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12 cases of Ropivacaine epidural abscess

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  • Joseph Eldor
    5.10.2004 Dear Lorraine Trainor AstraZeneca Enclosed a recent correspondence by Prof. Reynolds asking: I wonder whether AstraZeneca would consider that the
    Message 1 of 3 , Oct 5, 2004
      5.10.2004
       
      Dear Lorraine Trainor
      AstraZeneca
       
      Enclosed a recent correspondence by Prof. Reynolds asking: "I wonder whether AstraZeneca would consider that the second letter might cause them to modify their response to Dr Eldor?"
       
      This question is based on a recent article by Cohen et al. : "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".

      This data contradicts your statement from 19.9.02: "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’."
       

      I will appreciate AstraZeneca opinion on this open letter to the public.
       
      Sincerely,
       
      Joseph Eldor, MD
       
       
      ----------

                               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

      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 13th 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.

       

    • Joseph Eldor
      Dear Prof. Reynolds, I hope it will not become a second Vioxx ... Best regards, Joseph Eldor ... Table 33-2. Possible etiological factors for epidural
      Message 2 of 3 , Oct 6, 2004
        Dear Prof. Reynolds,
        I hope it will not become a second "Vioxx"...
        Best regards,
        Joseph Eldor
        ----------

        Table 33-2.   Possible etiological factors for epidural abscess and meningitis

         

        Epidural abscess

        Meningitis

        Entry point

        ·        Through the catheter or along its track

        ·        Blood, via the dural puncture

        Usual causative organism

        ·        Staphylococcus aureus

        ·        Viridans type Streptococcus

        Possible source of infection

        ·        patient's skin, tracking along the catheter entry point

        ·        epidural equipment contaminated by operator's skin

        ·        body fluids in the bed

        ·        injectate without local anaesthetic

        ·        operator’s mouth

        ·        talking without a mask

        ·        blood borne

        ·        vagina

        Risk factors

        ·        prolonged catheterization

        ·        poor aseptic technique

        ·        multiple attempts at insertion

        ·        epidural haematoma

        ·        no bacterial filter

        ·        lying in a wet contaminated bed

        ·        polyurethane occlusive dressing

        ·        absence of antimicrobial local anaesthetic

        ·        immunocompromise: steroids, diabetes, AIDS

        ·        dural puncture ± epidural catheterization

        ·        no face mask

        ·        vaginal delivery

        ·        manual removal of the placenta

        ·        vaginal infection

        ·        bacteremia

        ·        epidural blood patch

        ·        immunocompromise?

        ·        no bacterial filter if epidural catheter used

         
         
        ----- Original Message -----
        From: "FELICITY SPENCER" <felicity.reynolds@...>
        To: "Joseph Eldor" <csen_international@...>
        Sent: Wednesday, October 06, 2004 11:18 AM
        Subject: Re: 12 cases of Ropivacaine epidural abscess

