1. Name Of The Medicinal Product
BUFYL 1.25mg/ml and 2microgram/ml Solution for Infusion
2. Qualitative And Quantitative Composition
Each 1ml of solution contains 1.25mg bupivacaine hydrochloride and 2 micrograms fentanyl (as fentanyl citrate)
Also contains up to 3.5mg sodium per ml.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Solution for epidural infusion.
Clear, colourless aqueous sterile solution.
4. Clinical Particulars
4.1 Therapeutic Indications
Bufyl solution for infusion is indicated for:
(i) maintaining analgesia post-operatively and
(ii) for maintaining epidural analgesia during labour.
4.2 Posology And Method Of Administration
Route of administration: Epidural Infusion
Bufyl solution for infusion should only be administered epidurally and should only be used by, or under the supervision of, clinicians experienced in regional anaesthesia.
The dose administered must be tailored to the individual patient and procedure. When calculating the dosage for post-operative analgesia, the use of intra-operative bupivacaine and/or fentanyl (or other opioid agonist analgesic) should be taken into account. The rapid injection of bupivacaine with fentanyl solution should be avoided and the maximum accumulated dosage should not exceed 400 mg of bupivacaine and 720 microgram of fentanyl for a 24 hour period in a 70 kg adult.
Note: This formulation is not to be used as a bolus.
Adults:
The length of continuous epidural infusions given post-operatively should be minimized, due to the increased risks of reaching a toxic plasma concentration, inducing local neural injury or local infection. Administration of bupivacaine with fentanyl epidural infusion has not been adequately studied for more than 72 hours. The dosages in the following table are recommended as a guide for use in healthy adults during labour and in the post operative period. It should not be necessary to exceed an infusion dosage of 20mg/hour for bupivacaine. Standard textbooks should be consulted for factors affecting specific block techniques;dosing should be titrated to meet the individual patient requirements and the lowest dose required to provide adequate analgesia should be used.
Bufyl (Bupivacaine 1.25mg/mL + Fentanyl 2 microgram/mL) solution for infusion
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Careful aspiration before starting the infusion is recommended to prevent intravascular injection. The infusion rate should be slow, with continual assessment of the patient in order to optimise efficacy and safety considerations for the patient and to avoid overdosage.
• Following the start of an infusion a continuous review of the patient is required, including periodic monitoring of the patient's blood pressure/pulse and assessment of pain and sedation at a minimum of 30 minute intervals.
Where conscious, verbal contact with the patient should be maintained throughout.
• Segmental testing of the level of the block is required at least at hourly intervals throughout the time the infusion is administered. Appropriate monitoring should be carried out to detect progressive spread of the block or an increasing density of block.
• Motor block should be assessed periodically using the Bromage score. For obstetric analgesia the test level T5/T6 should be clearly marked, for postoperative analgesia the level of block should be determined relative to the site of surgery.
• Routine maternal cardiovascular and foetal monitoring should be performed. In the case of labour, foetal heart rate should be monitored every 5 minutes for 30 minutes and then as appropriate.
Children:
The use of bupivacaine with fentanyl in children is not recommended since experience in paediatric patients is limited.
Elderly:
Debilitated or elderly patients, including those with advanced liver disease or severe renal dysfunction should be given a reduced dosage commensurate with their physical condition.
Hepatic / Renal Impairment:
Since bupivacaine and fentanyl are metabolized in the liver and excreted via the kidneys, the possibility of medicine accumulation should be considered in patients with hepatic and/or renal impairment, with a possible reduction in dosage depending on the severity of their impairment.
Adequate filtering should be an integral part of the infusion line. The infusion line should be clearly marked to avoid confusion with intravenous lines. Also to avoid confusion, consideration should be given to using a different brand of proprietary pump to that used for IV infusions. In addition, the following pump specifications should be considered:
-accurate infusion rates down to 1ml/hour should be able to be set.
-positive pressure drive, (not gravity feed), should be present.
-a back-up battery should be present.
-an automatic infusion shut-off should be present in case power is lost or the front of the pump is accidentally opened.
