Norcuron® 10 mg, powder for solution for injection

Norcuron 10 mg

1 vial contains 10 mg vecuronium bromide, which corresponds to 2 mg vecuronium bromide per ml.

For excipients, see 6.1.

Powder for solution for injection.

Norcuron is indicated as an adjunct to general anaesthesia to facilitate tracheal intubation and to provide skeletal muscle relaxation during surgery.

Dosage

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.

As with all other neuromuscular blocking agents, the dosage of Norcuron should be individualised in each patient. The anaesthetic method used, the expected duration of surgery, the possible interaction with other drugs that are administered before or during anaesthesia 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 to monitor neuromuscular block and recovery.

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.

Dosages of Norcuron for surgical procedures after intubation with suxamethonium:

Recommended doses: 30 to 50 micrograms vecuronium bromide per kg body weight.

If suxamethonium is used for intubation, the administration of Norcuron should be delayed until the patient has clinically recovered from the neuromuscular block induced by suxamethonium.

Maintenance dosing:

The recommended maintenance dose is 20 to 30 micrograms vecuronium bromide per kg body weight.

These maintenance doses should best be given when twitch height has recovered to 25% of control twitch height.

Dose requirements for administration of Norcuron by continuous infusion:

If Norcuron is administered by continuous infusion, it is recommended to give a loading dose first (see 'Tracheal Intubation') and, when neuromuscular block starts to recover, to start administration of Norcuron 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, the infusion rate required to maintain neuromuscular block at this level, ranges from 0.8 to 1.4 micrograms vecuronium bromide/kg/min. For neonates and infants see below. Repeat monitoring of neuromuscular block is recommended since infusion rate requirements vary from patient to patient and with the anaesthetic method used.

Dosing in elderly patients

The same intubation and maintenance doses as for younger adults (80 – 100 micrograms/kg and 20 -30 micrograms/kg, respectively) can be used. However, the duration of action is prolonged in elderly compared to younger subjects due to changes in pharmacokinetic mechanisms. The onset time in elderly is similar to younger adults.

Dosing in paediatric patients:

Because of the possible variations of the sensitivity of the neuromuscular junction, especially in neonates (up to 4 weeks) and probably in infants up to 4 months of age, an initial test dose of 10 – 20 micrograms vecuronium bromide per kg body weight followed by incremental doses until 90 to 95% depression of twitch response is achieved is recommended. In neonatal surgery the dose should not exceed 100 micrograms/kg.

Dose requirements in neonates and infants (1-12 months) are the same as in adults. However, since the onset time of Norcuron in these patients is considerably shorter than in adults and children, the use of high intubating doses in general is not required for early development of good intubating conditions.

Since the duration of action and recovery time with Norcuron is longer in neonates and infants than in children and adults, maintenance doses are required less frequently (see 'paediatric patients' in section 5.1 ).

Dose requirements in children (2-10 years) are higher than for adults and neonates (see 'paediatric patients' in section 5.1). However, the same intubation and maintenance doses as for adults (80 – 100 micrograms/kg and 20-30 micrograms/kg, respectively) are usually sufficient. Since the duration of action is shorter in children, maintenance doses are required more frequently.

Although there is very little information on dosage in adolescents, it is advised to use the same dose as in adults, based on the physiological development at this age.

Dosing in 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 an ideal body weight.

Higher doses

Should there be reason for selection of larger doses in individual patients, initial doses ranging from 150 micrograms up to 300 micrograms vecuronium bromide per kg body weight have been administered during surgery both under halothane and neurolept anaesthesia without adverse cardiovascular effects being noted as long as ventilation is properly maintained. The use of these high dosages of Norcuron pharmacodynamically decreases the onset time and increases the duration of action.

In caesarean section (see also section 4.6) and neonatal surgery the dose should not exceed 100 micrograms/kg.

Administration

Norcuron should be administered following reconstitution with water. Norcuron is administered intravenously either as a bolus injection or as a continuous infusion (see also section 6.6) .

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

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.

Since Norcuron has no cardiovascular effects within the clinical dosage range, it does not attenuate bradycardia that may occur due to the use of some types of anaesthetics and opiates or due to vagal reflexes during surgery. Therefore, reassessment of the use and/or dosage of vagolytic drugs such as atropine for premedication or at induction of anaesthesia, may be of value for surgical procedures during which vagal reactions are more likely to occur (e.g. surgical procedures where anaesthetic drugs with known vagal stimulatory effects are used, opthalmic, abdominal or anorectal surgery, etc.).

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.

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

Hepatic and/or biliary tract disease and renal failure.

