Esmeron 10mg / 1ml Injection

ESMERON is indicated as an adjunct to general anaesthesia to facilitate tracheal intubation during routine and rapid sequence induction, and to provide skeletal muscle relaxation during surgery. ESMERON is also indicated as an adjunct in the Intensive Care Unit to facilitate intubation and mechanical ventilation for up to 3 days in adults 18 to 65 years.

Dosage
ESMERON should only be administered by, or under supervision of, experienced doctors who are familiar with the action and use of these medicines. 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 medication that is 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 potentiate the neuromuscular blocking effects of ESMERON. 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). Risk of Medication Errors: Accidental administration of neuromuscular blocking agents may result in serious adverse events, including fatal outcomes. Store ESMERON with the cap and ferrule intact and in a manner that minimizes the possibility of selecting the wrong product (see section 4.4).

In adult patients the following dosage recommendations 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 ESMERON, after which adequate intubation conditions are established within 90 seconds. A dose of 1 mg/kg ESMERON is recommended for facilitating tracheal intubation conditions during rapid sequence induction of anaesthesia. At this dose adequate intubation conditions are established within 60 seconds in nearly all patients. Higher doses should there be reason for selection of larger doses in individual patients, initial doses up to 2 mg/kg ESMERON have been administered during surgery without adverse cardiovascular effects being noted. The use of these high dosages of ESMERON decreases the onset time and increases the duration of action (see section 5, 5.1 Pharmacodynamic properties).

Maintenance dosing
The recommended maintenance dose is 0,15 mg/kg ESMERON. In the case of long-term inhalational anaesthesia, this should be reduced to 0,075 to 0,1 mg/kg ESMERON. The maintenance doses should best be given as a bolus when twitch height has recovered to 25 % of control twitch height, or when 2 to 3 responses to train of four stimulation are present (see section 5, 5.1 Pharmacodynamic properties). No cumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed. Continuous infusion: If ESMERON is administered by continuous infusion it is recommended to give a loading dose of 0,6 mg/kg ESMERON 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 to 0,6 mg/kg/h and under inhalational anaesthesia the infusion rate ranges from 0,3 to 0,4 mg/kg/h. Continuous monitoring of neuromuscular block is recommended since infusion rate requirements vary from patient to patient and with the anaesthetic method used.

Paediatric patients
For infants (28 days to 23 months), children (2 to 11 years) and adolescents (12 to 18 years) the recommended intubation dose during routine anaesthesia and maintenance dose are similar to those in adults. For continuous infusion in paediatrics the infusion rates, with exception of children, are the same as for adults. For children higher infusion rates might be necessary. For children the same initial infusion rates as for adults are recommended, and 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 ESMERON in rapid sequence induction in paediatric patients is limited. ESMERON is therefore not recommended, for facilitating tracheal intubation conditions during rapid sequence induction in paediatric patients.

Special populations
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 ESMERON. Regardless of the anaesthetic technique used, the recommended maintenance dose for these patients is 0,075 to 0,1 mg/kg ESMERON, and the recommended infusion rate is 0,3 to 0,4 mg/kg/h (see Continuous infusion). See section 4.4. Overweight and obese patients: When used in overweight or obese patients (defined as patients with a body mass of 30 % or more above ideal body mass) doses should be reduced taking into account an 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 ESMERON 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 to 90 % (1 to 2 twitches to train of four stimulation) in adult patients is 0,3 to 0,6 mg/kg/h during the first hour of administration, which will need to be decreased during the following 6 to 12 hours, according to individual response. Thereafter, individual dose requirements remain relatively constant. A large between patient variability in hourly infusion rates has been found, with mean hourly infusion rates ranging from 0,2 to 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. Safety and efficacy beyond 3 days has not been established. 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 to 5) hours in patients without multiple organ failure and 4 (1 to 25) hours in patients with multiple organ failure.

Administration
ESMERON is administered intravenously either as a bolus injection or as a continuous infusion.

Hypersensitivity to rocuronium or to the bromide ion or to any of the excipients. There is insufficient data to support recommendations for the use of ESMERON in neonates (0 to 1 month). 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. Safety in pregnancy and lactation has not been demonstrated (see section 4.6).

Anaphylaxis
Anaphylactic and anaphylactoid reactions may occur. Precautions for treating such reactions should always be taken, particularly in the case of previous anaphylactic reactions to neuromuscular blocking agents, since allergic cross-reactivity to neuromuscular blocking agents has been reported.

Histamine Release and Histaminoid Reactions
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 reactions at the site of injection and/or generalised histaminoid (anaphylactoid) reactions should always be taken into consideration when administering these medicines. In clinical studies only a slight increase in mean plasma histamine levels has been observed following rapid bolus administration of 0,3 to 0,9 mg/kg ESMERON. It is not recommended to use potentially dangerous machinery or drive a car within 24 hours after the full recovery from the neuromuscular blocking action of ESMERON.

Appropriate Administration and Monitoring
Since ESMERON causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this medicine until adequate spontaneous respiration is restored. It is important to anticipate intubation difficulties, particularly when used as part of a rapid sequence induction technique.

Residual Curarisation
Residual curarisation has been reported for ESMERON. In order to prevent complications resulting from residual curarisation, 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 curarisation after extubation in the post-operative phase (such as medicine interactions or patient condition) should also be considered. If not used as part of standard clinical practice, the use of a reversal agent should be considered, especially in those cases where residual curarisation is more likely to occur.

