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Information for the doctor

ESMERON®

10 mg/ml

solution for injection

ROCURONIUM BROMIDE

1.    NAME OF THE MEDICINAL PRODUCT

Esmeron® 10 mg/ml solution for injection

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml Esmeron contains 10 mg rocuronium bromide.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Solution for injection. pH: 3.8-4.2

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Esmeron is indicated in adult and paediatric patients (from term neonates to adolescents [0 to <18 years]) as an adjunct to general anaesthesia to facilitate tracheal intubation during routine sequence induction and to provide skeletal muscle relaxation during surgery.

In adults Esmeron is also indicated to facilitate tracheal intubation during rapid sequence induction and as an adjunct in the intensive care unit (ICU) to facilitate intubation and mechanical ventilation.

4.2    Posology and method of administration Posology

Like other neuromuscular blocking agents, Esmeron should only be administered by, or under supervision of, experienced clinicians who are familiar with the action and use of these drugs.

As with other neuromuscular blocking agents, the dosage of Esmeron should be individualised in each patient. The method of anaesthesia and the expected duration of surgery, the method of sedation and the expected duration of mechanical ventilation, the possible interaction with other drugs that are administered concomitantly, and the condition of the patient should be taken into account when determining the dose.

The use of an appropriate neuromuscular monitoring technique is recommended for the evaluation of neuromuscular block and recovery.

Inhalational anaesthetics do potentiate the neuromuscular blocking effects of Esmeron. This potentiation however, becomes clinically relevant in the course of anaesthesia, when the volatile agents have reached the tissue concentrations required for this interaction. Consequently, adjustments with Esmeron should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of Esmeron during long lasting procedures (longer than 1 hour) under inhalational anaesthesia (see section 4.5).

In adult patients the following dosage recommendations may serve as a general guideline for tracheal intubation and muscle relaxation for short to long lasting surgical procedures and for use in the intensive care unit.

Surgical Procedures Tracheal intubation

The standard intubating dose during routine anaesthesia is 0.6 mg/kg rocuronium bromide, after which adequate intubation conditions are established within 60 seconds in nearly all patients. A dose of 1.0 mg/kg rocuronium bromide is recommended for facilitating tracheal intubation conditions during rapid sequence induction of anaesthesia, after which adequate intubation conditions are established within 60 seconds in nearly all patients. If a dose of

0.6 mg/kg rocuronium bromide is used for rapid sequence induction of anaesthesia, it is recommended to intubate the patient 90 seconds after administration of rocuronium bromide.

For use of rocuronium bromide during rapid sequence induction of anaesthesia in patients undergoing Caesarean section reference is made to section 4.6.

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Information for the user

ESMERON®

10 mg/ml

solution for injection

ROCURONIUM BROMIDE

Read all of this leaflet carefully before you are given this medicine

because it contains important information for you.

•    Keep this leaflet. You may need to read it again.

•    If you have any further questions, ask your anaesthetist or other doctor.

•    If you get any side effects, talk to your anaesthetist or other doctor. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1.    What Esmeron is and what it is used for

2.    What you need to know before Esmeron is given

3.    How Esmeron is given

4.    Possible side effects

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Higher doses

Should there be reason for selection of larger doses in individual patients, there is no indication from clinical studies that the use of initial doses up to 2 mg/kg rocuronium bromide is associated with an increased frequency or severity of cardiovascular effects. The use of these high dosages of rocuronium bromide decreases the onset time and increases the duration of action (see section 5.1).

Maintenance dosing

The recommended maintenance dose is 0.15 mg/kg rocuronium bromide; in the case of long-term inhalational anaesthesia this should be reduced to

0.075-0.1 mg/kg rocuronium bromide. The maintenance doses should best be given when twitch height has recovered to 25% of control twitch height, or when 2 to 3 responses to train of four stimulation are present.

Continuous infusion

If rocuronium bromide is administered by continuous infusion, it is recommended to give a loading dose of 0.6 mg/kg rocuronium bromide and, when neuromuscular block starts to recover, to start administration by infusion. The infusion rate should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 to 2 responses to train of four stimulation. In adults under intravenous anaesthesia, the infusion rate required to maintain neuromuscular block at this level ranges from 0.3-0.6 mg/kg/h (300-600 micrograms/kg/h) and under inhalational anaesthesia the infusion rate ranges from 0.3-0.4 mg/kg/h. Continuous monitoring of neuromuscular block is essential since infusion rate requirements vary from patient to patient and with the anaesthetic method used.

