Immaroc 50mg Solution for Injection

IMMAROC 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. IMMAROC 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.

Posology
IMMAROC should only be administered by, or under supervision of, experienced medical practitioners who are familiar with the action and use of these medicines. The dosage of IMMAROC 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 IMMAROC. 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 IMMAROC should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of IMMAROC 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 IMMAROC 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 IMMAROC, after which adequate intubation conditions are established within 90 seconds. A dose of 1 mg/kg IMMAROC 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 IMMAROC have been administered during surgery without adverse cardiovascular effects being noted. The use of these high dosages of IMMAROC 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 IMMAROC. In the case of long-term inhalational anaesthesia, this should be reduced to 0,075 to 0,1 mg/kg IMMAROC. 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 5.1). No cumulation of effect (progressive increase in duration of action) with repetitive maintenance dosing at the recommended level has been observed.

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 infants (28 days- 23 months), children (2-14 years) and adolescents (12-18 years) the recommended intubation dose during routine anaesthesia and maintenance dose are similar to those in adults. For children higher infusion rates might be necessary. Thus, for children 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.

Elderly patients and patients with hepatic and/or biliary tract disease and/or renal failure
The standard intubation dose for elderly patients and patients with hepatic and/or biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg rocuronium bromide. 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. 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.

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

Method of administration
IMMAROC is administered intravenously either as a bolus injection or as a continuous infusion (see section 6.6).

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 IMMAROC in neonates (0 to 1 month). IMMAROC is not recommended for the facilitation of mechanical ventilation in the intensive care in paediatric and elderly 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 IMMAROC.

It is not recommended to use potentially dangerous machinery or drive a vehicle [car] within 24 hours after the full recovery from the neuromuscular blocking action of IMMAROC.

Appropriate Administration and Monitoring
Since IMMAROC 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 IMMAROC. In order to prevent complications resulting from residual curarisation, it is recommended to extubate only after the patient has recovered sufficiently from neuromuscular block. Elderly 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 IMMAROC 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 IMMAROC. Patients should receive adequate analgesia and sedation. Furthermore, IMMAROC should be titrated to effect in the individual patients by, or under supervision of, experienced medical practitioners who are familiar with its actions and with appropriate neuromuscular monitoring techniques.

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

Use with Suxamethonium
If suxamethonium is used for intubation, the administration of IMMAROC 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 IMMAROC 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 IMMAROC: 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
IMMAROC 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 IMMAROC may have profound effects and IMMAROC should be titrated to the response.

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

Obesity
IMMAROC 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 IMMAROC
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.

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 IMMAROC
Increased effect:
u2022 Halogenated volatile anaesthetics potentiate the neuromuscular block of IMMAROC. The effect only becomes apparent with maintenance dosing (see section 4.2). Reversal of the block with acetylcholinesterase inhibitors could also be inhibited.
u2022 After intubation with suxamethonium (see section 4.4).
u2022 Long-term concomitant use of corticosteroids and IMMAROC in the ICU may result in prolonged duration of neuromuscular block or myopathy (see section 4.4 and 4.8).

Other medicines:
u2022 antibiotics: aminoglycoside, lincosamide and polypeptide antibiotics, acylamino-penicillin antibiotics.
u2022 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 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 section 4.4).

Decreased effect:
u2022 Prior chronic administration of phenytoin or carbamazepine.
u2022 Calcium chloride, potassium chloride.
u2022 Protease inhibitors (gabexate, ulinastatin).

Variable effect:
u2022 Administration of other non-depolarising neuromuscular blocking agents in combination with IMMAROC 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 IMMAROC may produce potentiation or attenuation of the neuromuscular blocking effect of IMMAROC.

Effect of IMMAROC on other medicines
IMMAROC 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.

Safety in pregnancy and lactation has not been demonstrated.

Caesarean Section
In patients undergoing Caesarean section, IMMAROC 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 IMMAROC, 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. IMMAROC 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 IMMAROC should be reduced and be titrated to twitch response.

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

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
MedDRA SOC FREQUENCY Less Frequent Immune system disorders Hypersensitivity Angioedema Anaphylactic reaction Anaphylactoid reaction Anaphylactic shock Anaphylactoid shock 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 Urticaria Rash Erythematous rash Musculoskeletal and connective tissue disorders Muscular weakness Steroid myopathy General disorders and administration site conditions Medicine ineffective Face oedema Medicine effect/ therapeutic response decreased Malignant hyperthemia Medicine effect/ therapeutic response increased Injection site pain Injection site reaction Injury, poisoning and procedural complications Airway complication of anaesthesia Delayed recovery from anaesthesia Anaphylaxis Severe anaphylactic reactions to neuromuscular blocking agents, including IMMAROC, have been reported. Anaphylactic/anaphylactoid reactions are: bronchospasm, cardiovascular changes (e.g. hypotension, tachycardia, circulatory collapse u2013 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 medicines. 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.

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 to SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8

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 IMMAROC, ventilation must be continued until spontaneous breathing is restored. Repeated dosage of an acetylcholinesterase inhibitor can be dangerous.