4.1. Therapeutic indications

Rocuronium bromide 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 rocuronium bromide 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, rocuronium bromide 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 rocuronium bromide 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 rocuronium bromide. 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 rocuronium bromide should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of rocuronium bromide 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.

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.

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. 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

Rocuronium bromide 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

Rocuronium bromide 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 listed in section 6.1.

4.4. Special warnings and precautions for use

Since rocuronium bromide causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this drug until adequate 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 rocuronium bromide. 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 rocuronium bromide, hypersensitivity to other neuromuscular blocking agents should be excluded. Rocuronium bromide 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 rocuronium bromide should be delayed until the patient has clinically recovered from the neuromuscular block induced by suxamethonium.

Because rocuronium bromide is always used with other drugs and because of the risk of malignant hyperthermia during anesthesia, even in the absence of known triggering factors, physicians should be aware of the early symptoms, confirmatory diagnosis and treatment of malignant hyperthermia prior to the start of anesthesia. Animal studies have shown that rocuronium bromide is not a triggering factor for malignant hyperthermia. Rare cases of malignant hyperthermia with rocuronium bromide have been observed thru post-marketing surveillance; however, the causal association has not been proven.

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

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, rocuronium bromide 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 rocuronium bromide may have profound effects and rocuronium bromide should be titrated to the response.

Hypothermia

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

Obesity

Like other neuromuscular blocking agents, rocuronium bromide 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 rocuronium bromide

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.

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml, that is to say essentially 'sodium free'.

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 rocuronium bromide

Increased effect:

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

• High doses of: thiopental, methohexital, ketamine, fentanyl, gamma-hydroxybutyrate, etomidate and propofol.

• Other non-depolarizing neuromuscular blocking agents.

• After intubation with suxamethonium (see section 4.4).

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

Other medicinal products:

• Antibiotics: aminoglycosides, lincosamides and polypeptide antibiotics, acylamino-penicillin antibiotics, tetracyclines, high doses of metronidazole.

• Diuretics, thiamine, MAO-inhibiting agents, quinidine and its isomer quinine, protamine, adrenergic blocking agents, magnesium salts, calcium channel blocking agents, lithium salts, local anaesthetics (lidocaine IV, bupivacaine epidural) and acute administration of phenytoin or ß-blocking agents.

Recurarisation has been reported after post-operative administration of: aminoglycosides, lincosamides, polypeptide and acylamino-penicillin antibiotics, quinidine, quinine and magnesium salts (see section 4.4).

Decreased effect:

• Neostigmine, edrophonium, pyridostigmine, aminopyridine derivatives.

• Prior chronic administration of corticosteroids, phenytoin or carbamazepine.

• Noradrenaline (norepinephrine), azathioprine (only transitory and limited effect), theophylline, calcium chloride, potassium chloride.

• Protease inhibitors (gabexate, ulinastatin).

Variable effect:

• Administration of other non-depolarising neuromuscular blocking agents in combination with rocuronium bromide 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 rocuronium bromide may produce potentiation or attenuation of the neuromuscular blocking effect of rocuronium bromide.

Effect of rocuronium bromide on other drugs

Rocuronium bromide 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. Fertility, 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 rocuronium bromide to pregnant women.

Caesarean section

In patients undergoing Caesarean section, rocuronium bromide 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, rocuronium bromide, 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.

Rocuronium bromide 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 toxaemia of pregnancy because magnesium salts enhance neuromuscular blockade. Therefore, in these patients the dosage of rocuronium bromide 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.

There are no human data on the use of rocuronium bromide during lactation. Rocuronium bromide should be given to lactating women only when the attending physician decides that the benefits outweigh the risks. After the administration of a single dose, it is recommended to abstain from next breast-feeding for five elimination half-lives of rocuronium, i.e. for about 6 hours.

Fertility

There is no data available regarding the effect in the fertility for this product.

4.7. Effects on ability to drive and use machines

Rocuronium bromide has a major influence on the ability to drive and use machines. Since rocuronium bromide is used as an adjunct to general anaesthesia, the usual precautionary measures after a general anaesthesia should be taken for ambulatory patients. It is not recommended to use potentially dangerous machinery or to drive a car during the first 24 hours after the full recovery from the neuromuscular blocking action of rocuronium bromide.

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.

The frequency of undesirable effects is classified into the following categories:

Uncommon

Rare

Very rare

Not known

(≥ 1/1 000 to < 1/100)

(≥ 1/10 000 to < 1/1 000)

(< 1/10 000)

(cannot be estimated from the available data)

Tabulated list of adverse reactions

MedDRA

System Organ Class

Preferred term1

Uncommon/rare2

Very rare

Not known

Immune system disorders

Hypersensitivity

Anaphylactic reaction

Anaphylactoid reaction

Anaphylactic shock

Anaphylactoid shock

Nervous system disorders

Flaccid paralysis

Eye disorders

Mydriasis3

Fixed pupils3

Cardiac disorders

Tachycardia

Kounis syndrome

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

Muscular weakness4

Steroid myopathy4

General disorders and administration site conditions

Drug ineffective

Drug effect/ therapeutic response decreased

Drug effect/ therapeutic response increased

Injection site pain

Injection site reaction

Face oedema

Injury, poisoning and procedural complications

Prolonged neuromuscular block

Delayed recovery from anaesthesia

Airway complication of anaesthesia

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 In the context of a potential increase of permeability or compromise of the integrity of the Blood-Brain Barrier (BBB).

4 After long-term use in the ICU.

Anaphylaxis

Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including rocuronium bromide, 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 non-depolarising 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 apnoea.

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 via the Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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 rocuronium bromide, 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.