        > On it goes. I gather they still have their heads in the sand.
        > Attached is what I put in a chapter I wrote for David Chestnut's
        book.
        >
        > With best wishes, Felicity
        >
        > Felicity
        Reynolds
        > Emeritus Professor  of Obstetric Anaesthesia
        > St
        Thomas's Hospital
        > London SE1 7EH, UK
        >
        > Telephone:
        >
        home: +44 (0)20 7735 9357
        > or +44 (0) 1730261096
        > work: +44 (0)20
        7188 0627
        > mobile +44 (0) 797 953 4267
        > email:
        href="mailto:felicity.reynolds@...">felicity.reynolds@...
        > ----- Original Message -----
        > From: "Joseph Eldor"
        <
        csen_international@...>
        > To: "Trainor, Lorraine M" <
        href="mailto:Lorraine.Trainor@...">Lorraine.Trainor@...>
        > Cc: <
        href="mailto:csen-anesthesia-mailing-list@yahoogroups.com">csen-anesthesia-mailing-list@yahoogroups.com>;
        > <
        href="mailto:eldor-products@yahoogroups.com">eldor-products@yahoogroups.com>; "Felicity Spencer"
        > <
        href="mailto:Felicity.Reynolds@...">Felicity.Reynolds@...>
        > Sent: Tuesday, October 05, 2004 8:53 PM
        > Subject: 12
        cases of Ropivacaine epidural abscess
        >
        >
        >
        5.10.2004
        >
        > Dear Lorraine Trainor
        > AstraZeneca
        >
        > Enclosed a recent correspondence by Prof. Reynolds asking: "I wonder
        whether
        > AstraZeneca would consider that the second letter might cause
        them to modify
        > their response to Dr Eldor?"
        >
        > This
        question is based on a recent article by Cohen et al. : "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".
        >
        >
        > This data contradicts your statement from
        19.9.02: "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’."
        >
        >
        > I will appreciate
        AstraZeneca opinion on this open letter to the public.
        >
        >
        Sincerely,
        >
        > Joseph Eldor, MD
        >
        href="http://www.csen.com/anesthesia">http://www.csen.com/anesthesia
        >
        >
        > ----------
        >
                                 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
        >      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 13th
        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:
        >   a.. Anaesthesia. 2003 Nov;58(11):1154.
        >
        > Local
        anaesthetic antibacterial activity.
        >
        > Eldor J.
        >
        >
        Publication Types:
        >   a.. Letter
        >
        > PMID: 12911387
        [PubMed - indexed for MEDLINE]
        > -------------
        >
              Anaesthesia. 2003 Sep;58(9):930. Related Articles, Links
        >
        >
        > Comment in:
        >   a..
        Anaesthesia. 2003 Nov;58(11):1154.
        >
        > Comment on:
        >  
        a.. Anaesthesia. 2002 Jun;57(6):593-6.
        >
        > Aseptic precautions for
        inserting an epidural catheter.
        >
        > Cohen S, Uzum N, Alptekin
        B.
        >
        > Publication Types:
        >   a.. Comment
        >  
        b.. Letter
        >
        > PMID: 12911393 [PubMed - indexed for
        MEDLINE]
        >
        >
        > ------------
        >
        >
              Anaesthesia. 2003 Nov;58(11):1154. Related Articles, Links
        >
        >
        > Comment on:
        >   a..
        Anaesthesia. 2003 Sep;58(9):926-8; discussion 928.
        >   b..
        Anaesthesia. 2003 Sep;58(9):930.
        >
        > In response to 'Local
        anaesthetic antibacterial activity', Eldor J,
        > Anaesthesia 2003; 58:
        926-8.
        >
        > Reynolds F.
        >
        > Publication Types:
        >
          a.. Comment
        >   b.. 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.
        >
      • Joseph Eldor
        Dear Lorraine, Thank you for your email. I will appreciate receiving the reply of the Global Product Physician on that issue. Please ask him or her to read the
        Message 3 of 3 , Oct 6, 2004
          Dear Lorraine,
           
          Thank you for your email.
          I will appreciate receiving the reply of the Global Product Physician on that issue.
          Please ask him or her to read the following webpages of the CSEN for reference except than the letters of mine, Prof. Reynolds and Dr. Cohen et al. which were published in Anaesthesia:
           
           
          Regards,
           
          Joseph Eldor, MD
           
          ----- Original Message -----
          Sent: Wednesday, October 06, 2004 6:54 PM
          Subject: RE: 12 cases of Ropivacaine epidural abscess

          Dear Dr Eldor
          Thank you for your e-mail dated 6th September .  I am no longer involved in this area and have therefore passed on your recent communication to the Global Product Physician involved in the original communications.
          Regards
           

          Lorraine
          Lorraine M Trainor
          Medical Information Group Manager - MSDO
          (Crestor & Exanta)
          Tel. +44 (0) 1625 515082  Internal 25082
          Fax. +44(0) 1625 512305
          Mobile. 
          Mail To: lorraine.trainor@...
          G15 Silk Court, Macclesfield

          -----Original Message-----
          From: Joseph Eldor [mailto:csen_international@...]
          Sent: 06 October 2004 14:08
          To: FELICITY SPENCER
          Cc: Trainor, Lorraine M; csen-anesthesia-mailing-list@yahoogroups.com; eldor-products@yahoogroups.com
          Subject: Re: 12 cases of Ropivacaine epidural abscess

          Dear Prof. Reynolds,
          I hope it will not become a second "Vioxx"...
          Best regards,
          Joseph Eldor
          ----------

          Table 33-2.   Possible etiological factors for epidural abscess and meningitis

           

