SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Midazolam 2mg/mlSolution for Injection or Infusion

2.    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Midazolam 2mg/ml

Each 5m1 ampoule contains 10mg midazolam.

3.    PHARMACEUTICAL FORM

Solution for injection or infusion (injection)

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Midazolam may be used as an intravenous sedative before and during minor medical, dental and surgical procedures.

As an intravenous sedative, (either by continuous infusion or intermittent bolus injection) in critically ill patients in intensive care.

As an alternative intravenous agent for the induction of anaesthesia in high risk and elderly patients where cardiovascular stability is of particular importance. Induction is more reliable when heavy opiate medication has been administered or when midazolam injection is given with a narcotic analgesic such as fentanyl.

4.2    Posology and method of administration

Dosage depends on the individual response, age and weight. Midazolam 2mg/ml may be given by intravenous or slow intravenous injection.

Intravenous sedation

One or more intravenous injections to be administered over a single operating session.

Dosage should be titrated according to an individual’s response, age and weight. The end-point of this titration is dependent on the procedure. Full sedation will be evident by drowsiness and slurred speech, although a response to commands will be maintained.

Adults    2mg, (1ml of 2mg/ml midazolam injection solution) over a

period of 30 seconds initially

Elderly    1 to 1.5mg (0.5 -0 .75m1 of 2mg/ml midazolam injection

solution) over a period of 30 seconds initially.

If adequate sedation is not achieved after two minutes, incremental doses of 0.5-1mg, (0.25-0.5m1 of 2mg/ml midazolam injection solution) should be given until the desired level of sedation is achieved, usually at a total dose of 2.5-7.5mg (about 70 micrograms/kg) in adults.

Renal/hepatic impairment: Reduce dose.

Children Not recommended. Midazolam injection has not been evaluated as an intravenous sedative in children.

Combination therapy:-

If analgesia is provided by a narcotic analgesic, the analgesic should be administered first. The dose of midazolam injection should then be carefully titrated. Low total doses of 1-2mg may be adequate with lower total doses of 0.5-1mg in the elderly.

Mode 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, always be present. It is recommended that patients should remain under medical supervision until at least one hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult.

Patients who have received only midazolam injection for iv sedation prior to minor procedures, should be warned not to drive or operate machinery for 12 hours. Where midazolam injection 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.

Sedation in the critically ill patient:-

Midazolam injection 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 injection will need to be determined for each patient.

The dose of midazolam injection needed to sedate critically ill patients varies considerably between patients. The dose should be titrated to the desired state of sedation. This will depend on clinical need, physical status, age and concomitant medication.

Midazolam injection 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 injection for sedation in the intensive care situation should receive ventilatory support.

Safe use for 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. (Refer to Section 4.5 Interactions with other medicaments and other forms of interaction).

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

Sedation by intermittent bolus dose in intensive care

Midazolam injection only

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

Midazolam injection and an opioid

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

Small doses of midazolam 1-2mg (0.5-1 .0ml of 2mg/ml midazolam injection solution) can be given, and repeated, until the required degree of sedation is reached. In the elderly, smaller doses as little as 0.5-1.0mg (0.25-0.5m1 of 2mg/ml midazolam injection solution) may be adequate.

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 injection only Adults, Elderly and children

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 given over a five minute period is recommended, depending on the level of sedation required. The loading dose should be reduced or omitted in hypovolaemic, vasoconstricted or hypothermic patients, renal or hepatic impairment.

Maintenance dose

A dose between 0.03-0.2mg/kg/hour is recommended, starting at the lower dose.

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

Midazolam injection 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.

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.

Whenever a continuous infusion of midazolam is used (with or without an 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.

The recommended concentration of a solution for infusion in a critically ill adult patient is 1mg/ml.

Induction of anaesthesia by slow intravenous injection

One or more bolus intravenous injections should be administered 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 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 0.1 mg/kg body weight in premedicated patients and 0.2mg/kg body weight in unpremedicated patients.

Renal/hepatic impairment: Reduce dose.

Children over seven years

Midazolam injection has been shown to be an effective agent for induction of anaesthesia in children over seven years of age, at a dose of 0.15mg/kg body-weight.

Mode 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, always be present. It is recommended that patients should remain under medical supervision until at least one hour has elapsed from the time of injection. They should always be accompanied home by a responsible adult.

4.3 Contra-indications

Known hypersensitivity to benzodiazepines or any of the ingredients.

Severe or acute respiratory insufficiency/depression.

Severe hepatic insufficiency.