Paediatric population

For neonates (0-27 days), infants (28 days-2 months), toddlers (3-23 months), children (2-11 years) and adolescents (12-17 years) the recommended intubation dose during routine anaesthesia and maintenance dose are similar to those in adults.

However, the duration of action of the single intubating dose will be longer in neonates and infants than in children (see section 5.1)

For continuous infusion in paediatrics, the infusion rates, with the exception of children (2-11 years), are the same as for adults. For children aged 2-11 years higher infusion rates might be necessary.

Thus, for children (2-11 years) the same initial infusion rates as for adults are recommended and then this should be adjusted to maintain twitch response at 10% of control twitch height or to maintain 1 or 2 responses to train of four stimulation during the procedure.

The experience with rocuronium bromide in rapid sequence induction in paediatric patients is limited. Rocuronium bromide is therefore not recommended for facilitating tracheal intubation conditions during rapid sequence induction in paediatric patients.

Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure

The standard intubation dose for geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg rocuronium bromide. A dose of 0.6 mg/kg should be considered for rapid sequence induction of anaesthesia in patients in which a prolonged duration of action is expected. Regardless of the anaesthetic technique used, the recommended maintenance dose for these patients is 0.075-0.1 mg/kg rocuronium bromide, and the recommended infusion rate is 0.3-0.4 mg/kg/h (see Continuous infusion). (See also section 4.4.)

Overweight and obese patients

When used in overweight or obese patients (defined as patients with a body weight of 30% or more above ideal body weight) doses should be reduced taking into account ideal body weight.

Intensive Care Procedures

Tracheal intubation

For tracheal intubation, the same doses should be used as described above under surgical procedures.

Maintenance dosing

The use of an initial loading dose of 0.6 mg/kg rocuronium bromide is recommended, followed by a continuous infusion as soon as twitch height recovers to 10% or upon reappearance of 1 to 2 twitches to train of four stimulation. Dosage should always be titrated to effect in the individual patient. The recommended initial infusion rate for the maintenance of a neuromuscular block of 80-90% (1 to 2 twitches to TOF stimulation) in adult patients is 0.3-0.6 mg/kg/h during the first hour of administration, which will need to be decreased during the following 6-12 hours, according to the individual response. Thereafter, individual dose requirements remain relatively constant.

A large between patient variability in hourly infusion rates has been found in controlled clinical studies, with mean hourly infusion rates ranging from 0.2-0.5 mg/kg/h depending on nature and extent of organ failure(s), concomitant medication and individual patient characteristics. To provide optimal individual patient control, monitoring of neuromuscular transmission is strongly recommended. Administration up to 7 days has been investigated. Special populations

Esmeron is not recommended for the facilitation of mechanical ventilation in the intensive care in paediatric and geriatric patients due to a lack of data on safety and efficacy.

Method of administration

Esmeron is administered intravenously either as a bolus injection or as a continuous infusion (see section 6.6).

4.3    Contraindications

Hypersensitivity to rocuronium or to the bromide ion or to any of the excipients.

4.4    Special warnings and precautions for use

Since Esmeron causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this drug until adequate

5.    How Esmeron is stored

6.    Contents of the pack and other information

1.    What Esmeron is and what it is used for

Esmeron is one of a group of drugs called muscle relaxants.

Muscle relaxants are used during an operation as part of a general anaesthetic. When you have an operation your muscles must be completely relaxed. This makes it easier for the surgeon to perform the operation. Normally, your nerves send messages called impulses to your muscles. Esmeron acts by blocking these impulses so that your muscles relax. Because your breathing muscles also relax, you will need help to breathe (artificial ventilation) during and after your operation until you can breathe on your own again.

During the operation your anaesthetist will keep a check on the effect of the muscle relaxant, and if necessary will give you some more. At the end of surgery, the effects of the drug are allowed to wear off and you will start breathing on your own. Sometimes the anaesthetist will give you another drug to help speed this up.

Esmeron can also be used in Intensive Care Units to keep your muscles relaxed.

2.    What you need to know before Esmeron is given You should not receive Esmeron

if you are allergic (hypersensitive) to rocuronium, the bromide ion or any of the other ingredients of this medicine (listed in section 6). Tell your anaesthetist if this applies to you.

spontaneous respiration is restored. As with all neuromuscular blocking agents, it is important to anticipate intubation difficulties, particularly when used as part of a rapid sequence induction technique.