4.3 Contraindications
The use of Bufyl solution for infusion is contraindicated in case of:
• allergy or hypersensitivity to bupivacaine, fentanyl or to any of the excipients (See Section 6.1),
• acute respiratory depression,
• acute alcoholism,
• raised intracranial pressure or head injury. As for any narcotic analgesic, fentanyl should not be used in patients with or susceptible to respiratory depression, such as comatose patients who may have head injuries or a brain tumour. Fentanyl may obscure the clinical course of patients with head injury,
• hypovolaemia and complete heart block,
• intravenous regional anaesthesia (Bier's block) as unintentional passage of local anaesthetic into the systemic circulation, despite the use of a tourniquet, may cause systemic toxic reactions,
• obstetrical paracervical block anaesthesia,
• concurrent administration of monoamine oxidase inhibitors (MAOI's) or within 2 weeks of their discontinuation,
Epidural anaesthesia, regardless of the local anaesthetic used, has its own contra-indications which include:
• active disease of the central nervous system such as meningitis, poliomyelitis, intracranial haemorrhage, subacute combined degeneration of the cord due to pernicious anaemia, spina bifida or meningomyelocele and cerebral or spinal tumors,
• tuberculosis of the spine,
• inflammation and/or pyogenic infection of the skin at or adjacent to the site of lumbar puncture,
• a diagnosed arteriovenous malformation in the vertebral column in close proximity to the proposed puncture site,
• cardiogenic shock,
• coagulation disorders or ongoing anticoagulant therapy,
• an expanding cerebral lesion, a tumour, cyst or abscess, which may, if the intracranial pressure is suddenly altered, cause obstruction to the cerebrospinal fluid or blood circulation (the pressure cone).
4.4 Special Warnings And Precautions For Use
Adequate equipment (e.g. oxygen, artificial airways) and medicines (e.g. intravenous fluids, vasopressors) necessary for monitoring and emergency resuscitation should be immediately available. Spinal and epidural anaesthesia may result in sympathetic block with resultant hypotension and bradycardia, therefore an intravenous cannula should be inserted before the local anaesthetic is injected.
Every precaution should be taken to avoid accidental intravascular administration.
The rapid onset of sensory or motor blockade with/without hypotension may indicate accidental intrathecal injection (see Section 4.8)
Caution should be used in patients with hypotension, hypothyroidism, asthma, decreased respiratory reserve, prostatic hypertrophy, convulsive disorders, shock and adrenocortical insufficiency. Local anaesthetics should be given with great caution (if at all) to patients with pre-existing abnormal neurological conditions, e.g. myasthenia gravis.
Debilitated, elderly or young patients may require reduced doses commensurate with their age and physical condition. Since bupivacaine and fentanyl are metabolized in the liver and excreted via the kidneys, the possibility of medicine accumulation should be considered in patients with hepatic and/or renal impairment, with a possible reduction in dosage depending on the severity of their impairment.
Bupivacaine hydrochloride should be administered with caution to patients with cardiovascular disease, hypertension or hyperthyroidism.
This medicine contains approximately 3.5mg sodium per ml. This should be taken into consideration by patients on a controlled sodium (salt) diet.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Anti-arrhythmic medicines
Local anaesthetics of the amide type, such as bupivacaine should be used with caution in patients receiving anti-arrhythmic medicines (e.g. amiodarone) since potentiation of cardiac effects may occur.
Bupivacaine should be used with care in patients receiving anti-arrhythmic drugs with local anaesthetic activity e.g. lignocaine or tocainide, since their toxic effects may be additive.
Profound bradycardia, sinus arrest and hypotension have occurred when patients receiving amiodarone have been given fentanyl for anaesthesia.
CNS depressants
Other CNS depressant agents, e.g. barbiturates, neuroleptics, opioid agonists and general anaesthetics, will have additive or potentiating effects when used with bupivacaine and fentanyl. When patients have received such agents, the dose of bupivacaine with fentanyl required will be less than usual. Likewise, following the administration of bupivacaine with fentanyl, the dose of other CNS depressant agents should be reduced.
The respiratory depressant effect of fentanyl may be enhanced or prolonged by opioid premedication, barbiturates, benzodiazepines, neuroleptics, halogenic gases, alcohol and other non-selective CNS depressants.
Antihypertensives
Antihypertensives like captopril and verapamil may cause severe hypotension and bradycardia in patients given epidural anaesthesia with bupivacaine. Beta-blockers, particularly propranolol, reduce the clearance of bupivacaine and may increase its toxicity.
Neuroleptics
When a neuroleptic such as droperidol is used with fentanyl, pulmonary arterial pressure may be decreased. Hypotension can occur and, possibly hypovolaemia (which should be managed with appropriate parenteral fluids). The following adverse reactions have also been reported: chills, shivering, restlessness, hypertension, postoperative hallucinatory episodes, and transient periods of mental depression. Extrapyramidal symptoms (dystonia, akathisia and oculogyric crisis) have been observed up to 24 hours postoperatively. When they occur, extrapyramidal symptoms can usually be controlled with antiparkinson agents.