4.4 Special warnings and precautions for use

Midazolam injection should be used with caution in patients with renal or hepatic dysfunction (see 4.2 Posology and Method of Administration), chronic pulmonary insufficiency, myasthenia gravis, coma, or a known history of drug or alcohol abuse.

Midazolam may enhance the effects of other CNS depressants and may result in severe respiratory or cardiovascular depression. Their concurrent use should be avoided. Elderly or debilitated patients are more prone to the CNS effects of benzodiazepines and, therefore, lower doses are required (see 4.2 Posology and Method of Administration).

Dependence and withdrawal symptoms

The dependence potential of midazolam increases with dose and duration of treatment and is greater in patients with a history of alcohol or drug abuse. It is low when limited to short term use. Due to the possibility of withdrawal symptoms, midazolam should be gradually reduced following a prolonged iv administration, abrupt discontinuation should be avoided. Withdrawal symptoms may occur with benzodiazepines following normal use of therapeutic doses for only short periods and may be associated with physiological and psychological sequelae (see Section 4.8 Undesirable effects). This should be considered when treating patients for more than a few days.

As with other benzodiazepines, extreme caution should be used if prescribing midazolam for patients with personality disorders. The disinhibiting effects of benzodiazepines may be manifested as the precipitation of suicide in patients who are depressed or show aggressive behaviour towards self and others.

This medicinal product contains 0.15mmol sodium per ampoule. To be taken into consideration by patients on a controlled sodium diet.

4.5 Interaction with other medicinal products and other forms of interaction

Alcohol: Alcohol should be avoided for at least eight hours before and after the administration of midazolam due to increased sedative effects.

Anaesthetics and narcotic analgesics: Enhanced sedation or respiratory and cardiovascular depression. If such centrally acting depressant drugs are given parenterally in conjunction with intravenous midazolam, severe respiratory and cardiovascular depression may occur; careful monitoring is required.

When intravenous midazolam is to be administered concurrently with a narcotic analgesic agent (e.g. fentanyl), it is recommended that midazolam be given after the analgesic and that the dose be carefully titrated to meet the patient’s needs. Fentanyl may reduce midazolam clearance.

Antibacterials: Agents that interfere with metabolism by hepatic enzymes (e.g. isoniazid, erythromycin, clarithromycin, quinupristin/dalfopristin) have been shown to reduce the clearance of benzodiazepines and may potentiate their actions, whilst known inducers of hepatic enzymes, for example, rifampicin, may increase the clearance of benzodiazepines.

Antidepressants: Enhanced sedation or respiratory and cardiovascular depression.

Midazolam plasma levels increased by concomitant nefazodone.

Antiepileptics: Enhanced sedation or respiratory or cardiovascular depression. Midazolam may interact with other hepatically metabolised drugs. E.g. phenytoin, causing potentiation.

Antifungals: Ketoconazole, nitraconazole, and possibly fluconazole, have been shown to reduce the clearance of benzodiazepines and may potentiate their actions.

Antihistamines: Enhanced sedation or respiratory and cardiovascular depression with sedative antihistamines.

Antihypertensives: Enhanced hypotensive effect. Enhanced sedative effect possible with moxonidine.

Antipsychotics: Enhanced sedation or respiratory and cardiovascular depression. Severe hypotension, collapse, respiratory depression, potentially fatal respiratory arrest and unconsciousness have been reported in a few patients on benzodiazepines and clozapine. Caution is advised when initiating clozapine therapy in patients taking benzodiazepines.

Antivirals: Concomitant use of midazolam with HIV-protease inhibitors (e.g. amprenavir, ritonavir) should be avoided due to the risk of extreme sedation and respiratory depression.

Anxiolytics and hypnotics: Enhanced sedation or respiratory and cardiovascular depression with other anxiolytics and hypnotics.

Calcium-channel blockers: Diltiazem and verapamil have been shown to reduce the clearance of benzodiazepines and may potentiate their actions.

Dopaminergic agents: Midazolam may cause inhibition of levodopa.

Disulfiram: Has been shown to reduce clearance of benzodiazepines and may potentiate their actions.

Muscle relaxants: e.g baclofen - Midazolam may cause potentiation, with increased CNS depressant effects.

Nabilone: Enhanced sedation or respiratory and cardiovascular depression.

Nicotine: Benzodiazepine metabolism is accelerated by smoking.

Non-steroidal anti-inflammatory drugs: The induction of anaesthesia with midazolam is more rapid in patients pre-treated with aspirin.

Probenecid: May reduce midazolam clearance.

Sedatives: Enhanced sedation or respiratory and cardiovascular depression.

Ulcer-healing drugs: Cimetidine, ranitidine and omeprazole have been shown to reduce the clearance of benzodiazepines and may potentiate their actions.