As with other neuromuscular blocking agents, residual neuromuscular blockade has been reported for Esmeron. In order to prevent complications resulting from residual neuromuscular blockade, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Geriatric patients (65 years or older) may be at increased risk for residual neuromuscular block. Other factors which could cause residual neuromuscular blockade after extubation in the post-operative phase (such as drug interactions or patient condition) should also be considered. If not used as part of standard clinical practice, the use of a reversal agent (such as sugammadex or acetylcholinesterase inhibitors) should be considered, especially in those cases where residual neuromuscular blockade is more likely to occur.

High rates of cross-sensitivity between neuromuscular blocking agents have been reported. Therefore, where possible, before administering Esmeron, hypersensitivity to other neuromuscular blocking agents should be excluded. Esmeron should only be used when absolutely essential in susceptible patients. Patients who experience a hypersensitivity reaction under general anaesthesia should be tested subsequently for hypersensitivity to other neuromuscular blockers.

Rocuronium may increase the heart rate.

In general, following long term use of neuromuscular blocking agents in the ICU, prolonged paralysis and/or skeletal muscle weakness has been noted. In order to help preclude possible prolongation of neuromuscular block and/or overdosage it is strongly recommended that neuromuscular transmission is monitored throughout the use of neuromuscular blocking agents. In addition, patients should receive adequate analgesia and sedation. Furthermore, neuromuscular blocking agents should be titrated to effect in the individual patients by or under supervision of experienced clinicians who are familiar with their actions and with appropriate neuromuscular monitoring techniques.

Myopathy after long term administration of other non-depolarising neuromuscular blocking agents in the ICU in combination with corticosteroid therapy has been reported regularly. Therefore, for patients receiving both neuromuscular blocking agents and corticosteroids, the period of use of the neuromuscular blocking agent should be limited as much as possible.

If suxamethonium is used for intubation, the administration of Esmeron should be delayed until the patient has clinically recovered from the neuromuscular block induced by suxamethonium.

The following conditions may influence the pharmacokinetics and/or pharmacodynamics of Esmeron:

Hepatic and/or biliary tract disease and renal failure Because rocuronium is excreted in urine and bile, it should be used with caution in patients with clinically significant hepatic and/or biliary diseases and/or renal failure. In these patient groups prolongation of action has been observed with doses of 0.6 mg/kg rocuronium bromide.

Prolonged circulation time

Conditions associated with prolonged circulation time such as cardiovascular disease, old age and oedematous state resulting in an increased volume of distribution, may contribute to a slower onset of action. The duration of action may also be prolonged due to a reduced plasma clearance.

Neuromuscular disease

Like other neuromuscular blocking agents, Esmeron should be used with extreme caution in patients with a neuromuscular disease or after poliomyelitis since the response to neuromuscular blocking agents may be considerably altered in these cases. The magnitude and direction of this alteration may vary widely. In patients with myasthenia gravis or with the myasthenic (Eaton-Lambert) syndrome, small doses of Esmeron may have profound effects and Esmeron should be titrated to the response. Hypothermia

In surgery under hypothermic conditions, the neuromuscular blocking effect of Esmeron is increased and the duration prolonged.

Obesity

Like other neuromuscular blocking agents, Esmeron may exhibit a prolonged duration and a prolonged spontaneous recovery in obese patients when the administered doses are calculated on actual body weight.

Burns

Patients with burns are known to develop resistance to non-depolarising neuromuscular blocking agents. It is recommended that the dose is titrated to response.

Conditions which may increase the effects of Esmeron Hypokalaemia (e.g. after severe vomiting, diarrhoea and diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia, cachexia.

Severe electrolyte disturbances, altered blood pH or dehydration should therefore be corrected when possible.

4.5 Interaction with other medicinal products and other forms of interaction

The following drugs have been shown to influence the magnitude and/or duration of action of non-depolarising neuromuscular blocking agents. Effect of other drugs on Esmeron Increased effect:

•    Halogenated volatile anaesthetics potentiate the neuromuscular block of Esmeron. The effect only becomes apparent with maintenance dosing (see section 4.2). Reversal of the block with acetylcholinesterase inhibitors could also be inhibited.

•    After intubation with suxamethonium (see section 4.4).

•    Long-term concomitant use of corticosteroids and Esmeron in the ICU may result in prolonged duration of neuromuscular block or myopathy (see section 4.4 and 4.8).

Warnings and precautions

Talk to your anaesthetist before you receive this medicine:

•    if you are allergic to muscle relaxants

•    if you have had kidney, heart, liver or gall bladder disease

•    if you have had diseases affecting nerves and muscles

•    if you have fluid retention (oedema).

Tell your anaesthetist if any of these applies to you.