Other drug interactions
Concurrent administration of monoamine oxidase inhibitors (MAOI's) or within 2 weeks of their discontinuation, is contraindicsted (see section 4.3)
Epidural anaesthesia is contra-indicated in patients receiving anticoagulant therapy.
Cimetidine may prolong the effects of bupivacaine and fentanyl if used concurrently.
Nitrous oxide has been reported to produce cardiovascular depression when given with high doses of fentanyl.
When fentanyl is used in a single dose, the concomitant use of potent CYP3A4 inhibitors such as ritonavir requires special patient care and observation. With continuous treatment dose reduction of fentanyl may be required to avoid accumulation of fentanyl, which may increase the risk of prolonged or delayed respiratory depression.
4.6 Pregnancy And Lactation
Pregnancy:
Bupivacaine crosses the placenta to a lesser degree than lidocaine or mepivacaine following maternal injection. A lower foetal maternal ratio (0.2-0.4) than for other local anaesthetics (e.g. lignocaine, prilocaine) has been observed for bupivacaine. The greater degree of protein-binding of bupivacaine compared with these other drugs not only limits the amount of bupivacaine available to cross the placenta but also reduces the relative amount of free drug in the foetal circulation.
There is no evidence of untoward effects when used during pregnancy.
Breast-feeding:
With recommended doses, bupivacaine enters breast milk but in such small quantities at therapeutic dose levels that there is generally no risk of affecting the child.
Fentanyl has been shown to have an umbilical cord to maternal vein ratio of 0.06 to 0.44. If fentanyl is administered during childbirth, a narcotic antagonist should be available for use in the unlikely event that respiratory depression occurs in the neonate.
Fentanyl is distributed into human milk in minute quantities and is unlikely to affect a healthy full-term breast feeding infant.
4.7 Effects On Ability To Drive And Use Machines
Even in the case of an early discharge (and clinically tested return of normal motor power) it is not envisaged that a patient should drive or operate machinery within 24 hrs.
4.8 Undesirable Effects
Bupivacaine
Reactions to bupivacaine are similar in character to those observed with other local anaesthetics of the amide type. Adverse reactions may be due to high plasma levels as a result of excessive dosage, rapid absorption, delayed elimination or metabolism, or inadvertent intravascular injection.
Such reactions are systemic in nature and involve the central nervous system and/or the cardiovascular system. Inadvertent subarachnoid injection may lead to cardiovascular collapse, unconsciousness and respiratory arrest. An accidental intrathecal injection may be recognized by early signs of spinal block such as hypotension, bradycardia and difficulty in breathing.
The adverse reactions considered at least possibly related to treatment with Bupivacaine hydrochloride from clinical trials with related products and post-marketing experience are listed below by body system organ class and absolute frequency. Frequencies are defined as very common ( 1/10), common ( 1/100, < 1/10), uncommon ( 1/1,000, < 1/100), rare ( 1/10,000, < 1/1,000) including isolated reports, or not known (identified through post-marketing safety surveillance and the frequency cannot be estimated from the available data).
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Fentanyl
The following table displays ADRs that have been reported with the use of fentanyl IV from either clinical trials or post-marketing experiences.
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4.9 Overdose
With accidental intravascular injections, the acute toxic systemic effect of bupivacaine will be obvious within 1-3 minutes, while with overdosage, peak plasma concentrations may not be reached for 20-30 minutes depending on the site of injection with signs of toxicity thus being delayed. Toxic reactions originate mainly in the central nervous and the cardiovascular systems. Pronounced acidosis, hyperkalaemia or hypoxia in the patient may increase the risk and severity of toxic reactions.
Central nervous system
Central nervous system toxicity is a graded response with symptoms and signs of escalating severity. The first symptoms are circumoral paraesthesia, numbness of the tongue, light-headedness, hyperacusis and tinnitus. Visual disturbance and muscular tremors are more serious and precede the onset of generalized convulsions. These signs must not be mistaken for a neurotic behaviour. Unconsciousness and grand mal convulsions may follow which may last from a few seconds to several minutes. Hypoxia and hypercarbia can occur rapidly following convulsions due to the increased muscular activity, together with the interference with normal respiration and loss of airway patency. In severe cases apnoea may occur.
Recovery due to redistribution of the local anaesthetic medicine from the central nervous system and metabolism may be rapid unless large amounts of the medicine have been injected.
During epidural analgesia, a marked fall in blood pressure and/or intercostal paralysis may be seen, possibly due to the use of excessive doses or due to improper positioning of the patient (e.g. women in labour).