Xanthines: Benzodiazepine metabolism is accelerated by xanthines.

4.6 Pregnancy and lactation

There is no evidence regarding the safety of midazolam in pregnancy. It should not be used, especially in the first and third trimesters, unless the benefit is considered to outweigh the risk.

If the product is prescribed to a woman of childbearing potential she should be warned to contact her physician regarding discontinuance of the product if she intends to become or suspects that she is pregnant.

There may be a small increase in the risk of congenital malformation, particularly oral cleft, with the use of benzodiazepines in the first trimester. In labour, high single doses or repeated low doses have been reported to produce effects on the neonate, such as hypothermia, hypotonia, moderate respiratory depression, irregularities in the foetal heart rate, and poor suckling in the neonate (floppy infant syndrome).

Infants born to mothers who take benzodiazepines chronically during the latter stages of pregnancy may develop physical dependence and may be at some risk for developing withdrawal symptoms in the postnatal period.

A small number of children exposed in utero to benzodiazepines have shown slow development in the early years but by four years of age have developed normally.

Since benzodiazepines are found in the breast milk, benzodiazepines should not be given to breast-feeding mothers.

4.7    Effects on ability to drive and use machines

The concurrent use of midazolam with other central nervous system depressants, may result in a prolonged recovery. A careful assessment should be undertaken prior to allowing the patient to go home or resume normal activities.

Patients treated with midazolam injection should not drive or use machinery for twelve hours after receiving this medicine.

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 of 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

Side-effects are usually mild.

Cardiovascular: Midazolam may cause bradycardia, chest pain and decreases in cardiac output, stroke volume and systemic vascular resistance. These effects are important in those patients with a reduced myocardial oxygen delivery capacity or suffering hypovolaemia. Also, hypotension, particularly with high dosage, and cardiac arrest. Local thrombophlebitis may occur.

CNS: Elderly or debilitated patients are particularly susceptible to the CNS side effects of benzodiazepines. It is recommended that dosage be limited to the smallest effective dose and increased gradually, if necessary, to decrease the possibility of development of ataxia, dizziness and oversedation, which may lead to falls and other accidents (see 4.2 Posology and method of administration).

Disorders of the eye: Visual disturbances.

Gastrointestinal: dry mouth, gastrointestinal disturbances.

General: Fatigue and a hangover effect. Local pain on injection. Hiccups. Haematological: Blood dyscrasias.

Hepatic: Jaundice.

Immunological: Skin reactions and other hypersensitivity reactions, including anaphylaxis, are rare.

Neurological: Headaches, confusion, slurred speech, tremor, drowsiness, reduced alertness, anterograde amnesia, extrapyramidal effects.

Psychiatric: Increased risk of postoperative delirium. Numbed emotions. In susceptible patients, an unnoticed depression may become evident. Paradoxical reactions (including aggressive behaviour, hostility, hallucinations, disinhibition, excitation, irritability and increased anxiety) are known to occur with benzodiazepines and are more likely in children and the elderly.

Reproductive: Changes in libido.

Respiratory: Midazolam can produce respiratory depression, apnoea and may cause respiratory arrest following iv administration, especially in the elderly with pre-existing respiratory insufficiency or when the dose is excessive or administered too rapidly.

Urinary: urinary retention, incontinence.

Withdrawal symptoms:

Development of dependence is common after regular use, even in therapeutic doses for short periods, particularly in patients with a history of drug or alcohol abuse or marked personality disorders. Discontinuation may be associated with withdrawal symptoms or rebound phenomena (see 4.4 Special Warnings and Precautions for Use). Symptoms of benzodiazepine withdrawal include anxiety, depression, impaired concentration, insomnia, headache, dizziness, tinnitus, loss of appetite, tremor, perspiration, irritability, perceptual disturbances such as hypersensitivity to physical, visual, and auditory stimuli and abnormal taste, nausea, vomiting, abdominal cramps, palpitations, mild systolic hypertension, tachycardia, and orthostatic hypotension, Rare and more serious withdrawal symptoms include muscle twitching, confusional or paranoid psychosis, convulsions, hallucinations, and a state resembling delirium tremens. Broken sleep with vivid dreams and increased REM sleep may persist for some weeks after withdrawal of benzodiazepines.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9 Overdose

a) Symptoms

The symptoms of mild overdose may include confusion, impairment of consciousness with somnolence or a sleep-like state, little or no

respiratory depression, ataxia, dysarthria, hypotension and muscular weakness. Cardiac rate and rhythm remain normal in the absence of anoxia or severe hypotension.