Some conditions may influence the effects of Esmeron — for example:

•    low calcium levels in the blood

•    low potassium levels in the blood

•    high magnesium levels in the blood

•    low levels of protein in the blood

•    too much carbon dioxide in the blood

•    loss of too much water from the body, for example by being sick, diarrhoea or sweating

•    over-breathing leading to too little carbon dioxide in the blood (alkalosis)

•    general ill-health

•    burns

•    being very overweight (obesity)

•    very low body temperature (hypothermia).

If you have any of these conditions, your anaesthetist will take it into account when deciding the correct dose of Esmeron for you.

Children and Elderly

Esmeron can be used in children (newborns and adolescence) and elderly but your anaesthetist should first assess your medical history.

Other drugs:

•    antibiotics: aminoglycoside, lincosamide and polypeptide antibiotics, acylamino-penicillin antibiotics.

•    diuretics, quinidine and its isomer quinine, magnesium salts, calcium channel blocking agents, lithium salts, local anaesthetics

(lidocaine i.v, bupivacaine epidural) and acute administration of phenytoin or B-blocking agents. Recurarisation has been reported after post-operative administration of: aminoglycoside, lincosamide, polypeptide and acylamino-penicillin antibiotics, quinidine, quinine and magnesium salts (see section 4.4). Decreased effect:

•    Prior chronic administration of phenytoin or carbamazepine.

•    Calcium chloride, potassium chloride.

•    Protease inhibitors (gabexate, ulinastatin).

Variable effect:

•    Administration of other non-depolarising neuromuscular blocking agents in combination with Esmeron may produce attenuation or potentiation of the neuromuscular block, depending on the order of administration and the neuromuscular blocking agent used.

•    Suxamethonium given after the administration of Esmeron may produce potentiation or attenuation of the neuromuscular blocking effect of Esmeron.

Effect of Esmeron on other drugs

Esmeron combined with lidocaine may result in a quicker onset of action of lidocaine.

Paediatric population

No formal interaction studies have been performed. The above mentioned interactions for adults and their special warnings and precautions for use (see section 4.4) should be taken into account for paediatric patients.

4.6    Pregnancy and lactation Pregnancy

For rocuronium bromide, no clinical data on exposed pregnancies are available. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development. Caution should be exercised when prescribing Esmeron to pregnant women. Caesarean section

In patients undergoing Caesarean section, Esmeron can be used as part of a rapid sequence induction technique, provided no intubation difficulties are anticipated and a sufficient dose of anaesthetic agent is administered or following suxamethonium facilitated intubation. However, Esmeron, administered in doses of 0.6 mg/kg may not produce adequate conditions for intubation until 90 seconds after administration. This dose has been shown to be safe in parturients undergoing Caesarean section. Esmeron does not affect Apgar score, foetal muscle tone or cardiorespiratory adaptation. From umbilical cord blood sampling it is apparent that only limited placental transfer of rocuronium bromide occurs which does not lead to the observation of clinical adverse effects in the newborn. Note 1: doses of 1.0 mg/kg have been investigated during rapid sequence induction of anaesthesia, but not in Caesarean section patients. Therefore, only a dose of 0.6 mg/kg is recommended in this patient group.

Note 2: Reversal of neuromuscular block induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients receiving magnesium salts for toxemia of pregnancy because magnesium salts enhance neuromuscular blockade. Therefore, in these patients the dosage of Esmeron should be reduced and be titrated to twitch response.

Breast-feeding

It is unknown whether rocuronium bromide is excreted in human breast milk. Animal studies have shown insignificant levels of rocuronium bromide in breast milk.

Insignificant levels of rocuronium bromide were found in the milk of lactating rats. There are no human data on the use of Esmeron during lactation. Esmeron should be given to lactating women only when the attending physician decides that the benefits outweigh the risks.

4.7    Effects on ability to drive and use machines

Since Esmeron is used as an adjunct to general anaesthesia, the usual precautionary measures after a general anaesthesia should be taken for ambulatory patients.

4.8    Undesirable effects Summary of the safety profile

The most commonly occurring adverse drug reactions include injection site pain/reaction, changes in vital signs and prolonged neuromuscular block. The most frequently reported serious adverse drug reactions during post-marketing surveillance is 'anaphylactic and anaphylactoid reactions' and associated symptoms. See also the explanations below the table.

Tabulated list of adverse reactions

Other medicines and Esmeron

Tell your anaesthetist if you are taking other medicines or

have recently taken them. This includes medicines or herbal products that you have bought without a prescription. Esmeron may affect other medicines or be affected by them.

