Text in red = new text
Text strikethrough = deleted text

 

 

 

4.4       Special warnings and precautions for use

 

 

Intrathecal anaesthesia with any local anaesthetic can cause may lead to hypotension and bradycardia. which should be anticipated and appropriate precautions taken. These may include preloading the circulation with crystalloid or colloid solution. If hypotension develops it should be treated with a vasopressor such as ephedrine 10–15 mg intravenously. The risk of such effects can be reduced, e.g., by injecting a vasopressor. Hypotension should be treated promptly with a sympathomimetic intravenously, repeated as necessary.  Severe hypotension may result from hypovolaemia due to haemorrhage or dehydration, or aorto-caval occlusion in patients with massive ascites, large abdominal tumours or late pregnancy. Marked hypotension should be avoided in patients with cardiac decompensation.

 

 

10        DATE OF REVISION OF THE TEXT

 

July 2017  Apr 2017

Text in red = new text
Text strikethrough = deleted text

 

 

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

 

 

7. Marketing Authorisation holder

Aspen Pharma Trading Limited

3016 Lake Drive

Citywest Business Campus

Dublin 24

Ireland.

 

AstraZeneca UK Ltd.,

600 Capability Green,

Luton, LU1 3LU, UK.

 

 

8.Marketing authorisation number

PA 1691/024/003

 

PA 970/45/3

 

10. Date of revision of the text

30^th June 2016

26 May 2015

 

 

 

 

 



Editorial changes to reflect Latest QRD for the following sections:

2

4.1

4.2

4.3

4.4

4.5

4.6

4.8

4.9

5.1

5.2

6.3

6.6

 

and Section 10 – change to date of revision



 Section 4.1 – Clarification that Marcain Heavy is indicated for intrathecal spinal anaesthesia in adults and children of all ages.

Section 4.2 – Addition of instructions for use in neonates, infants and children up to 40kg. Addition of dosage recommendations for neonates, infants and children.

Section 4.6 – Amendment to section title in line with QRD.

Section 4.8 – Addition of statement that adverse drug reactions in children are similar to those in adults, however, in children, early signs of local anaesthetic toxicity may be difficult to detect in cases where the block is given during sedation or general anaesthesia. Addition of of reporting of suspected adverse reactions statement.

Section 5.2 – Addition of statement that in children the pharmacokinetics is similar to that in adults.

Section 10 – Update to "Date of Revision"

 

Section 1

Following text in bold added:

Marcain Heavy Steripack, 0.5%w/v Solution for Injection

 

 

Section 2

Paragraph previously read:

Bupivacaine Hydrochloride Ph. Eur. equivalent to 5 mg/ml anhydrous bupivacaine hydrochloride and Dextrose Anhydrous Ph. Eur. equivalent to 80 mg/ml of dextrose monohydrate.

And now reads with new text in bold:

Each ml contains Bupivacaine Hydrochloride equivalent to 5.0 mg of anhydrous bupivacaine hydrochloride (20mg per 4ml ampoule) and Dextrose Anhydrous equivalent to 80 mg/ml of dextrose monohydrate.

 

New sentence added: For a full list of excipients see section 6.1

 

 

 

Section 3

New following text added: Solution for injection (injection)

 

 

 

Section 6.1

Following text in bold added:

Sodium hydroxide (for pH adjustment)

Hydrochloric acid (for pH adjustment)

Glucose anhydrous

Water for injections

 

 

Section 6.2

‘Not applicable’ deleted and replaced with following new text: The solution must not be stored in contact with metals, e.g. needles or metal parts of syringes, as dissolved metal ions may cause swelling at the site of the injection.

 

 

Section 6.3

Following new text added (bold)

Unopened: 3 years.

Once opened: The solution should be used immediately after opening of the ampoule. Any remaining solution should be discarded.

 

 

Section 6.4

Following text deleted:

The solution must not be stored in contact with metals, e.g. needles or metal parts of syringes, as dissolved metal ions may cause swelling at the site of the injection.

The solution should be used immediately after opening of the ampoule. Any remaining solution should be discarded.

 

And replaced with following new text:

Do not store above 25°C. Keep the ampoules in the outer carton.

 

 

Section 6.5

Following new sentence added: Each ampoule contains 4ml of solution for injection in blisters of 5 ampoules.

 

 

 

Section 6.6

Following heading deleted:

‘Instructions for use, handling and disposal’

And replaced with new heading:

Special precautions for disposal and other handling

 

Text deleted: ‘None stated’

And replaced with following new text: For single use only. The solution should be used immediately after opening the ampoule. Any remaining solution should be discarded.

 

Section 10

Date changed to 2^nd November 2007

Section 4.4

 

Following new paragraph added:

Cardiovascular and respiratory vital signs and the patient’s state of consciousness after local anaesthetic injection should be carefully and constantly monitored as sympathetic blockage occurring during spinal anaesthesia may result in peripheral vasodilatation and hypotension. Also, the level of anaesthesia should be carefully monitored because this is not always predictable in spinal techniques.

 

Following new text added to end of section 4.4:

 

A rare, though severe, adverse reaction following spinal anaesthesia is high or total spinal blockade resulting in cardiovascular and respiratory depression. The cardiovascular depression is caused by extensive sympathetic blockade, which may result in profound hypotension and bradycardia, or even cardiac arrest. Respiratory depression may be caused by blockade of the innervation of the respiratory muscles, including the diaphragm. There is an increased risk of high or total spinal blockade in the elderly and in patients in the late stages of pregnancy. The dose should therefore be reduced in these patients.

