Pavulon

The active substance of Pavulonium bromide is an amino steroid which effectively blocks transmission of motor nerve impulses to the striated muscle receptors. It is a non-depolarising neuromuscular blocking agent with a long duration of action and is used in the following indications:

1. As an adjuvant in surgical anaesthesia to obtain relaxation of skeletal muscles in a wide range of surgical procedures.

2. Use in intensive care as a non-depolarising neuromuscular blocker for the treatment of various pathologies eg intractable status asthmaticus and tetanus.

Pavulonium should be administered intravenously.

It is not recommended to be given by infusion.

The dosage should be individualised as there is a wide variation in individual response to muscle relaxants. When determining the dose, the method of anaesthesia, expected duration of surgery, potential interaction with other drugs that are administered before and during anaesthesia and the condition of the patient should be taken into account.

The use of a peripheral nerve stimulator is recommended for monitoring the neuromuscular block and recovery.

ADULT:

Initial dose: 50-80 micrograms/kg (intubation accomplished within 150-120 seconds) or 80-100 micrograms/kg (intubation accomplished within 120-90 seconds).

Incremental doses: 10-20 micrograms/kg

PAEDIATRIC:

Initial dose: 60-100 micrograms/kg

Incremental doses: 10-20 micrograms/kg

NEONATES:

Doses of Pavulonium in neonates up to one month of age must be carefully individualised since neonates are particularly sensitive to non-depolarising neuromuscular blocking agents.

Dosage 30-40 micrograms/kg initially I/V followed by 10-20 micrograms/kg thereafter.

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

Following the administration of suxamethonium the dosage of Pavulonium may be considerably reduced:

Adults:

Initial dose: 20-60 micrograms/kg

Incremental doses 10-20 micrograms/kg

Children:

Initial dose: 20-60 micrograms/kg

Incremental doses 10-20 micrograms/kg

ELDERLY:

The neuromuscular blocking activity of Pavulonium is prolonged in the elderly and lower doses may be necessary.

OBESITY:

In obese patients doses of Pavulonium based on a mg/kg basis may lead to overdosage. Dosage must be adjusted according to response.

INTENSIVE CARE:

Pavulonium is longer acting in the intensive care patient, and an intravenous dose of 60 micrograms/kg every one to one and a half hours, or even less frequently is usually adequate.

IMPAIRED LIVER AND RENAL FUNCTION:

Care must be exercised in patients with impaired liver or renal function as mentioned in the special warnings and precautions section.

Hyperdiuresis may result in a decreased neuromuscular blocking effect.

In the control of tetanus, duration of Pavulonium relaxation probably depends upon the severity of the spasm, therefore duration of effect can be variable.

The duration of action depends upon the clinical condition of the patient and the dose administered, but in normal subjects receiving perioperative muscle relaxant doses the duration of action is usually 45-60 minutes.

Pavulonium should not be mixed with other agents in the same syringe, or with solutions for intravenous infusions as a change in pH may cause precipitation.

Discard any unused solution.

Patients with a known hypersensitivity to Pavulonium or the bromide ion. Concurrent use of a depolarising neuromuscular blocking agent eg suxamethonium.

Anaphylactic reactions can occur following the administration of neuromuscular blocking agents.).

Particularly in the case of previous anaphylactic reactions to neuromuscular blocking agents, special precautions should be taken since allergic cross-reactivity to neuromuscular blocking agents has been reported (see also Section 4.8).

Renal Failure.

As Pavulonium bromide is excreted mainly in the renal system, the elimination half-life is prolonged in renal failure, resulting in a reduction in plasma clearance and prolonged duration of action.

The prolongation of half-life in patients with renal failure is often but not always associated with an extended duration of neuromuscular blockage. In these patients, the recovery from neuromuscular block may also be prolonged.

Impaired Hepatic/Biliary Tract Disease.

The duration of action may be prolonged in these conditions and resistance to neuromuscular blocking action of Pavulonium bromide may occur because of the increased volume of distribution of the drug.

In such conditions, the drug has a slower onset and coupled with the increased total dosage requirements, there may be a prolongation of blockade and recovering time in these patients.

Patients with carcinomatosis especially associated with bronchial carcinoma may exhibit a marked sensitivity to this agent, and the neuromuscular block produced may respond poorly to neostigmine.

As with other non-depolarising muscle relaxants Pavulonium should be used with care in patients with pre-existing pulmonary, hepatic or renal disease and with particular care in patients with muscular dystrophies, myasthenia gravis and myasthenic syndrome unless it is intended to administer prolonged post-operative respiratory assistance. As is the case with other curariform agents, in cases of neuromuscular disease or after poliomyelitis, Pavulonium should be used with extreme caution since the response to neuromuscular blocking agents may be considerably altered in these patients. The magnitude and direction of this alteration may vary widely.

Before administration of Pavulonium conditions such as electrolyte disturbance, altered pH, and dehydration should be corrected if possible. Pavulonium should be used cautiously in patients with a tendency to hypertension.

