PACKAGE INSERT

Package insert: information for the patient

Esmeron 10 mg/mL solution for intravenous injection

rocuronium bromide
Please read this leaflet carefully before this medicine is administered to you, because
it contains important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or nurse.
If you experience any side effects, including those not listed in this leaflet, tell your doctor or nurse. See section 4.

Contents of this leaflet:

What Esmeron is and what it is used for
What you must know before being administered Esmeron
How to use Esmeron
Possible side effects
How to store Esmeron
Package contents and other information

1. What Esmeron is and what it is used for

Esmeron is a medicine containing rocuronium bromide, an active substance that belongs to a class of medicines called muscle relaxants (medicines that induce relaxation of certain types of muscles).
Esmeron is indicated in general anaesthesia to facilitate endotracheal intubation (during surgical procedures, a tube is inserted into the trachea to support artificial ventilation and achieve relaxation of certain types of muscles. Artificial ventilation replaces natural breathing when spontaneous breathing is no longer occurring) in adult and paediatric patients (from term neonates to adolescents, aged between 0 and less than 18 years). Additionally, in adults, Esmeron is also indicated in Intensive Care Units (ICUs) to facilitate endotracheal intubation.

2. What you should know before being given Esmeron

Do not use Esmeron

if you are allergic to rocuronium bromide, bromide ions, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
At the end of the operation, the anaesthetist will allow the effect of Esmeron to wear off, so that you can breathe on your own again. In certain cases, you may receive another medicine to speed up recovery of spontaneous breathing.
Speak to your doctor or nurse before this medicine is administered to you

if you are allergic to any muscle relaxant medicine
if you have a kidney, liver or biliary disease (the biliary system carries bile)
if you have a heart condition or a disease affecting blood circulation
if one or more areas of your body are swollen due to fluid accumulation (e.g. in the ankles)
if you have a history of malignant hyperthermia (sudden fever with rapid heartbeat, fast breathing, and muscle stiffness, pain and/or weakness)
if you have had neuromuscular disorders (diseases affecting both nerves and the muscles they control), poliomyelitis (inflammation of the spinal cord caused by a virus leading to paralysis), myasthenia gravis (a disease characterised by muscle weakness), or Eaton-Lambert syndrome (a disease characterised by muscle weakness, impotence, constipation, and development of small blisters on hands and feet)
if you have previously experienced episodes of abnormally low body temperature during anaesthesia (hypothermia)
if you are overweight
if you have burns
if you have low calcium levels in the blood (hypocalcaemia)
if you have low potassium levels in the blood (hypokalaemia)
if you have high magnesium levels in the blood (hypermagnesaemia)
if you have low protein levels in the blood (hypoproteinaemia)
if you are dehydrated (the amount of water lost exceeds the amount taken in)
if you have an increased level of acids in the blood (acidosis)
if you have an increased level of carbon dioxide in the blood (hypercapnia)
if you have excessive weight loss (cachexia).

Inform your doctor if you have or have had:

a rare tumour of the adrenal glands (phaeochromocytoma); this may increase the risk of severe high blood pressure.

If you have any of the conditions listed above, your doctor will take this into account when determining the most appropriate dose of Esmeron for you.
Children and adolescents
Esmeron can be used in children (term neonates and adolescents); however, the anaesthetist must evaluate the clinical history.
Other medicines and Esmeron
Inform your doctor or nurse if you are taking, have recently taken, or might take any other medicines. The following medicines influence the effect and/or duration of action of Esmeron.
Medicines that increase the effect of Esmeron:

inhalational anaesthetics such as halothane, ether, enflurane, methoxyflurane and cyclopropane
suxamethonium, a muscle relaxant medicine
corticosteroids (medicines with anti-inflammatory action). Concomitant long-term use of corticosteroids and Esmeron in intensive care units may lead to myopathy (muscle disease) or prolonged muscle relaxation effect (see sections 2 and 4)
high doses of certain types of anaesthetics such as thiopental, methohexital, ketamine, fentanyl, gamma-hydroxybutyrate, etomidate and propofol
other muscle relaxants
other medicines:
- antibiotics (used to treat infections), such as aminoglycosides, lincosamides, polypeptides and acylaminopenicillins, tetracyclines, high doses of metronidazole
- diuretics (used to increase urine production)
- thiamine (important for cell functions)
- medicines for depression called monoamine oxidase inhibitors (MAO-I)
- quinidine (used in the treatment of heart conditions and regulation of high blood pressure)
- quinine (a medicine used to treat fever, pain and malaria)
- protamine (a medicine used to treat bleeding)
- adrenergic blocking agents, calcium antagonists (medicines used to regulate high blood pressure)
- magnesium salts (laxatives)
- lithium salts (antidepressants)
- certain local anaesthetics (lidocaine, bupivacaine).

Medicines that decrease the effect of Esmeron:

neostigmine, edrophonium (used to restore muscle function), previous chronic administration of corticosteroids
antiepileptic medicines (phenytoin or carbamazepine)
noradrenaline (also used to increase muscle tone, i.e. the state of mild and persistent muscle contraction present under normal conditions), azathioprine (a medicine used in immune system disorders that cause the body to react against its own components)
theophylline (a medicine used in the treatment of asthma)
calcium chloride, potassium chloride
protease inhibitors (medicines that counteract HIV viruses).

Variable effect

The administration of muscle relaxants in combination with Esmeron may either decrease or increase muscle blockade, depending on the order of administration and the type of muscle relaxant used.
Administration of suxamethonium after Esmeron may enhance or reduce muscle relaxation.
The combination of Esmeron and lidocaine may affect the effect of lidocaine.

No interaction studies (studies with medicines affecting the effect and duration of action of this medicine) have been conducted. The interactions of Esmeron with other medicines reported in adults (see “Other medicines and Esmeron”) and the warnings and precautions listed above (see “Warnings and precautions”) must also be taken into account for children and adolescents.
Pregnancy, breastfeeding and fertility
If you are pregnant, think you may be pregnant, are planning to become pregnant, or are breastfeeding, consult your doctor before this medicine is administered to you.
There are no clinical study data available on the use of rocuronium bromide during pregnancy or in women of childbearing age.
Caution is required when prescribing Esmeron to pregnant women.
It is not known whether Esmeron is excreted in human milk.
Esmeron should be administered to breastfeeding women only if the doctor considers that the benefits outweigh the risks.
After using this medicine, breastfeeding should be interrupted for the next 6 hours.
Caesarean section
In patients undergoing caesarean section, Esmeron may be used during anaesthesia.
The doctor will determine the most appropriate dose based on the patient’s condition.
Driving and using machines
Do not operate potentially dangerous machinery or drive until 24 hours after full recovery of muscle function.
Esmeron contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per vial, i.e. essentially “sodium-free”.

3. How to use Esmeron

This medicine will be administered to you by an anaesthetist or an experienced doctor who is familiar with the action and use of Esmeron.
As with other muscle relaxants, the dosage of Esmeron must be individually determined based on several factors such as: the type of anaesthesia and the expected duration of surgery, the sedation method (a state in which the patient does not completely lose consciousness), the expected duration of artificial ventilation, possible interactions with other medicines, and the patient's clinical condition.
Esmeron will be administered intravenously either as a bolus (single injection) or as a continuous infusion.

Use in children and adolescents
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 dose for tracheal intubation during anaesthesia and the maintenance dose (the dose required to maintain the therapeutic effect) are similar to those recommended for adults.
However, the duration of action of a single dose for tracheal intubation will be longer in neonates and infants compared to older children.

