EMSDO

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Your Ref	Our Ref	Direct Line	FAX Number	Date
	LT/pjf	+ 44 (0)1625 515508	+ 44 (0)1625 512305	19 September 2002

 

Dear Dr Eldor

 

Re: ‘Naropin’ (ropivacaine)

 

Many thanks for your patience in awaiting a response from AstraZeneca to the article on ropivacaine that you have prepared, as you will appreciate we have taken your comments very seriously and have taken due time in investigating the potential issue that you have raised.  We are delighted that you have approached us for clarification on this matter.

 

Our response will focus on the statement in your article, which questioned the safety of ropivacaine and challenged the wording in our prescribing information, namely:

 

“However, it seems that the statement “The adverse event profile of Naropin® is similar to that of other long-acting local anaesthetics of the amide-type.” Has to be rewritten related to the anti-bacterial activity of ropivacaine vs bupivacaine.”

 

We feel that it would be inappropriate for us to comment other aspects of your proposed publication, and we feel that, with the following clarification of the facts included, then it is at your discretion as whether you seek to publish your review article.  We would request that you replace our trade name ‘Naropin’, which the drug name ropivacaine, in all occurrences apart from where it has been used for initial identification purposes and where you directly quote the company prescribing information.

 

As you correctly point out, there are articles published which discuss the differing inherent antimicrobial profiles of the various anaesthetic agents.  Most local anaesthetic solutions have an inherent antimicrobial efficacy, to a greater or lesser extent. The antimicrobial activity varies with the local anaesthetic as well as with the concentration and additives such as adrenaline and preservatives.  The choice to preserve or not to preserve a solution for injection is only influenced by the route of administration and if the solution is packed in single or multi dose containers. Addition of preservative decreases the risk for microbial growth in the product but increases the risks for allergic reactions.   Due to this important factor, preservatives must not be added to products intended for spinal administration.  Products packed in single dose containers should not be preserved. The production, including filling, should be done under such conditions that the risks for a contamination are eliminated.  Ropivacaine is only packed in single dose containers. Therefore there is no need for preservation of ropivacaine.

 

From extensive review of the published literature and pharmacovigilance sources including the in-house, international confidential safety database we are able to conclude that there is no evidence of any increased frequency of infections associated with the clinical use of ‘Naropin’.

 

You also state “Since ropivacaine is now frequently used for epidural anesthesia and analgesia as well as for wound analgesia infiltration and peripheral nerve blocks this “unrecognized” poor antibacterial effect has a very important implication on its use.” 

 

In response to this I would appeal to you that you have in fact answered your own concerns, in that the issue that you seek to highlight is in fact unrecognized because ropivacaine use has not been associated with any increased frequency of infections.  This is supported by the lack of published reports suggesting any increased frequency infection, the lack of reports identified through external independent pharmacovigilance, and the absence of any evidence from our own extensive database to suggest an increased frequency of infections associated with the clinical use of Naropin.  AstraZeneca are an ethical company, and proud of our respected reputation as such, and if any evidence had come to light, from any source, suggesting a previously unrecognized safety issue with one of our products, then I can personally assure you that this would be acted on fully and promptly.

 

I hope that our extensive research and the conclusive outcome of our investigation will reassure you and I am delighted that we are able to assist you on this matter.

 

Please do not hesitate to contact me if you have further concerns or comments.

 

Yours sincerely

 

 

 

 

Lorraine Trainor BSc(Hons)

Medical Information Manager

                         EMSDO

                                                                                                Silk Court

                                                                                                Silk Road Business Park

                                                                                                Hulley Road

                                                                                                Macclesfield, Cheshire

                                                                                                SK10 2NA

                                                                                                England, UK

 

 

 

Your Ref	Our Ref	Direct Line	FAX Number	Date
	LT/pjf	+ 44 (0)1625 515508	+ 44 (0)1625 512305	4 November 2002

 

Dear Dr Eldor

 

Thank you for your most recent correspondence by e-mail (received 23-09-2002).  AstraZeneca, having considered your concerns and having already reviewed all of the available safety data relating to our product ‘Naropin’ (ropivacaine), remain satisfied with the appropriateness of the wording contained within the product prescribing information.  Based on the information available there is no reason to consider amending the regulatory documentation relating to this product.

 

Considering your comments on the definition of an adverse event I feel that explanation of the term ‘adverse event’ would help to clarify the matter and set the issue to rest.

 

The AstraZeneca definition of an adverse event are stated below and are in accordance with the principles of the International Conference on Harmonization (ICH) definitions, in particular ICH E2A.

 

AstraZeneca Definition of an Adverse Event (AE):

An AE is the development of an undesirable medical condition or the deterioration of a pre-existing medical condition following or during exposure to a pharmaceutical product, whether or not considered causally related to the product.

An undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory findings, electrocardiogram).

 

You will appreciate that this is based on the ICH definitions as detailed below. 

Excerpt from the “Clinical Safety Data Management:

Definitions And Standards For expedited Reporting - Recommended for Adoption at Step 4 of the ICH Process on 27 October 1994 by the ICH Steering Committee.”