Cardiovascular system
Effects on the cardiovascular system may be seen in severe cases. Hypotension, bradycardia, arrhythmia and even cardiac arrest may occur as a result of high systemic concentrations.
Cardiovascular toxic effects are generally preceded by signs of toxicity in the central nervous system, unless the patient is receiving a general anaesthetic or is heavily sedated with medicines such as a benzodiazepine or barbiturate.
Respiratory system
Overdosage due to fentanyl may result in narcosis, cardiorespiratory depression accompanied by cyanosis, followed by a fall in body temperature, circulatory collapse, coma and possibly death.
High doses of fentanyl may produce motor stimulation and muscle rigidity, particularly involving the muscles of respiration. Muscular rigidity may be associated with reduced pulmonary compliance and/or apnoea, laryngospasm or bronchospasm. This effect is related to the dose and speed of injection and may be reduced by slow infusion. It is unlikely to arise when recommended doses are used in epidural infusion.
Treatment of Overdosage
If signs of acute systemic toxicity appear, infusion of the local anaesthetic should be stopped immediately. If convulsions occur they should be treated immediately. The objectives of treatment are to maintain oxygenation, stop the convulsions and support the circulation. Oxygen must be given and ventilation assisted if necessary (mask and bag). An anticonvulsant should be given IV if the convulsions do not stop spontaneously in 15-20 seconds. Thiopentone 75-125 mg by slow intravenous injection will abort the convulsions rapidly. Alternatively intravenous diazepam 5-10 mg may be used, although its action is slower.
Mangement of respiratory depression
If respiratory depression occurs, assisted respiration and, if necessary, intravenous administration of a single dose of a neuromuscular blocking agent compatible with the patient's condition, such as suxamethonium will provide adequate ventilation without reversing analgesia. Suxamethonium which will stop the muscle convulsions rapidly, will require tracheal intubation and controlled ventilation and should only be used by those familiar with these procedures.
A specific narcotic antagonist, such as nalorphine or naloxone, should be available for use as indicated to manage respiratory depression. This does not preclude the use of more immediate countermeasures. Though opioid antagonists (e.g. naloxone) can immediately reverse the respiratory depression they will also reverse the central analgesic effect due to fentanyl, although the epidural analgesia may not be altered. The duration of respiratory depression following overdosage of fentanyl is usually longer than the duration of narcotic antagonist action.
Management of cardiovascular depression
Should circulatory arrest occur, immediate cardiopulmonary resuscitation should be instituted. In the presence of hypoventilation or apnoea, oxygen should be administered and respiration assisted or controlled as necessary. A patent airway must be maintained. Optimal oxygenation and ventilation and circulatory support, as well as treatment of acidosis, are of vital importance since hypoxia and acidosis will increase the systemic toxicity of local anaesthetics. Bradycardia and other cholinergic effects can be controlled with the appropriate dose of atropine. The inclusion of atropine or other anticholinergic agents in the pre-anaesthetic regimen tends to reduce the occurrence of such effects. If cardiovascular depression is evident (hypotension, bradycardia), a pressor drug like ephedrine 3-6 mg should be given by slow intravenous injection and repeated, if necessary, every 3-4 minutes according to response to a maximum of 30mg. Posture improvement with elevation of the legs, left lateral displacement (if pregnant) and prophylactic volume loading with intravenous fluids should be initiated as appropriate.
The patient should be carefully observed for 24 hours; body warmth and adequate fluid intake should be maintained. If severe or persistent hypotension occurs, the possibility of hypovolaemia should be considered and managed with appropriate parenteral fluid therapy.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic Group (ATC code): N01B B51
Bupivacaine
Bupivacaine Hydrochloride is a long acting local anaesthetic of the amide type. It prevents the generation and conduction of the nerve impulse by decreasing the permeability of the nerve cell membrane to sodium ions. As well as blocking conduction in nerve axons in the peripheral nervous system, local anaesthetics interfere with the function of all organs in which conduction or transmission of impulses occur.
Systemic absorption of local anaesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended direct intravascular injection of bupivacaine. Therefore, when epidural anaesthesia with bupivacaine is considered, incremental dosing is necessary.