If you use more Esmeron than you should
The anaesthetist will closely monitor you while you are under the effects of Esmeron, making it unlikely that too much Esmeron will be administered. However, if this were to happen, muscle relaxation could increase. In such a case, the anaesthetist may give you medicines to reverse this effect and will ensure that anaesthesia and artificial ventilation are continued until you are able to breathe independently again.

If you have any doubts about how to use this medicine, consult your doctor or nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone will experience them.
The most commonly observed side effects include pain and/or reactions at the injection site and prolonged muscle block.
The most frequently reported serious side effects are allergic reactions (anaphylactic and anaphylactoid reactions).

Detailed information on side effects is provided below (since data collected through the pharmacovigilance system do not allow precise incidence rates to be determined, the frequency of reported events has been divided into three categories instead of five):

Uncommon (may affect up to 1 in 100 people) / Rare (may affect up to 1 in 1,000 people):

tachycardia (increased heart rate)
hypotension (low blood pressure)
lack of effectiveness of the medicine, reduced therapeutic response, increased therapeutic response, injection site pain, allergic reactions at the injection site
prolonged neuromuscular block (blockage of impulse transmission from nerve to muscle), delayed awakening from anaesthesia

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

hypersensitivity, allergic reactions (anaphylactic reaction, anaphylactic shock, anaphylactoid shock)
flaccid paralysis (loss of normal muscle tone)
circulatory collapse and shock (inadequate blood circulation throughout the body with a marked drop in blood pressure), hot flushes
bronchospasm (difficulty breathing due to narrowing of the bronchi)
angioneurotic oedema (swelling of the skin, mucous membranes and submucosal tissues of allergic origin), urticaria, dermatitis, erythematous rash (skin allergic reactions)
muscle weakness, steroid myopathy (a pathological condition affecting skeletal muscles caused by corticosteroid medicines)
facial oedema (swelling of the face)
respiratory problems during anaesthesia

Not known (frequency cannot be estimated from the available data):

severe allergic spasm of the coronary blood vessels (Kounis syndrome), causing chest pain (angina) or heart attack (myocardial infarction)
dilated pupils (mydriasis) or fixed pupils that do not change size in response to light or other stimuli

Additional side effects in children
An analysis of 11 clinical studies conducted in paediatric patients (n = 704) treated with rocuronium bromide (up to 1 mg/kg) reported tachycardia as a side effect of the medicine, occurring at a frequency of 1.4%.

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, consult your doctor or nurse. You may also report side effects directly via the Italian Medicines Agency (Agenzia Italiana del Farmaco) website: https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Esmeron

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after "Exp" and on the label after "EXP". The expiry date refers to the last day of that month.
The stated expiry date applies to the product as long as it is stored unopened and under the recommended storage conditions.
Do not use this medicine if you notice any visible signs of deterioration.
Store in a refrigerator (2 °C–8 °C). The medicine may be stored outside the refrigerator at a temperature not exceeding 30 °C for up to 3 months. The medicine may be moved in and out of the refrigerator at any time during the 36-month shelf life, but the total cumulative time outside the refrigerator must not exceed 3 months. The storage period must not extend beyond the expiry date indicated on the label.
After opening the vial, the solution is chemically stable for 24 hours at room temperature. Since Esmeron does not contain preservatives, it is recommended not to use any remaining solution.

6. Contents of the pack and other information

What Esmeron contains

The active substance is: rocuronium bromide. 1 mL of Esmeron contains 10 mg of rocuronium bromide.
The other components are: sodium acetate, sodium chloride, glacial acetic acid and water for injections. Esmeron contains 1.64 mg of sodium per 1 mL.

Description of the appearance of Esmeron and contents of the pack
Injectable solution for intravenous use.
Packs:

12 vials of 5 mL solution 10 mg/mL;
10 vials of 5 mL solution 10 mg/mL;
10 vials of 10 mL solution 10 mg/mL.

