Inspironium

NAME OF THE MEDICINAL PRODUCT

Inspironium 10mg / 1ml solution for injection or Infusion

CLINICAL PARTICULARS

Therapeutic indications

Inspironium 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. Inspironium is also indicated as an adjunct in the intensive care unit (ICU) to facilitate intubation and mechanical ventilation.

Posology and method of administration

Like other neuromuscular blocking agents, Inspironium 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 Inspironium should be individualized 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 Inspironium. 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 Inspironium should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of Inspironium 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 patients
For infants (28 days–23 months), children (2-11 years) and adolescents (12–18 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 the 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.
There are insufficient data to support dose recommendations for the use of rocuronium bromide in neonates (0-1 month).
The experience with rocuronium bromide in rapid sequence induction in paediatric patients is limited. Rocuronium bromide is therefore not recommended for facilitating tracheal intubation conditions during rapid sequence induction in paediatric patients.
Geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure
The standard intubation dose for geriatric patients and patients with hepatic and/or biliary tract disease and/or renal failure during routine anaesthesia is 0.6 mg/kg rocuronium bromide. A dose of 0.6 mg/kg should be considered for rapid sequence induction of anaesthesia in patients in which a prolonged duration of action is expected. Regardless of the anaesthetic technique used, the recommended maintenance dose for these patients is 0.075-0.1 mg/kg rocuronium bromide, and the recommended infusion rate is 0.3-0.4 mg/kg/h (see also Continuous infusion).
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
Inspironium 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.
Administration
Inspironium is administered intravenously either as a bolus injection or as a continuous infusion (see section 6.6).

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 Inspironium
Increased effect:

  • Halogenated volatile anaesthetics potentiate the neuromuscular block of Inspironium. The effect only becomes apparent with maintenance dosing (see section 4.2). Reversal of the block with anticholinesterase inhibitors could also be inhibited.
  • After intubation with suxamethonium (see section 4.4).
  • Long-term concomitant use of corticosteroids and Inspironium in the ICU may result in prolonged duration of neuromuscular block or myopathy (see section 4.4 and 4.8).
  • Other drugs:
  • antibiotics: aminoglycoside, lincosamide and polypeptide antibiotics, acylamino-penicillin antibiotics.
  • diuretics, quinidine and its isomer quinine, magnesium salts, calcium channel blocking agents, lithium salts, local anaesthetics (lidocaine i.v, bupivacaine epidural) and acute administration of phenytoin or β-blocking agents.
  • Recurarisation has been reported after post-operative administration of: aminoglycoside, lincosamide, polypeptide and acylamino-penicillin antibiotics, quinidine, quinine and magnesium salts (see section 4.4).

Decreased effect:

  • Prior chronic administration of phenytoin or carbamazepine.
  • Calcium chloride, potassium chloride.
  • Protease inhibitors (gabexate, ulinastatin).

Variable effect:

  • Administration of other non-depolarising neuromuscular blocking agents in combination with Inspironium 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 Inspironium may produce potentiation or attenuation of the neuromuscular blocking effect of Inspironium.
  • Effect of Inspironium on other drugs
  • Inspironium combined with lidocaine may result in a quicker onset of action of lidocaine.

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 Inspironium to pregnant women.
Caesarean section
In patients undergoing Caesarean section, Inspironium 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, Inspironium, 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. Inspironium does not affect Apgar score, foetal muscle tone or cardiorespiratory adaptation.
From umbilical cord blood sampling it is apparent that only limited placental transfer of rocuronium bromide occurs which does not lead to the observation of clinical adverse effects in the newborn.
Note 1: doses of 1.0 mg/kg have been investigated during rapid sequence induction of anaesthesia, but not in Caesarean section patients. Therefore, only a dose of 0.6 mg/kg is recommended in this patient group.
Note 2: Reversal of neuromuscular block induced by neuromuscular blocking agents may be inhibited or unsatisfactory in patients receiving magnesium salts for toxemia of pregnancy because magnesium salts enhance neuromuscular blockade. Therefore, in these patients the dosage of Inspironium should be reduced and be titrated to twitch response.
Lactation
It is unknown whether rocuronium bromide is excreted in human breast milk. Animal studies have shown insignificant levels of rocuronium bromide in breast milk.
Insignificant levels of rocuronium bromide were found in the milk of lactating rats. There are no human data on the use of Inspironium during lactation. Inspironium should be given to lactating women only when the attending physician decided that the benefits outweigh the risks

Effects on ability to drive and use machines

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

Overdose

In the event of overdosage and prolonged neuromuscular block, the patient should continue to receive ventilatory support and sedation. Upon 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 Inspironium, 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.

Special precautions for storage

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