          Epidural abscess

          Meningitis

          Entry point

          ·        Through the catheter or along its track

          ·        Blood, via the dural puncture

          Usual causative organism

          ·        Staphylococcus aureus

          ·        Viridans type Streptococcus

          Possible source of infection

          ·        patient's skin, tracking along the catheter entry point

          ·        epidural equipment contaminated by operator's skin

          ·        body fluids in the bed

          ·        injectate without local anaesthetic

          ·        operator’s mouth

          ·        talking without a mask

          ·        blood borne

          ·        vagina

          Risk factors

          ·        prolonged catheterization

          ·        poor aseptic technique

          ·        multiple attempts at insertion

          ·        epidural haematoma

          ·        no bacterial filter

          ·        lying in a wet contaminated bed

          ·        polyurethane occlusive dressing

          ·        absence of antimicrobial local anaesthetic

          ·        immunocompromise: steroids, diabetes, AIDS

          ·        dural puncture ± epidural catheterization

          ·        no face mask

          ·        vaginal delivery

          ·        manual removal of the placenta

          ·        vaginal infection

          ·        bacteremia

          ·        epidural blood patch

          ·        immunocompromise?

          ·        no bacterial filter if epidural catheter used

           
           
          ----- Original Message -----
          From: "FELICITY SPENCER" <felicity.reynolds@...>
          To: "Joseph Eldor" <csen_international@...>
          Sent: Wednesday, October 06, 2004 11:18 AM
          Subject: Re: 12 cases of Ropivacaine epidural abscess

          > On it goes. I gather they still have their heads in the sand.
          > Attached is what I put in a chapter I wrote for David Chestnut's book.
          >
          > With best wishes, Felicity
          >
          > Felicity Reynolds
          > Emeritus Professor  of Obstetric Anaesthesia
          > St Thomas's Hospital
          > London SE1 7EH, UK
          >
          > Telephone:
          > home: +44 (0)20 7735 9357
          > or +44 (0) 1730261096
          > work: +44 (0)20 7188 0627
          > mobile +44 (0) 797 953 4267
          > email:
          felicity.reynolds@...
          > ----- Original Message -----
          > From: "Joseph Eldor" <
          csen_international@...>
          > To: "Trainor, Lorraine M" <
          Lorraine.Trainor@...>
          > Cc: <
          csen-anesthesia-mailing-list@yahoogroups.com>;
          > <
          eldor-products@yahoogroups.com>; "Felicity Spencer"
          > <
          Felicity.Reynolds@...>
          > Sent: Tuesday, October 05, 2004 8:53 PM
          > Subject: 12 cases of Ropivacaine epidural abscess
          >
          >
          > 5.10.2004
          >
          > Dear Lorraine Trainor
          > AstraZeneca
          >
          > Enclosed a recent correspondence by Prof. Reynolds asking: "I wonder whether
          > AstraZeneca would consider that the second letter might cause them to modify
          > their response to Dr Eldor?"
          >
          > This question is based on a recent article by Cohen et al. : "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".
          >
          >
          > This data contradicts your statement from 19.9.02: "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’."
          >
          >
          > I will appreciate AstraZeneca opinion on this open letter to the public.
          >
          > Sincerely,
          >
          > Joseph Eldor, MD
          >
          http://www.csen.com/anesthesia
          >
          >
          > ----------
          >                          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
          >      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 13th 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:
          >   a.. Anaesthesia. 2003 Nov;58(11):1154.
          >
          > Local anaesthetic antibacterial activity.
          >
          > Eldor J.
          >
          > Publication Types:
          >   a.. Letter
          >
          > PMID: 12911387 [PubMed - indexed for MEDLINE]
          > -------------
          >       Anaesthesia. 2003 Sep;58(9):930. Related Articles, Links
          >
          >
          > Comment in:
          >   a.. Anaesthesia. 2003 Nov;58(11):1154.
          >
          > Comment on:
          >   a.. Anaesthesia. 2002 Jun;57(6):593-6.
          >
          > Aseptic precautions for inserting an epidural catheter.
          >
          > Cohen S, Uzum N, Alptekin B.
          >
          > Publication Types:
          >   a.. Comment
          >   b.. Letter
          >
          > PMID: 12911393 [PubMed - indexed for MEDLINE]
          >
          >
          > ------------
          >
          >       Anaesthesia. 2003 Nov;58(11):1154. Related Articles, Links
          >
          >
          > Comment on:
          >   a.. Anaesthesia. 2003 Sep;58(9):926-8; discussion 928.
          >   b.. Anaesthesia. 2003 Sep;58(9):930.
          >
          > In response to 'Local anaesthetic antibacterial activity', Eldor J,
          > Anaesthesia 2003; 58: 926-8.
          >
          > Reynolds F.
          >
          > Publication Types:
          >   a.. Comment
          >   b.. 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.
          >
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