It is possible that not all pack sizes are marketed.
Marketing Authorization Holder and Manufacturer
Marketing Authorization Holder
MSD Italia S.r.l.
Via Vitorchiano, 151
00189 Rome
Italy
Manufacturer
N.V. Organon
Kloosterstraat 6
5349 AB Oss
The Netherlands
Merck Sharp & Dohme B.V.
Waarderweg 39
2031 BN Haarlem
The Netherlands

The following information is intended exclusively for healthcare professionals:

Warnings and precautions
Since Esmeron causes paralysis of the respiratory muscles, artificial ventilation is essential for patients treated with this medicine until spontaneous respiration is restored.
As with all neuromuscular blocking agents, it is important to anticipate potential difficulties with intubation, especially when the medicine is used as part of a rapid sequence induction technique.
In cases of difficult intubation requiring immediate reversal of neuromuscular blockade induced by rocuronium, the use of sugammadex should be considered.
Cases of residual curarization have been reported with Esmeron, as with other neuromuscular blocking agents. To avoid complications arising from possible residual neuromuscular blockade, extubation should only be performed once the patient has sufficiently recovered from neuromuscular blockade. Elderly patients (aged 65 years or older) may be at increased risk of residual neuromuscular blockade. Other factors (e.g. potential pharmacological interactions or patient condition) that may lead to residual curarization in the postoperative period should also be considered. If not already part of standard clinical practice, the use of reversal agents (such as sugammadex or acetylcholinesterase inhibitors) should be considered, particularly in cases where residual curarization is more likely.
Anaphylactic reactions may occur following administration of neuromuscular blocking agents. Appropriate precautions must always be taken to manage such reactions. Particular caution is required in patients with a history of anaphylactic reactions to neuromuscular blocking agents, as cross-allergies have been reported.
In general, prolonged paralysis and/or skeletal muscle weakness have been observed following long-term administration of neuromuscular blocking agents in Intensive Care Units. To avoid possible prolongation of neuromuscular blockade and/or overdose, monitoring of neuromuscular transmission is recommended during administration of neuromuscular blocking agents. Patients should also receive adequate analgesia and sedation. The dose of neuromuscular blocking agents should be titrated according to individual response and administered under the supervision of an experienced physician familiar with the action of these medicines and appropriate neuromuscular monitoring techniques.
Myopathy has been regularly reported following long-term administration of other non-depolarizing neuromuscular blocking agents in Intensive Care Units, particularly when used in combination with corticosteroid therapy. Therefore, in patients receiving corticosteroids and neuromuscular blocking agents, the duration of use of the latter should be minimized as much as possible. If suxamethonium is used for intubation, administration of Esmeron should be delayed until the patient has clinically recovered from suxamethonium-induced neuromuscular blockade.

Hypertensive crisis in patients with phaeochromocytoma
Post-marketing data have identified cases of hypertensive crisis temporally associated with rocuronium administration in patients with diagnosed or latent phaeochromocytoma. Therefore, rocuronium should be used with caution in these patients.

The pharmacokinetic and/or pharmacodynamic properties of Esmeron may be influenced by the following conditions:

Hepatic and/or biliary disease and renal insufficiency
Since rocuronium is excreted in urine and bile, it should be used with caution in patients with clinically significant hepatic and/or biliary disease and/or renal insufficiency. Prolonged duration of action of rocuronium bromide has been observed in these patients with doses of 0.6 mg/kg body weight.

Prolonged circulation time
Conditions associated with prolonged circulation time, such as cardiovascular disease, advanced age, and oedematous states, which increase the volume of distribution, may contribute to a prolonged onset time. Duration of action may also be prolonged due to reduced plasma clearance.

Neuromuscular diseases
Like other neuromuscular blocking agents, Esmeron should be used with extreme caution in patients with neuromuscular disorders or a history of poliomyelitis, as responses to neuromuscular blocking agents may be significantly altered. The extent and direction of this alteration may vary considerably. In patients with myasthenia gravis or myasthenic syndrome (Eaton-Lambert), even small doses of Esmeron may produce profound effects; therefore, the dose should be titrated according to the observed response.