Medicines which increase the effect of Esmeron:

•    certain antibiotics

•    certain medicines for heart disease or high blood pressure

(water tablets, calcium channel blockers, beta-blockers and quinidine)

•    certain anti-inflammatory medicines (corticosteroids)

•    medicines for manic depressive illness (bipolar disorder)

•    magnesium salts

•    certain medicines used to treat malaria.

Medicines which decrease the effect of Esmeron:

•    certain medicines for epilepsy

•    calcium chloride and potassium chloride

•    certain protease inhibitors called gabexate and ulinastatin.

In addition, you may be given other medicines before or during surgery which can alter the effects of Esmeron. These include certain anaesthetics, other muscle relaxants, medicines such as phenytoin and medicines which reverse the effects of Esmeron. Esmeron may make certain anaesthetics work more quickly. Your anaesthetist will take this into account when deciding the correct dose of Esmeron for you.

MedDRA version 8.1 Anaphylaxis

Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including Esmeron, have been reported. Anaphylactic/anaphylactoid reactions are: bronchospasm, cardiovascular changes (e.g. hypotension, tachycardia, circulatory collapse - shock), and cutaneous changes (e.g. angioedema, urticaria). These reactions have, in some cases, been fatal. Due to the possible severity of these reactions, one should always assume they may occur and take the necessary precautions.

Since neuromuscular blocking agents are known to be capable of inducing histamine release both locally at the site of injection and systemically, the possible occurrence of itching and erythematous reaction at the site of injection and/or generalised histaminoid (anaphylactoid) reactions (see also under anaphylactic reactions above) should always be taken into consideration when administering these drugs.

In clinical studies only a slight increase in mean plasma histamine levels has been observed following rapid bolus administration of 0.3-0.9 mg/kg rocuronium bromide.

Prolonged neuromuscular block

The most frequent adverse reaction to nondepolarising blocking agents as a class consists of an extension of the drug's pharmacological action beyond the time period needed. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnea.

Myopathy

Myopathy has been reported after the use of various neuromuscular blocking agents in the ICU in combination with corticosteroids (see section 4.4).

Local injection site reactions

During rapid sequence induction of anaesthesia, pain on injection has been reported, especially when the patient has not yet completely lost consciousness and particularly when propofol is used as the induction agent. In clinical studies, pain on injection has been noted in 16% of the patients who underwent rapid sequence induction of anaesthesia with propofol and in less than 0.5% of the patients who underwent rapid sequence induction of anaesthesia with fentanyl and thiopental.

Paediatric population

A meta-analysis of 11 clinical studies in paediatric patients (n=704) with rocuronium bromide (up to 1 mg/kg) showed that tachycardia was identified as adverse drug reaction with a frequency of 1.4%. 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 (see details below)

United Kingdom: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. Malta: ADR Reporting at: www.medicinesauthority.gov.mt/adrportal

¹    Frequencies are estimates derived from post-marketing surveillance reports and data from the general literature.

²    Post-marketing surveillance data cannot give precise incidence figures. For that reason, the reporting frequency was divided over two rather than five categories.

³    after long-term use in the ICU

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Pregnancy and breast feeding

Tell your anaesthetist if you are pregnant or might be pregnant, or if you are breast feeding.

Your anaesthetist may still give you Esmeron, but you need to discuss it first. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your anaesthetist or other doctor for advice before taking this medicine. Esmeron may be given to you if you are having a Caesarean section.

Driving and using machines

A Do not drive or use machines until advised it is safe to do so. Because Esmeron is given as part of a general anaesthetic, you may feel tired, weak or dizzy for some time afterwards. Your anaesthetist will be able to advise you on how long the effects are likely to last.

3. How Esmeron is given Dose

Your anaesthetist will work out the dose of Esmeron you need based on:

• the type of anaesthetic • the expected length of the operation •    other drugs you are taking

•    your state of health.

The normal dose is 0.6 mg per kg body weight and the effect will last 30-40 minutes.

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4.9 Overdose

In the event of overdosage and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. There are two options for the reversal of neuromuscular block: (1) In adults, sugammadex can be used for reversal of intense (profound) and deep block. The dose of sugammadex to be administered depends on the level of neuromuscular block. (2) An acetylcholinesterase inhibitor (e.g. neostigmine, edrophonium, pyridostigmine) or sugammadex can be used once spontaneous recovery starts and should be administered in adequate doses. When administration of an acetylcholinesterase inhibiting agent fails to reverse the neuromuscular effects of Esmeron, ventilation must be continued until spontaneous breathing is restored. Repeated dosage of an acetylcholinesterase inhibitor can be dangerous.

In animal studies, severe depression of cardiovascular function, ultimately leading to cardiac collapse did not occur until a cumulative dose of 750 x ED₉₀ (135 mg/kg rocuronium bromide) was administered.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, ATC code: M03AC09.