 

“Definitions for the terms adverse event (or experience), adverse reaction, and unexpected adverse reaction have previously been agreed to by consensus of the more than 30 Collaborating Centres of the WHO International Drug Monitoring Centre (Uppsala, Sweden). [Edwards, I.R., et al, Harmonisation in Pharmacovigilance. Drug Safety 10(2): 93-102, 1994.] Although those definitions can pertain to situations involving clinical investigations, some minor modifications are necessary, especially to accommodate the pre-approval, development environment.

 

Adverse Event (or Adverse Experience)

Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event (AE) can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.”

 

I trust that this clarifies the issue.  We thank you for your interest in our product and trust that the matter is now considered closed.

 

Finally I would like to thank you for forwarding details of the articles, which discuss osteomyelitis in patients receiving epidural anaesthesia.  AstraZeneca frequently and regularly review the published literature and are aware of these publications, which have been reviewed as part of the drug safety recording procedure.

 

Yours sincerely

 

 

 

 

Lorraine Trainor BSc(Hons)

Medical Information Manager

                         EMSDO

                                                                                                Silk Court

                                                                                                Silk Road Business Park

                                                                                                Hulley Road

                                                                                                Macclesfield, Cheshire

                                                                                                SK10 2NA

                                                                                                England, UK

 

 

 

Your Ref	Our Ref	Direct Line	FAX Number	Date
	LT05/pjf	+ 44 (0)1625 515508	+ 44 (0)1625 512305	2 June 2003

 

Dear Dr Eldor

 

Thank you for your recent communication (e-mail 13^th April 2003) with regard to the development of patent pending modification to products within AstraZeneca’s anaesthesia portfolio – namely lidocaine, bupivacaine and ropivacaine.

As you are aware AstraZeneca are a highly ethical company committed to monitoring and maintaining the excellent safety record of our products.  Safety review is on an ongoing basis and any appropriate action is identified and implemented to ensure that safety standards are maintained to the highest degree.

 

We thank you for your interest in our products but after careful consideration regarding this matter we will not be pursuing your proposal.

 

As I am on maternity leave, Moira Rice will pick up this issue if any further input is required from MSDO Medical Information.

 

Kind regards

 

Yours sincerely

 

 

Lorraine Trainor BSc(Hons)

Medical Information Group Manager

Anaesthesia. 2003 Sep;58(9):926-8; discussion 928.

Related Articles, Links

Comment in:

• Anaesthesia. 2003 Nov;58(11):1154.

 
Local anaesthetic antibacterial activity.

Eldor J.

Publication Types:

• Letter

PMID: 12911387 [PubMed - indexed for MEDLINE]

-------------

 

 

 

Anaesthesia. 2003 Nov;58(11):1154.

Related Articles, Links

Comment on:

• Anaesthesia. 2003 Sep;58(9):926-8; discussion 928.
• Anaesthesia. 2003 Sep;58(9):930.

 
In response to 'Local anaesthetic antibacterial activity', Eldor J, Anaesthesia 2003; 58: 926-8.

Reynolds F.

Publication Types:

• Comment
• Letter

PMID: 14616657 [PubMed - indexed for MEDLINE]

 

There is an interesting juxtaposition of two items in the correspondence columns of the September issue of Anaesthesia. In the first, Dr Eldor reminds us that the long-recognised antibacterial properties of chiral local anaesthetics appear to reside largely in their R-isomers, hence are not shared to the full by ropivacaine [1]. The same is true of levobupivacaine [2]. Dr Eldor ends with a plea that the manufacturer should emphasise the poor antibacterial activity of ropivacaine in its drug information. In response, AstraZeneca refute this suggestion. The second letter reports 12 cases of epidural site abscess (presumably meaning an abscess anywhere along the track of the epidural catheter, from skin to epidural space) in the past 3 years, in association with the use of patient-controlled epidural analgesia using a combination of ropivacaine, fentanyl and epinephrine [3], but the authors attribute this to the type of dressing used to cover the catheter entry site.
The patient's skin frequently acts host to the staphylococcus, the most likely causative agent in epidural and skin abscess [4] and no amount of sterile gauze, therefore, can be expected to keep this organism out. Did not the arrival of this cluster of cases also coincide with the advent of ropivacaine for this application in Dr Cohen's institution? I wonder whether AstraZeneca would consider that the second letter might cause them to modify their response to Dr Eldor?
The principle risk factors for epidural abscess (far commonner than epidural haematoma, which we all worry about perhaps to excess) are prolonged epidural catheterisation, multiple attempts at insertion and immunocompromise [4,5]. In any of these circumstances, it must be unwise to omit an antibacterial local anaesthetic. There can be little danger of using the more toxic bupivacaine in the low concentrations needed for analgesia, when combined with an opioid.

References
1. Eldor J. Local anaesthetic antibacterial activity. Anaesthesia 2003; 58: 926-7.
2. Hodson M, Gajraj R, Scott NB. A comparison of the antibacterial activity of levobupivacaine vs. bupivacaine: an in vitro study with bacteria implicated in epidural infection. Anaesthesia 1999; 54: 699-702.
3. Cohen S, Uzum N, Aptekin B. Aseptic precautions for inserting an epidural catheter. Anaesthesia 2003; 58: 930.
4. Loo CC, Dahlgren G, Irestedt L. Neurological complications in obstetric regional anaesthesia. International Journal of Obstetric Anesthesia 2000; 9: 99-124.
5. Reynolds F. Contraindications to regional analgesia? In: Reynolds F (ed) Regional analgesia in obstetrics. London: Springer, 2000: 357-69.