Hypothermia
During surgical procedures performed under hypothermic conditions, the neuromuscular blocking effect of Esmeron increases in both intensity and duration.

Obesity
As with other neuromuscular blocking agents, Esmeron may prolong the duration of action and spontaneous recovery time in obese patients when doses are calculated based on actual body weight.

Burns
Since burn patients may develop resistance to non-depolarizing neuromuscular blocking agents, dosage should be titrated according to the observed response.

Conditions that may increase the effects of Esmeron
Hypokalaemia (e.g. after severe vomiting, diarrhoea, or diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnia, cachexia.
Therefore, severe electrolyte imbalances, blood pH abnormalities, or dehydration should be corrected if possible.

Other medicines and Esmeron
The following medicines may influence the intensity and/or duration of action of non-depolarizing neuromuscular blocking agents.

Effect of other medicines on Esmeron
Increased effect

Anaesthetics: Halothane, ether, enflurane, methoxyflurane, cyclopropane. Volatile halogenated anaesthetics potentiate the neuromuscular blockade induced by Esmeron. This potentiation becomes evident only with maintenance doses. Inhibition of the antagonistic effect of acetylcholinesterase inhibitors may also occur.
After intubation with suxamethonium.
Concomitant long-term use of corticosteroids and Esmeron in Intensive Care Units may induce myopathy or prolong the duration of neuromuscular blockade.
High doses of thiopental, methohexital, ketamine, fentanyl, gamma-hydroxybutyrate, etomidate, and propofol.
Other neuromuscular blocking agents (non-depolarizing).
Other medicines
- Antibiotics: aminoglycosides, lincosamides, polypeptides, acylaminopenicillins, tetracyclines, high doses of metronidazole.
- Diuretics, thiamine, MAO inhibitors, quinidine and its isomer quinine, protamine, adrenergic blocking agents, magnesium salts, calcium antagonists, lithium salts, local anaesthetics (intravenous lidocaine, epidural bupivacaine), and acute administration of phenytoin and β-blockers. Cases of recurrent curarization have been reported following postoperative administration of quinidine, quinine, magnesium salts, and the following antibiotics: aminoglycosides, lincosamides, polypeptides, and acylaminopenicillins.

Decreased effect

Neostigmine, edrophonium, pyridostigmine, aminopyridine derivatives.
Chronic prior administration of corticosteroids, phenytoin, or carbamazepine.
Noradrenaline, azathioprine (only transient and limited effect), theophylline, calcium chloride, potassium chloride.
Protease inhibitors (gabexate, ulinastatin).

Variable effect

Administration of other non-depolarizing neuromuscular blocking agents in combination with Esmeron may result in either attenuation or potentiation of neuromuscular blockade, depending on the order of administration and the type of neuromuscular blocking agent used.
Administration of suxamethonium following Esmeron may result in either potentiation or attenuation of the neuromuscular blockade induced by Esmeron.

Effect of Esmeron on other medicines
The combination of Esmeron and lidocaine may reduce the latency time of lidocaine.

Paediatric patients
No formal interaction studies have been conducted. Interactions observed in adults and the related warnings and precautions should be considered for paediatric patients.

Pregnancy and breastfeeding
Pregnancy
There are no clinical data on exposure to rocuronium bromide during pregnancy. Animal studies have not shown any direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Caution is required when prescribing Esmeron to pregnant women.

Caesarean section
In patients undergoing caesarean section, Esmeron may be used as part of a rapid sequence induction technique, provided that no intubation difficulties are anticipated and an adequate dose of anaesthetic is administered, or after intubation following suxamethonium administration. Esmeron administered at a dose of 0.6 mg/kg body weight has been shown to be safe in parturients undergoing caesarean section. Esmeron does not affect Apgar scores, fetal muscle tone, or cardiorespiratory adaptation. Umbilical cord blood analysis indicates that rocuronium bromide crosses the placenta only to a minimal extent and does not result in observable adverse clinical effects in the neonate.