Mechanism of Action

Esmeron (rocuronium bromide) is a fast onset, intermediate acting non-depolarising neuromuscular blocking agent, possessing all of the characteristic pharmacological actions of this class of drugs (curariform). It acts by competing for nicotinic cholinoceptors at the motor end-plate. This action is antagonised by acetylcholinesterase inhibitors such as neostigmine, edrophonium and pyridostigmine.

Pharmacodynamic effects

The EDji, (dose required to produce 90% depression of the twitch response of the thumb to stimulation of the ulnar nerve) during intravenous anaesthesia is approximately 0.3 mg/kg rocuronium bromide. The ED₉₅ in infants is lower than in adults and children (0.25, 0.35 and 0.40 mg/kg respectively).

The clinical duration (the duration until spontaneous recovery to 25% of control twitch height) with 0.6 mg/kg rocuronium bromide is 30-40 minutes. The total duration (time until spontaneous recovery to 90% of control twitch height) is 50 minutes. The mean time of spontaneous recovery of twitch response from 25 to 75% (recovery index) after a bolus dose of 0.6 mg/kg rocuronium bromide is 14 minutes. With lower dosages of 0.3-0.45 mg/kg rocuronium bromide (1 -1y x ED₉₀), onset of action is slower and duration of action is shorter. With high doses of 2 mg/kg, clinical duration is 110 minutes.

Intubation during routine anaesthesia

Within 60 seconds following intravenous administration of a dose of 0.6 mg/kg rocuronium bromide (2 x ED₉₀ under intravenous anaesthesia), adequate intubation conditions can be achieved in nearly all patients of which in 80% intubation conditions are rated excellent. General muscle paralysis adequate for any type of procedure is established within 2 minutes. After administration of 0.45 mg/kg rocuronium bromide, acceptable intubation conditions are present after 90 seconds.

Rapid Sequence Induction

During rapid sequence induction of anaesthesia under propofol or fentanyl/ thiopental anaesthesia, adequate intubation conditions are achieved within 60 seconds in 93% and 96% of the patients respectively, following a dose of 1.0 mg/kg rocuronium bromide. Of these, 70% are rated excellent. The clinical duration with this dose approaches 1 hour, at which time the neuromuscular block can be safely reversed. Following a dose of 0.6 mg/kg rocuronium bromide, adequate intubation conditions are achieved within 60 seconds in 81% and 75% of the patients during a rapid sequence induction technique with propofol or fentanyl/thiopental, respectively. Paediatric population

Mean onset time in infants, toddlers and children at an intubation dose of 0.6 mg/kg is slightly shorter than in adults. Comparison within paediatric age groups showed that the mean onset time in neonates and adolescents (1.0 min.) is slightly longer than in infants, toddlers and children (0.4, 0.6 and 0.8 min., respectively). The duration of relaxation and the time to recovery tend to be shorter in children compared to infants and adults. Comparing within paediatric age groups demonstrated that mean time to reappearance of T₃ was prolonged in neonates and infants (56.7 and 60.7 min., respectively) when compared to toddlers, children and adolescents (45.4, 37.6 and 42.9 min., respectively).

Mean (SD) time to onset and clinical duration following 0.6 mg/kg rocuronium initial intubating dose* during sevoflurane/nitrous oxide and isoflurane/nitrous oxide (maintenance) anaesthesia (Paediatric patients) PP group

How Esmeron is given

Esmeron will be given to you by your anaesthetist. Esmeron is given intravenously (into a vein), either as single injections or as a continuous infusion (a drip).

If you are given more Esmeron than you need

As your anaesthetist will be monitoring your condition carefully it is unlikely that you will be given too much Esmeron. However, if this happens, your anaesthetist will keep you breathing artificially (on a ventilator) until you can breathe on your own. You will be kept asleep while this takes place.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. If these side effects occur while you are under anaesthetic, they will be seen and treated by your anaesthetist.

Uncommon side effects (may affect up to 1 in 100 people)

•    the drug is too effective, or not effective enough

•    the drug works for longer than expected

•    lowering of blood pressure

•    increase in heart rate

•    pain near the site of injection.

Very rare side effects

(may affect up to 1 in 10,000 people)

•    allergic (hypersensitivity) reactions (such as difficulty in breathing, collapse of the circulation and shock)

•    wheezing of the chest

Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure

The duration of action of maintenance doses of 0.15 mg/kg rocuronium bromide might be somewhat longer under enflurane and isoflurane anaesthesia in geriatric patients and in patients with hepatic and/or renal disease (approximately 20 minutes) than in patients without impairment of excretory organ functions under intravenous anaesthesia (approximately 13 minutes) (see section 4.2). No accumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed.

