Merck Sharp & Dohme Limited

Section 2: Qualitative and quantitative composition

Norcuron 10 mg, 1 vial contains: Vecuronium bromide 10mg

Changed to: Norcuron® 10 mg, powder for solution for injection

Section 3: Pharmaceutical form

Powder for injection.

Changed to: Powder for solution for injection.

Section 4.1: Therapeutic indications

The word endotracheal  changed to tracheal

Section 4.2: Posology and method of administration

New statements added:

• As with other neuromuscular blocking agents, Norcuron should only be administered by, or under supervision of, experienced clinicians who are familiar with the action and use of these drugs.

• Inhalational anaesthetics potentiate the neuromuscular blocking effects of Norcuron. 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 Norcuron should be made by administering smaller maintenance doses at less frequent intervals or by using lower infusion rates of Norcuron 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.

• Tracheal intubation:

The standard intubating dose during routine anaesthesia is 80 to 100 micrograms vecuronium bromide per kg body weight, after which adequate intubation conditions are established within 90 to 120 seconds in nearly all patients.

The use of a peripheral nerve stimulator is recommended to monitor neuromuscular blockade and recovery.

Replaced with:

The use of an appropriate neuromuscular monitoring technique is recommended to monitor neuromuscular block and recovery.

New paragraph with headings titled:

Section 4.3: Contraindications

Statement: Former anaphylactic reactions to vecuronium or the bromide ion.

Replaced with: Hypersensitivity to vecuronium or the bromide ion or to any of the excipients of Norcuron.

Section 4.4: Special warnings and special precautions for use

New additions:

Since Norcuron causes paralysis of the respiratory muscles, ventilatory support is mandatory for patients treated with this drug until adequate spontaneous respiration is restored.

As with other neuromuscular blocking agents, residual neuromuscular blockade has been reported for Norcuron. 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. 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 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 Norcuron, hypersensitivity to other neuromuscular blocking agents should be excluded.  Norcuron 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.

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, muscle relaxants 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 non-depolarising neuromuscular blocking agents in the ICU in combination with corticosteroid therapy has been reported frequently. 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.

Paragraph titled Hepatic &/or biliary tract disease and renal failure deleted.

New paragraph on Obesity & Burns added

Section 4.5: Interaction with other medicinal products and other forms of interaction

New additions titled:

Section 4.6: Pregnancy and lactation

New paragraph on lactation added.

Section 4.7: Effects on ability to drive and use machines

Deleted: 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 Norcuron.

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

Section 4.8: Undesirable effects

New AE tabled added

Section 4.9: Overdose

Changes to statement.

Section 5.1: Pharmacodynamic properties

succinylcholine, replaced with suxamethonium

New headings and changes:

Within the clinical dosage range,vecuronium does not block the sympathetic nicotininic receptors, and thus exerts no ganglion  blocking activity.  In addition, in this dose range vecuronium does not block the parasympathetic muscarinic receptors, and thus exerts no vagolytic activity.

Tracheal intubation

Within 90 to 120 seconds following intravenous administration of a dose of 80 to 100 micrograms vecuronium bromide per kg body weight, good to excellent conditions for endotracheal intubation occur and within 3 to 4 minutes following administration of these dosages, general muscle paralysis adequate for any type of surgery is established. The duration of action to 25% recovery of control twitch height (clinical duration) with this dose is 24 to 60 minutes.  The time to 95% recovery of control twitch height following this dose is approximately 60 to 80 minutes. With higher dosages of Norcuron, onset time to maximal block is shortened and duration of action is prolonged. 

Continuous intravenous infusion

When Norcuron is administered by continuous intravenous infusion, a steady state neuromuscular block of 90% can be maintained at a constant rate of drug delivery and without clinically significant prolongation of the recovery time from neuromuscular block at termination of the infusion. 

Norcuron has no cumulative effects if maintenance doses are administered at 25% recovery of control twitch height.  Several maintenance doses can therefore be given in succession.

These properties allow the use of Norcuron in short, medium and long lasting surgical procedures.