Note 1: Doses of 1.0 mg/kg body weight have been studied for rapid sequence induction, but not in patients undergoing caesarean section. Therefore, in this patient group, a dose of 0.6 mg/kg body weight is recommended.

Note 2: Reversal of neuromuscular blockade induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients treated with magnesium salts for pregnancy toxemia, as magnesium salts enhance neuromuscular blockade. Therefore, in these patients, the dose of Esmeron should be reduced and carefully adjusted according to the response to stimulation.

Breastfeeding
It is not known whether Esmeron is excreted in human milk. Animal studies have shown negligible concentrations of Esmeron in maternal milk. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development.
Esmeron should be administered to breastfeeding women only if the physician considers that the benefits outweigh the risks. After administration of a single dose, breastfeeding should be avoided for five elimination half-lives of rocuronium, approximately 6 hours.

Dosage and administration
As with other neuromuscular blocking agents, the dosage of Esmeron should be individualized. Factors to consider when determining the dose include the type of anaesthesia, expected duration of surgery, sedation method, expected duration of mechanical ventilation, potential interactions with concomitantly administered medicines, and the patient's condition.
Appropriate neuromuscular monitoring techniques are recommended to monitor neuromuscular blockade and recovery.
Inhalational anaesthetics potentiate the neuromuscular blocking effects of Esmeron. However, this potentiation becomes clinically relevant during anaesthesia when volatile agents have reached tissue concentrations sufficient for interaction. Therefore, dosage adjustments with Esmeron should involve smaller maintenance doses administered at longer intervals or reduced infusion rates during prolonged procedures (over 1 hour) under inhalational anaesthesia.

In adults, the following recommended doses may be used as a general guide for endotracheal intubation, muscle relaxation during short to long procedures, and use in Intensive Care Units.

Surgical procedures
Endotracheal intubation
The standard dose for intubation during standard anaesthesia is 0.6 mg/kg body weight of rocuronium bromide, which is sufficient to achieve adequate intubating conditions within 60 seconds in nearly all patients. To facilitate endotracheal intubation during rapid sequence induction, a dose of 1.0 mg/kg body weight of rocuronium bromide is recommended, which is sufficient to achieve adequate intubating conditions within 60 seconds in nearly all patients. If rocuronium bromide is administered at a dose of 0.6 mg/kg body weight for rapid sequence induction, a waiting time of 90 seconds before intubation is recommended.

High doses
If higher doses of rocuronium bromide are required in certain patients, it should be noted that initial doses up to 2 mg/kg body weight have been administered intraoperatively without observed cardiovascular adverse effects. High doses of rocuronium bromide reduce onset time and prolong duration of action.

Maintenance doses
The recommended maintenance dose is 0.15 mg/kg body weight of rocuronium bromide; under prolonged inhalational anaesthesia, the dose should be reduced to 0.075–0.1 mg/kg body weight. Maintenance doses should be administered when the response amplitude returns to 25% of control value, or when 2 or 3 responses are present to TOF (Train of Four) stimulation.

Continuous infusion
If rocuronium is administered by continuous infusion, a loading dose of 0.6 mg/kg body weight is recommended, followed by initiation of infusion at the first signs of recovery from neuromuscular blockade. The infusion rate should be adjusted to maintain neuromuscular response amplitude at 10% of control value or to maintain 1 or 2 responses to TOF stimulation. In adults, the infusion rate required to maintain neuromuscular blockade at these levels ranges from 0.3 to 0.6 mg/kg/h under intravenous anaesthesia and from 0.3 to 0.4 mg/kg/h under inhalational anaesthesia.
Continuous monitoring of neuromuscular blockade is recommended, as infusion rates vary between patients and according to anaesthetic technique.