Neurological disorders, such as multiple sclerosis, haemiplegia, paraplegia and neuromuscular disorders are thought not to be adversely affected by intrathecal anaesthesia, but call for caution. Before treatment is instituted, consideration should be taken if the benefits outweigh the possible risks for the patient.

Section 4.8.3

Following text all deleted:

No treatment is required for milder symptoms of systemic toxicity but if convulsions occur then it is important to ensure adequate oxygenation and to arrest the convulsions if they last more than 15–30 seconds. Oxygen should be given by face mask and the respiration assisted or controlled if necessary. Convulsions can be arrested by injection of thiopental 100–150 mg intravenously or with diazepam 5–10 mg intravenously. Alternatively, succinylcholine 50–100 mg intravenously may be given but only if the clinician has the ability to perform endotracheal intubation and to manage a totally paralysed patient.

 

High or total spinal blockade causing respiratory paralysis should be treated by ensuring and maintaining a patent airway and giving oxygen by assisted or controlled ventilation.

 

Hypotension should be treated by the use of vasopressors, e.g. ephedrine 10–15 mg intravenously and repeated until the desired level of arterial pressure is reached. Intravenous fluids, both electrolytes and colloids, given rapidly can also reverse hypotension.

 

And replaced with following new text:

If signs of acute systemic toxicity or total spinal block appear, injection of the local anaesthetic should be stopped immediately and CNS symptoms (convulsion, CNS depression) must promptly be treated with appropriate airway/respiratory support and the administration of anticonvulsant drugs.

If circulatory arrest should occur, immediate cardiopulmonary resuscitation should be instituted. Optimal oxygenation and ventilation and circulatory support as well as treatment of acidosis are of vital importance.

 

If cardiovascular depression occurs (hypotension, bradycardia), appropriate treatment with intravenous fluids, vasopressor, and or inotropic agents should be considered. Children should be given doses commensurate with age and weight.

Section 5.2

Following text all deleted:

Marcain Heavy has rapid onset of action and long duration. The duration of analgesia in the T10–T12 segments is 2–3 hours.

Marcain Heavy produces a moderate muscular relaxation of the lower extremities lasting 2–2.5 hours. The motor blockade of the abdominal muscles makes the solution suitable for performance of abdominal surgery lasting 45–60 minutes. The duration of motor blockade does not exceed the duration of analgesia.

 

And replaced with following new text:

Bupivacaine has a pKa of 8.2 and a partition coefficient of 346 (25°C n-octanol/ phosphate buffer pH 7.4. The metabolites have a pharmacological activity that is less than that of bupivacaine.

 

Bupivacaine shows complete and biphasic absorption from the subarachnoid space with half-lives of the two phases of the order of 50 and 408 minutes. The slow absorption phase is the rate-limiting factor in the elimination of bupivacaine, which explains why the apparent terminal half-life is longer after subarachnoidal administration than after intravenous administration. The plasma concentration of bupivacaine after intrathecal block is low compared with those after other regional anaesthetic procedures, due to the small dose required for intrathecal anaesthesia. Generally, the increment in maximum plasma concentration is approximately 0.4 mg/L for every 100 mg injected. This means that a dose of 20 mg would result in plasma levels in the order of 0.1 mg/L.

 

After iv injection bupivacaine has a total plasma clearance of 0.58 L/min, a volume of distribution at steady state of 73 L a terminal half-life of 2.7 h and an intermediate hepatic extraction ratio of 0.38 after iv administration. It is mainly bound to alpha-l-acid glycoprotein in plasma with a plasma binding of 96%. Clearance of bupivacaine is almost entirely due to liver metabolism, and more sensitive to changes in intrinsic hepatic enzyme function than to liver perfusion.

 

Bupivacaine readily crosses the placenta, and equilibrium with regard to the unbound concentration is rapidly reached. The degree of plasma protein binding in the foetus is less than in the mother, which results in lower total plasma concentrations in the foetus.

 

Bupivacaine is excreted in breast milk, but in such small quantities that there is no risk to the child.

Bupivacaine is extensively metabolised in the liver, predominately by aromatic hydroxylation to 4-hydroxy-bupivacaine and N-dealkylation to PPX, both mediated by cytochrome P4503A4. About 1% of bupivacaine is excreted in the urine as unchanged drug in 24 h and approximately 5% as PPX. The plasma concentrations of PPX and 4-hydroxy-bupivacaine during and after continuous administration of bupivacaine are low as compared to the parent drug.

 

 

Section 10

Date changed to 19^th November 2007

Section 4.2

• A dosing table and two explanatory paragraphs have been added.

Section 4.4

• A paragraph on patients receiving anti-arrhythmic drugs class III has been added.

Section 4.5

• A sentence on specific interaction studies with bupivacaine and anti-arrhythmic drugs class III has been added.

Section 4.8

This section has been divided into

4.8.1 – General

4.8.2 – Acute systemic toxicity

4.8.3 – Treatment of acute systemic toxicity

Text has been moved from section 4.9 to this section.

• A paragraph on concomitantly administered local anaesthetics and systemic toxicity has been added.

Section 4.9

Text from this section has been moved to sections 4.8.1 – 4.8.3.

 

Section 5.1

• The Pharmacotherapeutic group (ATC code) has been added (N01B B01)
• A paragraph on the spread in the intrathecal space of Marcain Heavy has been added.