Because vecuronium is excreted in bile and in urine, Norcuron 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, especially when high doses of vecuronium (200 micrograms/kg bodyweight) were administered in patients with hepatic disease.

Prolonged circulation time

Conditions associated with prolonged circulation time such as cardiovascular disease, old age, oedematous state resulting in an increased volume of distribution, may contribute to an increase in the onset time of neuromuscular block. The duration of action may also be prolonged due to a reduced plasma clearance.

Neuromuscular disease

As with other neuromuscular blocking agents, Norcuron should be used with extreme caution in cases of neuromuscular disease or after poliomyelitis since the response to neuromuscular blocking agents may be considerably altered in these patients. The magnitude and direction of this alteration may vary widely. In patients with myasthenia gravis or the myasthenic (Eaton Lambert) syndrome, small doses of Norcuron may have profound effects and Norcuron should be titrated to the response.

Hypothermia

In operations under hypothermia, the neuromuscular blocking effect of Norcuron is increased and the duration is prolonged.

Obesity

Like other neuromuscular blocking agents, Norcuron 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 agents. It is recommended that the dose is titrated to response.

Other conditions which may increase the effects of Norcuron are:

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.

Based on preclinical findings, Norcuron may cause a reduction in the partial thromboplastin time and the prothrombin time, like pancuronium bromide, d-tubocurarine or other non-depolarising neuromuscular blocking agents.

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 Norcuron

Increased effect:

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

After intubation with suxamethonium (see section 4.2).

Long-term concomitant use of corticosteroids and Norcuron in the ICU may result in prolonged duration of neuromuscular block or myopathy (see also section 4.4 and 4.8).

Other drugs:

• antibiotics: aminoglycoside, lincosamide and polypeptide antibiotics, acylamino-penicillin antibiotics.

• diuretics, quinidine, magnesium salts, calcium channel blocking agents, lithium salts, cimetidine, lidocaine and acute administration of phenytoin or ß-blocking agents.

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

Decreased effect:

Prior chronic administration of phenytoin or carbamazepine

Calcium chloride, potassium chloride

Variable effect:

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

Effect of Norcuron on other drugs

Effect of Norcuron on lidocaine

Norcuron combined with lidocaine may result in a quicker onset of action of lidocaine.

There are insufficient data on the use of Norcuron during animal or human pregnancy to assess potential harm to the foetus. Norcuron should be given to a pregnant woman only when the attending physician decides that the benefits outweigh the risks.

Caesarean section

Studies with Norcuron, administered in doses up to 100 micrograms/kg, have shown its safety for use in caesarean section. In caesarean section the dose should not exceed 100 micrograms/kg.

In several clinical studies Norcuron did not affect Apgar score, foetal muscle tonus or cardiorespiratory adaptation. From umbilical cord blood sampling it is apparent that only very little placental transfer of Norcuron occurs which did not lead to the observation of any clinical adverse effect in the new-born.

Note:

Reversal of Norcuron-induced neuromuscular block may be unsatisfactory in patients receiving magnesium sulphate for toxaemia of pregnancy because magnesium salts enhance neuromuscular block.

Therefore, in patients receiving magnesium sulphate, the dosage of Norcuron should be reduced and be carefully titrated to twitch response.

Lactation

It is unknown whether vecuronium bromide is excreted in human breast milk. The excretion of vecuronium bromide in milk has not been studied in animals. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with vecuronium bromide should be made taking into account the benefit of breast-feeding to the child and the benefit of vecuronium bromide therapy to the woman.

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

Adverse drug reactions (ADRs) are rare (<1/1000). The most commonly occurring ADRs include changes in vital signs and prolonged neuromuscular block. The most frequently reported ADR during post-marketing surveillance is 'anaphylactic and anaphylactoid reactions' and associated symptoms (reporting frequency <1/100 000). See also the explanations below the table.

¹ Frequencies are estimates derived from post-marketing surveillance reports and data from the general literature.

² after long-term use in the ICU

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. A few cases of myopathy have been reported after Norcuron was used in the ICU in combination with corticosteroids (see section 4.4).

Anaphylactic reactions

Although very rare, severe anaphylactic reactions to neuromuscular blocking agents, including Norcuron, have been reported. Anaphylactic/anaphylactoid reactions usually comprise of several signs or symptoms e.g. 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.

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 (see also under anaphylactic reactions above) should always be taken into consideration when administering these drugs.

Experimental studies with intradermal injection of Norcuron have demonstrated that this drug has only a weak capacity for inducing local histamine release. Controlled studies in man failed to demonstrate any significant rise in plasma histamine levels after intravenous administration of Norcuron. Nevertheless, such cases have rarely been reported during large scale use of Norcuron.