Paediatric patients
For neonates (0–27 days), infants (28 days–2 months), toddlers (3 months–23 months), children (2–11 years), and adolescents (12–17 years), the recommended dose for intubation during standard anaesthesia and maintenance doses are similar to those recommended for adults.
However, the duration of action of a single intubation dose will be longer in neonates and infants compared to older children.
For continuous infusion in paediatrics, except in children (2–11 years), infusion rates are the same as in adults.
In children aged 2–11 years, higher infusion rates may be required.
Therefore, in children (2–11 years), it is recommended to start with the same initial infusion rate as in adults and then adjust it to maintain neuromuscular response amplitude at 10% of control value or to maintain 1 or 2 responses to TOF stimulation during surgery.
Experience with rocuronium bromide for rapid sequence induction in paediatric patients is limited. Therefore, the use of rocuronium bromide to facilitate endotracheal intubation during rapid sequence induction is not recommended in this patient group.

Elderly patients and patients with hepatic and/or biliary disease and/or renal insufficiency
The standard dose for intubation in elderly patients and those with hepatic and/or biliary disease and/or renal insufficiency during routine anaesthesia is 0.6 mg/kg body weight of rocuronium bromide. For rapid sequence induction in patients expected to have prolonged duration of action, a dose of 0.6 mg/kg body weight should be considered. Regardless of anaesthetic technique, the recommended maintenance dose for this patient group is 0.075–0.1 mg/kg body weight of rocuronium bromide, with an infusion rate of 0.3–0.4 mg/kg/h.

Overweight and obese patients
When the medicine is used in overweight or obese patients (defined as patients with body weight 30% or more above ideal body weight), dosing should be based on ideal body weight.

Intensive care procedures
Endotracheal intubation
For endotracheal intubation, refer to the same doses indicated above for surgical procedures.

Maintenance dose
An initial loading dose of rocuronium bromide of 0.6 mg/kg body weight is recommended, followed by continuous infusion as soon as the response amplitude returns to 10% or at reappearance of 1 or 2 responses to TOF stimulation.
Dosing should always be titrated according to the observed effect in each individual patient. In adult patients, the recommended initial infusion rate to maintain 80–90% neuromuscular blockade (presence of 1 or 2 responses to TOF stimulation) is 0.3–0.6 mg/kg/h for the first hour, which should then be reduced over the next 6–12 hours according to individual response. After this period, the individual dose required remains relatively constant in each patient.
Controlled clinical studies have shown considerable individual variability in hourly infusion rates, averaging 0.2–0.5 mg/kg/h depending on the nature and extent of organ insufficiency, concomitant medications, and individual patient characteristics. To ensure optimal patient control, neuromuscular transmission monitoring is strongly recommended. Administration for up to 7 days has been studied.

Special patient populations
Esmeron is not indicated to facilitate mechanical ventilation in intensive care in paediatric and elderly patients due to lack of safety and efficacy data.

Adverse effects
The most commonly observed adverse reactions to the medicine include pain and/or reactions at the injection site, changes in vital signs, and prolonged muscle blockade.
The most frequently reported serious adverse reactions to the pharmacovigilance system are anaphylactic and anaphylactoid reactions and associated symptoms.

Anaphylaxis
Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including Esmeron, have been described. Anaphylactic/anaphylactoid reactions include bronchospasm, cardiovascular changes (e.g. hypotension, tachycardia, circulatory collapse – shock), and cutaneous changes (e.g. angioedema, urticaria). These reactions have been fatal in some cases. Given the potential severity of these reactions, their occurrence must always be considered and all necessary precautions taken.
Since neuromuscular blocking agents may induce histamine release both locally at the injection site and systemically, pruritus and erythematous reactions at the injection site and/or generalized histaminoid (anaphylactoid) reactions should always be considered when administering these medicines (see also above regarding anaphylactic reactions).
In clinical studies, only a slight increase in mean plasma histamine levels was observed following rapid bolus administration of 0.3–0.9 mg/kg body weight of rocuronium bromide.