Intensive Care Unit

Following continuous infusion in the Intensive Care Unit, the time to recovery of the train of four ratio to 0.7 depends on the level of block at the end of the infusion. After a continuous infusion for 20 hours or more the median (range) time between return of T₂ to train of four stimulation and recovery of the train of four ratio to 0.7 approximates 1.5 (1-5) hours in patients without multiple organ failure and 4 (1-25) hours in patients with multiple organ failure.

Cardiovascular surgery

In patients scheduled for cardiovascular surgery the most common cardiovascular changes during the onset of maximum block following 0.6-0.9 mg/kg rocuronium bromide are a slight and clinically insignificant increase in heart rate up to 9% and an increase in mean arterial blood pressure up to 16% from the control values.

Reversal of muscle relaxation

Administration of acetylcholinesterase inhibitors, (neostigmine, pyridostigmine or edrophonium) at reappearance of T₂ or at the first signs of clinical recovery, antagonises the action of Esmeron.

5.2 Pharmacokinetic Properties

After intravenous administration of a single bolus dose of rocuronium bromide the plasma concentration time course runs in three exponential phases. In normal adults, the mean (95% CI) elimination half-life is 73 (66-80) minutes, the (apparent) volume of distribution at steady state conditions is 203 (193-214) ml/kg and plasma clearance is 3.7 (3.5-3.9) ml/kg/min.

Rocuronium is excreted in urine and bile. Excretion in urine approaches 40% within 12-24 hours. After injection of a radiolabeled dose of rocuronium bromide, excretion of the radiolabel is on average 47% in urine and 43% in faeces after 9 days. Approximately 50% is recovered as the parent compound. No metabolites are detected in plasma.

Paediatric population

Pharmacokinetics of rocuronium bromide in paediatric patients (n=146) with ages ranging from 0 to 17 years were evaluated using a population analysis of the pooled pharmacokinetic datasets from two clinical trials under sevoflurane (induction) and isoflurane/nitrous oxide (maintenance) anesthesia. All pharmacokinetic parameters were found to be linearly proportional to body weight illustrated by a similar clearance (l.hr^-1.kg^-1). The volume of distribution (l.kg^-1) and elimination half-life (h) decrease with age (years). The pharmacokinetic parameters of typical paediatrics within each age group are summarized below:

Estimated PK parameters (Mean [SD]) of rocuronium bromide in typical paediatric patients during sevoflurane and nitrous oxide (induction) and isoflurane/nitrous oxide (maintenance anaesthesia)

Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure

In controlled studies the plasma clearance in geriatric patients and in patients with renal dysfunction was reduced, in most studies however without reaching the level of statistical significance. In patients with hepatic disease, the mean elimination half-life is prolonged by 30 minutes and the mean plasma clearance is reduced by 1 ml/kg/min. (See section 4.2.)

Intensive Care unit

When administered as a continuous infusion to facilitate mechanical ventilation for 20 hours or more, the mean elimination half-life and the mean (apparent) volume of distribution at steady state are increased.

A large between patient variability is found in controlled clinical studies, related to nature and extent of (multiple) organ failure and individual patient characteristics. In patients with multiple organ failure a mean (± SD) elimination half-life of 21.5 (± 3.3) hours, a (apparent) volume of distribution at steady state of 1.5 (± 0.8) l/kg and a plasma clearance of

2.1 (± 0.8) ml/kg/min were found. (See section 4.2.)

5.3 Preclinical safety data

Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.

There is no proper animal model to mimic the usually extremely complex clinical situation of the ICU patient. Therefore the safety of Esmeron when used to facilitate mechanical ventilation in the Intensive Care Unit is mainly based on results obtained in clinical studies.

•    muscle weakness

•    sudden fever with rapid heartbeat, rapid breathing and stiffness, pain and/or weakness in your muscles

•    swelling, a rash or redness of the skin.

If any of the side effects gets serious

Or if you notice any side effects not listed in this leaflet:

Tell your anaesthetist or other doctor.

Reporting of side effects

If you get any side effects, talk to your anaesthetist or other doctor.

This includes any possible side effects not listed in this leaflet. You can also report side effects directly (see details below). By reporting side effects you can help provide more information on the safety of this medicine.

United Kingdom: Yellow Card Scheme at: www.mhra.gov.uk/yellowcard Malta: ADR Reporting at: www.medicinesauthority.gov.mt/adrportal

5.    How Esmeron is stored

The hospital will keep Esmeron according to the correct storage conditions, and will ensure that it's in its expiry date.