In severe overdose, deep coma, or other manifestations of severe depression of brainstem vital functions, particularly the respiratory centre may occur.

As drug levels fall, severe agitation, insomnia and, possibly, major convulsions may develop.

b) Treatment

Treatment is symptomatic. Respiration, heart rate, blood pressure and body temperature should be monitored and supportive measures taken to maintain cardiovascular function. Ventilation should be used to support respiratory function if appropriate.

Flumazenil is a specific antidote for use in midazolam overdosage but expert advice is essential since adverse effects may occur (e.g. convulsions in patients dependent on benzodiazepines).

5.    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Midazolam is a soluble benzodiazepine with marked properties of suppression of tension, agitation and anxiety as well as sedative and hypnotic effects. In addition, midazolam demonstrates muscle relaxant and anticonvulsive properties. In clinical use, the main action is sleep induction.

Midazolam binds to specific receptors in the central nervous system (CNS). The benzodiazepine receptors in the CNS have a close functional connection with receptors of the GABA-ergic transmitter system. After binding to the benzodiazepine receptor, midazolam augments the inhibitory effect of GABA-ergic transmission.

5.2 Pharmacokinetic properties

Midazolam is highly lipid soluble and crosses the blood brain barrier. These properties qualify it for intravenous use in short term anaesthetic procedures since it acts promptly on the brain, and its initial effects decrease rapidly as it is distributed into fat deposits and tissues. Following the administration of 150 micrograms/kg intravenously, plasma concentrations in the range 291425 ng/ml are reached within five minutes.

Midazolam is almost completely absorbed following intramuscular injection, peak plasma levels being attained within 45 minutes.

Midazolam is extensively protein bound (94-98%). The volume of distribution is between 0.8 and 1.7 litres/kg. Midazolam crosses the placenta. It is not known whether midazolam enters breast milk, but this is likely as it is known to occur with other benzodiazepines.

Midazolam is extensively metabolised in the liver, involving the P450 TTTA enzymes. The principal metabolite, 1-hydroxy midazolam, appears in the urine as a glucuronide. The metabolite is less pharmacologically active than midazolam and has a shorter half-life of about one hour. Midazolam has a mean elimination half-life of two to three hours. The half-life is short compared with other benzodiazepines. Less than 1% midazolam is excreted unchanged via the kidneys and the drug is cleared virtually entirely by the liver. The half-life of midazolam is prolonged in neonates, in the elderly and patients with liver disorders.

5.3 Preclinical safety data

In vitro and in vivo microbial and mammalian test systems have revealed no evidence of mutagenicity. No evidence of carcinogenic potential was seen in rats or mice given oral midazolam maleate in doses up to 25 times the human recommended daily dose for two years.

Tn humans, the risk of congenital abnormalities from the ingestion of therapeutic doses of benzodiazepines is slight, although a few epidemiological studies have pointed to an increased risk of cleft palate. There are case reports of congenital abnormalities and mental retardation in prenatally exposed children following overdosage and intoxication with benzodiazepines.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Chloride Hydrochloric Acid Solution 3M Sodium Hydroxide Solution 3M Water for Injections

6.2    Incompatibilities

Midazolam is incompatible with alkaline solutions (due to reduced solubility) and some medicines.

Published data show that midazolam injection is incompatible with alkaline injections such as some antibiotic and steroid injections, bumetanide, frusemide, omeprazole sodium, sodium bicarbonate and thiopental sodium. It is also incompatible with dimenhydrinate, foscarnet sodium, imipenem with cilastin, pentobarbital sodium, albumin, clonidine, perphenazine, prochlorperazine, ranitidine and certain parenteral solutions including parenteral nutrition solutions.

Mixture or dilution with Hartmann’s solution is not recommended, as the potency of midazolam decreases.

Compatibility must be checked before administration, if intended to be mixed with other drugs.

6.3    Shelf life

Three years.

6.4 Special precautions for storage

Do not store above 25°C. Keep container in outer carton.

6.5 Nature and contents of container

Neutral glass ampoules Type I Ph Eur 5ml packed in 5 or 10s in an outer printed carton.

6.6 Special precautions for disposal

The injection is for single patient use and should be used immediately after opening. The injection should not be used if particles are present. Any unused portion should be discarded.

Midazolam for infusion may be prepared by dilution with infusion fluids containing 5% glucose, 4% glucose with 0.18% sodium chloride or 0.9% sodium chloride.

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

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

7    MARKETING AUTHORISATION HOLDER

Wockhardt UK Ltd Ash Road North Wrexham Industrial Estate Wrexham LL13 9UF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0140

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

27/03/2007

10    DATE OF REVISION OF THE TEXT

24/11/2015