Prolonged neuromuscular blockade
The most frequent adverse reaction in the class of non-depolarizing neuromuscular blocking agents is the persistence of pharmacological action beyond the required time period. Effects may range from skeletal muscle weakness to profound and prolonged paralysis, potentially leading to respiratory insufficiency or apnoea.

Myopathy
Cases of myopathy have been reported following the use of various neuromuscular blocking agents in Intensive Care Units in combination with corticosteroids (see section “Warnings and precautions”).

Local reactions at injection site
Pain at the injection site has been reported during rapid sequence induction, particularly when the patient has not yet fully lost consciousness, and especially when propofol is used for induction. In clinical studies, injection site pain was reported in 16% of patients undergoing rapid sequence induction with propofol, and in less than 0.5% of patients undergoing rapid sequence induction with fentanyl and thiopental.

Overdose
In cases of overdose and prolonged neuromuscular blockade, the patient should remain under controlled ventilation and sedation. In this situation, two options are available for reversal of neuromuscular blockade: 1) in adults, sugammadex may be used to reverse intense and profound blockade. The dose of sugammadex depends on the level of neuromuscular blockade; 2) an acetylcholinesterase inhibitor (neostigmine, edrophonium, pyridostigmine) or sugammadex may be used at the first signs of spontaneous recovery, administered in appropriate doses.
If administration of anticholinesterases fails to antagonize the neuromuscular effects of Esmeron, ventilation should be continued until spontaneous respiration resumes. Repeated administration of acetylcholinesterase inhibitors may be dangerous.
In animal studies, severe cardiovascular depression leading to cardiac collapse occurred only after administration of a cumulative dose of 750 x ED (135 mg/kg body weight of rocuronium bromide).

How to store Esmeron
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton after "Exp" and on the label after "EXP". The expiry date refers to the last day of that month.
The stated expiry date applies to the product if unopened and stored correctly.
Do not use this medicine if visible signs of deterioration are present.
Store in a refrigerator (2°C–8°C). The medicine may be stored outside the refrigerator at a temperature up to 30°C for a maximum of 3 months. The medicine may be moved in and out of the refrigerator at any time during the 36-month shelf life, but the total storage time outside the refrigerator must not exceed 3 months. The storage period must not exceed the expiry date stated on the label.
After opening the vial, the solution is chemically stable for 24 hours at room temperature. Since Esmeron does not contain preservatives, unused solution should be discarded.

Instructions for use and handling
Compatibility studies have been performed with the following infusion solutions. At nominal concentrations of 0.5 mg/mL and 2.0 mg/mL, Esmeron was found to be compatible with:

0.9% Sodium chloride
5% Dextrose
5% Dextrose in physiological saline
Water for injections
Lactated Ringer's solution
Haemaccel.

Solutions should be used within 24 hours and immediately after mixing.
Discard unused solution.

Incompatibilities
Physical incompatibility has been documented when Esmeron is added to solutions containing the following medicines: amphotericin, amoxicillin, azathioprine, cefazolin, cloxacillin, dexamethasone, diazepam, enoximone, erythromycin, famotidine, furosemide, hydrocortisone sodium succinate, insulin, methohexital, methylprednisolone, prednisolone sodium succinate, thiopental, trimethoprim, and vancomycin.
Esmeron is also incompatible with Intralipid.
Esmeron must never be mixed with medicinal products other than those listed in the section "Instructions for use and handling". If Esmeron is administered through the same infusion line used for other medicines, it is important to adequately flush the line (e.g. with 0.9% NaCl) between administration of Esmeron and medicines with which it is known to be incompatible or whose compatibility with Esmeron has not been established.
Do not dispose of any medicine via wastewater or household waste. This will help protect the environment.

Esmiron