Fentanyl
Fentanyl citrate a potent narcotic analgesic is a synthetic opiate with a clinical potency of 50 to 100 times that of morphine. Its onset of action is rapid and its duration of action is short. In man, a single IV dose of 0.5-1 mg/70 kg body weight immediately produces a pronounced state of surgical analgesia, respiratory depression, bradycardia and other typical morphine-like effects. The duration of action of the peak effects is about 30 minutes. The principal actions of therapeutic value are analgesia and sedation. When used with a neuroleptic agent it can induce a state of neuroleptanalgesia. As with other narcotic analgesics, the effect of fentanyl on respiratory depression increases as the drug dosage is increased. All potent morphine-like drugs produce relief from pain, ventilatory depression, emesis, constipation, physical dependence, certain vagal effects and varying degrees of sedation. Fentanyl, however, differs from morphine not only by its short duration of action but also by its lack of emetic effect and minimal hypotensive activity in animals. Epidural fentanyl enhances the epidural analgesia achieved with bupivacaine.
5.2 Pharmacokinetic Properties
Bupivacaine
Absorption & Distribution
Bupivacaine is a long acting, amide type local anaesthetic chemically related to lignocaine and mepivacaine. It is approximately four times as potent as lignocaine. Bupivacaine has a pKa of 8.1 and is extensively bound to plasma proteins. Bupivacaine exhibits a high degree of lipid solubility with an oil/water partition coefficient of 27.5. These factors contribute to its prolonged duration of action.
The onset of blockade is slower than with lignocaine, especially when anaesthetizing large nerves. When used in low concentrations (2.5 mg/mL or less) there is less effect on motor nerve fibres and the duration of action is shorter. Low concentrations may, however, be used with advantage for prolonged pain relief, e.g. in labour or postoperatively.
After epidural injection peak plasma levels of bupivacaine in the blood are reached within 30 to 45 minutes, followed by a decline to insignificant levels during the next 3 to 6 hours. Intercostal blocks give the highest peak plasma concentration due to a rapid absorption (maximum plasma concentrations in the order of 1-4 mg/L after a 400 mg dose), while epidural and major plexus blocks result in intermediate plasma concentrations.. In children rapid absorption and high plasma concentrations (in the order of 1-1.5 mg/L after a dose of 3 mg/kg) are seen with caudal block.
Absorption of bupivacaine from the epidural space occurs in 2 phases; the first phase is in the order of 7 minutes and the second is in 6 hours. The slow absorption is rate-limiting in the elimination of bupivacaine, which explains why the apparent elimination half-life after epidural administration is longer than after intravenous administration.
Metabolism & Excretion
Bupivacaine is excreted in the urine principally as metabolites with about 6% as unchanged medicine. Following epidural administration the urinary recovery of unchanged bupivacaine is about 0.2%, of pipecolylxylidine (PPX) about 1% and of 4-hydroxy-bupivacaine about 0.1% of the administered dose.
Various pharmacokinetic parameters can be significantly altered by a number of factors including the presence of hepatic and renal disease, route of administration, age of the patient and certain concomitant medication. The drug crosses the placenta.
Fentanyl
Absorption & Distribution
Fentanyl is a lipid-soluble drug and its pharmacokinetics can be described in terms of a three-compartment model. Following intravenous injection, there is a short distribution phase during which high concentrations of fentanyl are achieved quickly in well-perfused tissues such as the lungs, kidneys and brain.
Metabolism & Excretion
The drug is redistributed to other tissues; it accumulates more slowly in skeletal muscle and yet more slowly in fat, from which it is gradually released into the blood. Up to 80% of fentanyl is bound to plasma proteins. Fentanyl is primarily metabolized in the liver, probably by N-dealkylation, and it is excreted mainly in the urine with less than 10% representing the unchanged drug. The drug clearance in ml/min/kg is 13±2 with a volume of distribution in litres/kg of 4.0±0.4. Estimates of terminal half-life of fentanyl range from 141 to 853 minutes with an average of 3.7 hours.
5.3 Preclinical Safety Data
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Sodium chloride, Sodium hydroxide (for pH adjustment), Water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products. The pH range is 5.0 to 6.5.
6.3 Shelf Life
3 years
After opening, the product should be used immediately. The product is for single use only and should not be used for more than 24 hours.
6.4 Special Precautions For Storage
Not applicable.
6.5 Nature And Contents Of Container
250ml or 500ml polypropylene infusion bags.
6.6 Special Precautions For Disposal And Other Handling
Solutions showing discolouration and unused portions of solutions should be discarded. For single use only. Do not reconnect partially used bags.
7. Marketing Authorisation Holder
Antigen International Limited
Roscrea,
Co. Tipperary,
Ireland
8. Marketing Authorisation Number(S)
PL 02848/0237
9. Date Of First Authorisation/Renewal Of The Authorisation
14/09/2011
10. Date Of Revision Of The Text
14/09/2011
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