Pavulonium can cause a reduction in the partial prothromboplastin time and prothrombin time. Conditions associated with slower circulation times eg cardiovascular disease, oedema, old age result in an increased volume of distribution which may lead to an increased onset time.

Pavulonium should be used with particular care in neonates, in ill or cachetic patients, in the presence of liver disease or obstructive jaundice (resistant to the effects of drugs) in states with altered plasma protein levels or when there is diminished renal blood flow or renal disease. In operations employing the hypothermic techniques the neuromuscular blocking effect of non-depolarising drugs is decreased and increased by warming the patient.

Pavulonium should be administered in carefully adjusted dosage or under the supervision of a qualified anaesthetist and only when facilities for controlled ventilation, insufflation with oxygen and endotracheal intubation are available for immediate use.

Since Pavulonium causes relaxation of the respiratory muscles, respiration must be assisted in all patients. It is essential to ensure that the patient is breathing spontaneously, deeply and regularly before leaving the theatre after anaesthesia. The neuromuscular blockage achieved with Pavulonium can be reversed with a cholinesterase inhibiting agent (e.g. neostigmine) in an adequate dose, together with atropine as an anticholinergic agent.

Care should be exercised if there is a danger of regurgitation when intubating the patient, for example during crash induction.

Other conditions which may increase the effect of Pavulonium are: hypokalaemia (e.g. after severe vomiting, diarrhoea, digitalisation and diuretic therapy), hypermagnesaemia, hypocalcaemia (after massive transfusions), hypoproteinaemia, dehydration, acidosis, hypercapnoea and cachexia.

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

High doses of a depolarising drug may cause end-plate desensitisation and prolong post-operative apnoea.

Cardiovascular: Increased pulse rate and cardiac output. Blood pressure may rise. Arrhythmias may occur occasionally.

Gastrointestinal: Salivation is sometimes noted during anaesthesia.

Hypersensitivity: Occasional transient rash has been noted.

Injection Site Reactions: Pain or local skin reactions noted at the site of injection.

Respiratory: Bronchospasm has rarely been reported

Serious or life threatening reactions: Severe anaphylactoid reactions have been reported uncommonly. In the case of previous anaphylactic reactions to neuromuscular blocking agents, special precautions should be taken since allergic cross reactivity between neuromuscular blocking agents has been reported.

Since neuromuscular blocking agents in general are known to be capable of inducing histamine release both locally and systemically, the possible occurrence of itching and erythematous reactions at the site of injection and/or generalised histaminoid (anaphylactoid) reactions such as bronchospasm and cardiovascular changes should always be taken into consideration when administering these drugs.

Ocular: Pavulonium decreases intra-ocular pressure and induces miosis, both effects being favourable in opththalmic surgery.

Clinical features: The symptoms are those of prolonged apnoea, respiratory depression and/or muscle weakness. Death may follow acute respiratory failure.

Management: Neostigmine at a dose of 2.5mg and Atropine at a dose of 1.2mg can be administered to reverse the neuromuscular block whilst ventilation is continued. When administration of the cholinesterase inhibiting agent fails to reverse the neuromuscular blocking effects of Pavulonium ventilation must continue until spontaneous breathing is restored. Repeated dosage of cholinesterase inhibitor can be dangerous.

Pharmacotherapeutic group: Muscle relaxants, peripherally acting agents, other quaternary ammonium compounds, M03AC01

ATC code: M03AC01

Pavulonium bromide produces pharmacologic effects similar to those of other non-depolarising neuromuscular blocking agents. The drug may produce an increase in heart rate which appears to result from a direct blocking effect on the acetylcholine receptors of the heart. The increase in heart rate appears to be dose related and is minimal with usual doses. Pavulonium causes little or no histamine release and no ganglionic blockade and therefore does not cause hypotension or bronchospasm. Despite its steroidal structure, the drug exhibits no hormonal activity.

Following I/V administration of Pavulonium bromide 60micrograms /kg, muscle relaxation reaches a level suitable for endotracheal intubation within 2-3 minutes, slightly more rapidly than with tubocurarine. The onset and duration of paralysis are dose related. After a dose of 60micrograms/kg, the effects of the drug begin to subside in about 35-45 minutes. Supplemental doses may increase the magnitude and duration of the neuromuscular blockade. The duration of action depends upon the clinical condition of the patient and the dose administered, but in normal subjects receiving perioperative muscle relaxant doses the duration of action is usually 45-60 minutes.

Protein binding of Pavulonium does not appear to be substantial. The activity of the drug is not greatly affected by plasma carbon dioxide concentrations or pH. Redistribution is responsible for the termination of activity following single doses. Pavulonium crosses the placenta in small amounts.

Plasma concentrations appear to decline in a triphasic manner. In adults with normal renal and hepatic function, the half-life in the terminal phase is about 2 hours. The elimination half-life may be prolonged in patients with impaired renal and/or hepatic function. The drug is eliminated mainly unchanged by the kidneys, although small amounts may be metabolised and some of the drug may be eliminated in the bile.

There is no pre-clinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

Do not mix other solutions in the same syringe as a change in pH can cause precipitation.

For single use only. Any unused solution should be discarded.