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 a cholinesterase inhibiting agent fails to reverse the neuromuscular effects of Norcuron, ventilation must be continued until spontaneous breathing is restored. Repeated dosage of a cholinesterase inhibitor can be dangerous.

Pharmacotherapeutic group: muscle relaxants, peripherally acting agents, ATC code: MO3A C03.

Norcuron (vecuronium bromide) is a non-depolarising neuromuscular blocking agent, chemically designated as the aminosteroid 1-(3α, 17β-diacetoxy-2β piperidino-5α -androstan-16β-yl)-1 methylpiperidinium bromide.

Norcuron blocks the transmission process between the motor nerve-ending and striated muscle by binding competitively with acetylcholine to the nicotinic receptors located in the motor end-plate region of striated muscle.

Unlike depolarising neuromuscular blocking agents, such as suxamethonium, Norcuron does not cause muscle fasciculations.

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.

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.

The extent of metabolism of vecuronium is relatively low. In humans, a 3-hydroxy derivative having approximately 50% less neuromuscular blocking potency than vecuronium is formed in the liver. In patients not suffering from renal or hepatic failure, the plasma concentration of this derivative is below detection limit, and does not contribute to the neuromuscular block occurring after administration of Norcuron.

Biliary excretion is the main elimination route. It is estimated that within 24 hours after intravenous administration of Norcuron, 40 to 60% of the dose administered is excreted into the bile as monoquaternary compounds. Approximately 95% of these monoquaternary compounds is unchanged vecuronium and less than 5% is 3-hydroxy vecuronium. Prolonged duration of action has been observed in patients with liver disease and/or biliary tract disease, probably as a result of decreased clearance leading to an increased elimination half-life.

Renal elimination is relatively low. The amount of monoquaternary compounds excreted in the urine collected by intravesical catheter for 24 hours following Norcuron administration is 20-30% of the dose administered. In patients with renal failure, the duration of action may be prolonged. This is probably the result of an increased sensitivity to vecuronium, but it could also be the result of a reduced plasma clearance.

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.

Norcuron is supplied as a freeze dried powder containing:

• Citric acid monohydrate

• Disodium hydrogen phosphate dihydrate

• Mannitol (E421)

• Sodium hydroxide (for pH correction)

• Phosphoric acid (for pH correction)

No preservative has been added.

As is the case for many other drugs, incompatibility has been documented for Norcuron when added to thiopental.

Except for those solutions with which Norcuron has been shown to be compatible, it is not recommended to mix Norcuron with other solutions, or drugs in the same syringe or bag (see Section 6.6).

If Norcuron is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed (e.g. with 0.9% sodium chloride) between administration of Norcuron and drugs for which incompatibility with Norcuron has been demonstrated or for which compatibility with Norcuron has not been established.

Norcuron can be kept until the expiry date indicated on the packaging, provided it is stored under the prescribed conditions.

The shelf life is as follows: Norcuron 10mg - 2 years

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.

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.

Packaging of 10 vials each containing 10 mg vecuronium bromide.

Vials are made of type I glass. In correspondence please quote batch number.

Reconstitution:

Norcuron 10 mg

Addition of 5ml water for injections results in an isotonic solution of pH 4 containing 2 mg vecuronium bromide per ml. (2 mg/ml).

Alternatively, in order to obtain a solution with a lower concentration Norcuron 10 mg may be reconstituted with a volume up to 10 ml of the following infusion fluids:

• 5% glucose injection fluid

• 0.9% sodium chloride injection fluid

• Lactated Ringer's solution

• Lactated Ringer's injection and 5% glucose

• Glucose 5% and 0.9% sodium chloride injection

• Water for injections

Compatibilities

When Norcuron is reconstituted with water for injections, the resultant solution can be mixed with the following infusion fluids, packed in PVC or glass, to a dilution up to 40 mg/litre:

• 0.9% NaCl solution

• 5% glucose solution

• Ringer's solution

• Ringer's glucose

The above-mentioned reconstituted solution can also be injected in to the line of a running infusion of the following fluids:

• Lactated Ringer's solution

• Lactated Ringer's solution and 5% glucose

• Glucose 5% and 0.9% sodium chloride solution

• Haemaccel

• Dextran-40 5% in 0.9% sodium chloride solution

• Water for injections

Compatibility studies with other infusion fluids have not been performed.

N V Organon, Kloosterstraat 6, PO Box 20, 5340 BH, Oss, The Netherlands

PL 05003/0044

4/8/2000

26/03/2010

Prescription Only Medicine

RA 8720 UK S7 (ref 3.0)

Norcuron/UK/04-10/2