Reversal of neuromuscular block

Administration of acetylcholinesterase inhibitors, such as neostigmine, pyridostigmine or edrophonium, antagonises the action of Norcuron.

Paediatric patients

Neonates and infants:

In neonates and infants the ED₉₅ dose of vecuronium bromide under balanced anaesthesia was found to be approximately the same (approx. 47 micrograms/kg body weight) as in adults.

The onset time of Norcuron in neonates and infants is considerably shorter as compared to children and adults, probably due to the shorter circulation time and larger cardiac output. Also, a greater sensitivity of the neuromuscular junction to the action of neuromuscular blocking agents in these patients may account for a more rapid onset of action.

The duration of action and recovery time with Norcuron is longer in neonates and infants than in adults. Maintenance doses of Norcuron should therefore be less frequently administered.

Children:

In children the ED₉₅ dose of vecuronium bromide under nitrous oxide in oxygen anaesthesia was found to be higher than in adults (81 vs 43 micrograms/kg bodyweight, respectively).  In comparison to adults, the duration of action and recovery time with Norcuron in children are in general approximately 30% and 20-30% shorter respectively.

Similar to adults, cumulative effects with repeat maintenance doses of approximately one quarter of the initial dose and administered at 25% recovery of control twitch height are not observed in paediatric patients. 

Section 5.2: Pharmacokinetic properties

After intravenous administration of Norcuron, the distribution half-life of vecuronium amounts to approx. 2.2 (+ 1.4) minutes.  Vecuronium is mainly distributed in the extracellular fluid compartment.  At steady state, the volume of distribution averages 0.27 l.kg-1 and its plasma elimination half-life averages 71 (+ 20) minutes.

Replaced with:

After intravenous administration of 100–150 micrograms/kg vecuronium, the distribution half-life of vecuronium amounts to 1.2-1.4 minutes. 

Vecuronium is mainly distributed in the extracellular fluid compartment.  At steady state, the volume of distribution is 0.18-0.51 l.kg-1 in adult patients. 

The plasma clearance of vecuronium amounts to 3.0-6.4 ml.kg^-1.min^-1  and its plasma elimination half-life is 36-117 minutes.

Paragraph titled: Use in paediatrics:  Neonates and infants, Children removed.

Section 5.3: Preclinical safety data

Deleted: In animal studies, at high doses, a toxicity related to the pharmacological activity of vecuronium bromide was seen.

Replaced with: Vecuronium bromide showed no genotoxic, embryotoxic or teratogenic potential. Single and repeated dose toxicity studies in rats, dogs and cats revealed no special hazard for humans.

Changes to layout of section 6.1

Section 6.3: Shelf life

Deleted: When reconstituted as indicated under 'Reconstitution' or diluted as described under 'Compatibility', the solution obtained can be kept for 24 hours at room temperature and in daylight.  However, in order to avoid microbiological contamination it is recommended to discard any unused solution.

Replaced with: Chemical and physical in-use (i.e. following reconstitution) stability has been demonstrated for 24 hours at 15 to 25°C.

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless reconstitution/dilution (etc.) has taken place in controlled and validated aseptic conditions.

The date mentioned after "exp.:" on the label of the vial is the expiry date up to which Norcuron may be used.

Section 6.4: Special precautions for storage

Deleted:Norcuron should be stored at a temperature below 25°C, protected from light.

Replaced with: Do not store above 25°C. Keep vials in the outer carton in order to protect from light.

For storage conditions of the reconstituted solution, see section 6.3.

Do not use Norcuron when the solution after reconstitution contains particles or is not clear

Section 6.5: Nature and contents of containers

New addition - Vials and ampoules are made of type I glass. In correspondence please quote batch number.

Section 6.6 titled changed from: Instructions for use and handling (and disposal) to Special precautions for disposal and other handling

Compatibilities statement changed.

Section 10: Date OF REVISION of the text

Date of revision of text changed from August 2005 to July 2009

New section added: Section 11 – Legal category