. agitation, restlessness, disorientation, excitement and aggression have been reported (especially in children and the elderly), although this is rare.

Hallucinations, some of a sexual nature, have been reported.

Midazolam may cause dysarthria, urinary retention, incontinence, changes in libido, blood disorders, muscle weakness, headache, dizziness, hiccoughs, visual disturbances, salivation changes and skin reactions. Anterograde amnesia frequently accompanies the period of peak sedation. Local effects on veins are infrequent, however pain on injection and thrombophlebitis may occur.

4.9. Overdose

The symptoms of overdosage are mainly an intensification of the therapeutic effects (sedation, muscle weakness, profound sleep) or paradoxical excitation. Extreme overdosage may lead to coma, areflexia, cardiopulmonary depression and apnoea requiring appropriate counter measures (ventilation, cardiovascular support). Flumazenil is a specific iv antidote for use in emergency situations. Patients requiring such intervention should be monitored closely in hospital (see separate prescribing information).

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Midazolam is a potent imidazobenzodiazepine, forming water-soluble salts which are stable and well tolerated by injection. Midazolam possesses the typical pharmacological properties of the benzodiazepines, namely hypnotic, anxiolytic, muscle-relaxant and anticonvulsant activity. In clinical use the induction of sleep is the main action.

5.2. Pharmacokinetic Properties

At sedative and anaesthetic doses, given intravenously, the action is rapid in onset and of short duration. Anterograde amnesia frequently accompanies the period of peak sedation.

Midazolam is principally cleared by hepatic enzymes (particularly cytochrome p450 IIIA), with a mean elimination half-life of about 2 hours, but this may be prolonged in critically ill patients.

The ‘second peak’ effect, which is known to occur following intravenous diazepam, has not been observed with midazolam.

The metabolites of midazolam do not contribute significantly to the clinical effects of the drug.

5.3. Preclinical Safety Data

There are no pre-clinical safety data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Dilute Hydrochloric Acid Sodium Chloride Sodium Hydroxide Water for Injections

6.2. Incompatibilities

Midazolam is incompatible with certain parenteral solutions, causing precipitation. A white precipitate forms immediately on mixing dimenhydrinate, pentobarbital sodium, perphenazine, prochlorperazine edisylate or ranitidine. Y-site injection of midazolam with Foscarnet Sodium causes gas production; with Methotrexate Sodium a yellow precipitate is produced; with Sodium Bicarbonate, and with Thiopental Sodium, a white precipitate forms immediately.

The absence of any stated incompatibility does not mean that the mixing with other drugs is recommended.

There is no evidence of adsorption of midazolam to plastic administration equipment except to PVC after 24 hours.

6.3. Shelf Life

36 months

6.4. Special Precautions for Storage

Do not store above 25°C.

Keep in the outer container and protect from light. See also Incompatibilities above.

6.5. Nature and Contents of Container

50ml clear type 1 glass vial containing 50ml of sterile midazolam (as the hydrochloride) solution for injection 1mg or 2mg/1ml, with halobutyl rubber stopper and aluminium crimp seal.

6.6. Instruction for Use/Handling

Use once only and discard container and any remaining solution in appropriate manner.

Each vial contains 100mg of Midazolam in 50ml, at a user dilution of 2mg/ml. It is not to be used for multi-dose use.

7. MARKETING AUTHORISATION HOLDER

Aurum Pharmaceuticals Ltd

Bampton Road

Harold Hill

Romford

Essex RM3 8UG

United Kingdom

8. MARKETING AUTHORISATION NUMBER(S)

PL 12064/0077

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/02/2007

10 DATE OF REVISION OF THE TEXT

31/03/2014