Long-Term Use in an Intensive Care Unit
Following long term use of ESMERON in the Intensive Care Unit, 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 ESMERON.

Patients should receive adequate analgesia and sedation. Furthermore, ESMERON should be titrated to effect in the individual patients by, or under supervision of, experienced doctors who are familiar with its actions and with appropriate neuromuscular monitoring techniques.

Myopathy after long-term administration of ESMERON in the Intensive Care Unit, in combination with corticosteroid therapy, has been reported. Therefore, for patients receiving both ESMERON and corticosteroids, the period of use of ESMERON should be limited as much as possible.

Use with Suxamethonium
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.

Risk of Death due to Medication Errors
Administration of ESMERON results in paralysis, which may lead to respiratory arrest and death, a progression that may be more likely to occur in a patient for whom it is not intended. Confirm proper selection of intended product and avoid confusion with other injectable solutions that are present in critical care and other clinical settings. If another healthcare provider is administering the product, ensure that the intended dose is clearly labelled and communicated.

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, ESMERON 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 ESMERON.

Prolonged circulation time
Conditions associated with prolonged circulation time such as cardiovascular disease, old age and oedematous states 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 reduced plasma clearance.

Neuromuscular disease
ESMERON should be used with extreme caution in patients with 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
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, hypercapnoea, cachexia. Severe electrolyte disturbances, altered blood pH or dehydration should therefore be corrected when possible.

The following medicines have been shown to influence the magnitude and/or duration of action of non-depolarising neuromuscular blocking agents:

Effect of other medicines on ESMERON
Increased effect
u2022 Halogenated volatile anaesthetics potentiate the neuromuscular block of ESMERON. The effect only becomes apparent with maintenance dosing (see u201csection 4.2, Surgical Procedures, Maintenance dosingu201d). Reversal of the block with acetylcholinesterase inhibitors could also be inhibited.
u2022 After intubation with suxamethonium (see u201csection 4.2u201d).

Long-term concomitant use of corticosteroids and ESMERON in the Intensive Care Unit may result in prolonged duration of neuromuscular block or myopathy (see u201csection 4.4u201d).

Other medicines
u2022 Antibiotics: Aminoglycoside, lincosamide and polypeptide antibiotics, acylaminopenicillin antibiotics.
u2022 Diuretics, quinidine and its isomer quinine, magnesium salts, calcium channel blocking agents, lithium salts, local anaesthetics (lidocaine iv bupivacaine epidural) and acute administration of phenytoin or u00df-blocking agents. Recurarisation has been reported after post-operative administration of: aminoglycoside, lincosamide, polypeptide and acylamino-penicillin antibiotics, quinidine, quinine and magnesium salts (see u201csection 4.4u201d).

Decreased effect
u2022 Prior chronic administration of phenytoin or carbamazepine.
u2022 Protease inhibitor homologues (such as gabexate and ulinastatin).

Variable effect
u2022 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.
u2022 Suxamethonium given after the administration of ESMERON, may produce potentiation or attenuation of the neuromuscular blocking effect of ESMERON.

Effect of ESMERON on other medicines
ESMERON combined with lidocaine (lignocaine) may result in a quicker onset of action of lidocaine.

Safety in pregnancy and lactation has not been demonstrated. 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 patients 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. 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. Reversal of neuromuscular block, induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients receiving magnesium salts for toxaemia 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.

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

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 u2018anaphylactic and anaphylactoid reactionsu2019 and associated symptoms. See also further explanations below. The following side effects have been reported and the frequencies indicators are as follows: Uncommon/Rare ( 1/10 000); Very rare (< 1/10 000) Uncommon/Rare ( 1/10 000); Very rare (< 1/10 000) Immune system disorders hypersensitivity, anaphylactic reaction, anaphylactoid reaction, anaphylactic shock, anaphylactoid shock (see section 4.4)

Eye disorders Mydriasis Fixed pupils Nervous system disorders flaccid paralysis Cardiac disorders tachycardia Vascular disorders hypotension circulatory collapse and shock, flushing Respiratory, thoracic and mediastinal disorders bronchospasm Skin and subcutaneous tissue disorders angioneurotic oedema, urticaria, rash, erythematous rash Musculoskeletal and connective tissue disorders after long-term use in the Intensive Care Unit muscular weakness and a few cases of steroid myopathy have been reported (see section 4.4)

General disorders and administration site conditions medicine ineffective, decreased medicine effect/therapeutic response, increased medicine effect/therapeutic response, injection site pain, injection site reaction facial oedema, malignant hyperthermia Injury, poisoning and procedural complications prolonged neuromuscular block, delayed recovery from anaesthesia airway complication of anaesthesia. Anaphylaxis Although very rare, severe anaphylactic reactions to 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, the necessary precautions should always be taken in anticipation thereof.

Histamine release See u201csection 4.4u201d. Prolonged neuromuscular block The most frequent adverse reaction to ESMERON consists of an extension of the medicineu2019s pharmacological action beyond the time period required. This may vary from skeletal muscle weakness to profound and prolonged skeletal muscle paralysis resulting in respiratory insufficiency or apnoea. Myopathy has been reported in the Intensive Care Unit after the use of ESMERON in combination with corticosteroids (see section 4.4). Local injection site reactions Pain on injection has been noted in patients who underwent rapid sequence induction of anaesthesia.

In the event of overdosage and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. At the start of spontaneous recovery an acetylcholinesterase inhibitor (e.g. neostigmine, edrophonium, pyridostigmine) 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 was administered. Further treatment is symptomatic and supportive.