6.    Contents of the pack and other information What Esmeron contains

The active substance of Esmeron is rocuronium bromide 10 mg/ml.

The other ingredients are sodium acetate (E262), sodium chloride, acetic acid (E260) and water for injections. Each millilitre (ml) of Esmeron contains 1.72 mg of sodium. No preservative has been added.

6.    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Esmeron contains the following excipients:

•    Sodium acetate (E262) (for pH adjustment)

•    Sodium chloride

•    Acetic acid (E260) (for pH adjustment)

•    Water

No preservative has been added

6.2    Incompatibilities

Physical incompatibility has been documented for Esmeron when added to solutions containing the following drugs: amphotericin, amoxicillin, azathioprine, cefazolin, cloxacillin, dexamethasone, diazepam, enoximone, erythromycin, famotidine, furosemide, hydrocortisone sodium succinate, insulin, intralipid, methohexital, methylprednisolone, prednisolone sodium succinate, thiopental, trimethoprim and vancomycin.

Esmeron must not be mixed with other medicinal products except those mentioned in section 6.6.

If Esmeron is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed (e.g. with 0.9% NaCl) between administration of Esmeron and drugs for which incompatibility with Esmeron has been demonstrated or for which compatibility with Esmeron has not been established.

6.3    Shelf life

Esmeron has a shelf life of 3 years, provided it is stored under the prescribed conditions (see Special precautions for storage). The date mentioned on the carton and on the label of the vial is the expiry date; this is the date up to which Esmeron may be used.

Since Esmeron does not contain a preservative, the solution should be used immediately after opening the vial.

After dilution with infusion fluids (see section 6.6), chemical and physical in-use stability has been demonstated for 72 hours at 30°C. From a microbiological point of view, the diluted product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user/ administrator and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4    Special precautions for storage Storage in the Refrigerator

Esmeron should be stored at 2°-8°C in the dark and used within the expiry date given on the pack.

Storage out of the refrigerator

Esmeron may also be stored outside of the refrigerator at a temperature of up to 30°C for a maximum 12 weeks, after which it should be discarded. The product should not be placed back into the refrigerator, once it has been kept outside. The storage period must not exceed the shelf-life.

For storage conditions after first opening of the medicinal product, see section 6.3.

6.5    Nature and contents of containers

Esmeron 25 mg in 2.5 ml (10mg/ml)

Packaging of 10 vials each containing 25 mg rocuronium bromide. Esmeron 50 mg in 5 ml (10mg/ml)

Packaging of 10 vials each containing 50 mg rocuronium bromide. Esmeron 100 mg in 10 ml (10mg/ml)

Packaging of 10 vials each containing 100 mg rocuronium bromide. Not all pack sizes may be marketed.

Type 1 Ph.Eur., clear, colourless, glass vial with a rubber closure and flip off cap. The rubber stopper of the vial does not contain latex.

In correspondence please quote lot number.

6.6    Special precautions for disposal and other handling

Compatibility studies with the following infusion fluids have been performed: In nominal concentrations of 0.5 mg/ml and 2.0 mg/ml Esmeron has been shown to be compatible with: 0.9% NaCl,

5% dextrose, 5% dextrose in saline, sterile water for injections, Lactated Ringers and Haemaccel. Administration should be begun immediately after mixing, and should be completed within 24 hours. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7.    MARKETING AUTHORISATION HOLDER

NV Organon, Kloosterstraat 6, PO Box 20, 5340 BH Oss,

The Netherlands

8.    MARKETING AUTHORISATION NUMBER

UK:    PL 05003/0041

MALTA: MA 031/00201

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 15^th July 1996 Date of latest renewal: 7^th May 2002

10.    DATE OF REVISION OF THE TExT

MARCH 2015

SPC.ESM.15.UK.4480.UV97

What Esmeron looks like and contents of the pack

Esmeron is a colourless to slightly yellow/brown solution for injection. It is available in vials containing 25 mg (10 vials per pack), 50 mg (10 vials per pack) or 100 mg (10 vials per pack) of rocuronium bromide.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer Marketing Authorisation Holder: NV Organon, Kloosterstraat 6,

PO Box 20, 5340 BH Oss, The Netherlands.

Manufacturer: NV Organon, Kloosterstraat 6, PO Box 20, 5340 BH Oss, The Netherlands.

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Product name: Esmeron Reference Number: PL 05003/0041

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This leaflet was last revised in March 2015. PIL.ESM.15.UK.4481.UV97