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Drugs and Health Products

Scientific Advisory Panel on Anti-Infective Therapies (SAP-AIT)

Record of Proceedings

October 6, 2016

Panel members: Gerald A. Evans (Chair), Edith Blondel-Hill, John Conly, Susan Fryters, Andrew Morris

Health Canada presenters: Melissa Hunt, Philippa McDonald

Health Canada staff observers: Shiv Brar, Jiazhen Minnie Dai, Caroline Hunt, Hema Gupta, Bindu Islam, Rajkumar Kadaba, Marion Law, Celia Lourenco, Sylvie Martin, Chinonso Okenwa, Lynda O’Reilly, Conrad Pereira, Fabianne Phillipoussiss, Andrew Raven, Andrea Roper, Chantal Tremblay-Ruest, Shelley Wagner, Cathy Younger-Lewis

Swissmedic observers: Renate Essen, Barbara Freche, Charlotte Geluk, Christine Haenggeli, Hans Kemmler, Rudolf Stoller

Welcome and opening remarks (Marion Law)

The Director General of Therapeutics Products Directorate welcomed the scientific advisory panel members and meeting attendees. She indicated that the meeting was called as a result of Health Canada’s re-examination of issues around the safety and efficacy of fluoroquinolones for different indications, such as, treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, uncomplicated acute bacterial cystitis and acute uncomplicated gonorrhea. She then explained the process to be followed for the meeting, and once again thanked the panel for their time and willingness to provide advice to Health Canada. She then handed the meeting over to the Chair of the panel.

Chairĺs address (Gerald A. Evans)

The Chair reiterated the role of the panel in providing advice to Health Canada. Any decisions being made as a result of that advice would be made by Health Canada. He then confirmed acceptance of the draft agenda for the meeting and the terms of reference of the panel. A clarification to one of the sections of the terms of reference was recommended, to indicate that the Record of Proceedings would be the only record of the meeting. The Chair then indicated that following the presentations, the panel would deliberate on what they had heard, and formulate responses to Health Canada’s questions.

Presentations

1. Fluoroquinolones and Persistent Disability (Melissa Hunt)

The presentation included an overview of relevant information from the US Food and Drug Administration, and a review of Health Canada information including: Canadian spontaneous reporting data, a literature review summary and current safety labelling in Canada for fluoroquinolones, focussing on the issue of persistent disability.

Issues raised by the panel, in questioning the presenter, included, but were not limited to:

  • Differences between Canada and the US in their analyses with respect to proportion of adverse events to the number of prescriptions.
  • Whether definitions of adverse events should be harmonized with other regulatory agencies (specifically referring to the US FDA case definition of ‘Fluoroquinolone Associated Disability’).
  • Consideration of relative severity of the different adverse events, including aortic dissection and aneurysm, for fluoroquinolones.
  • Consideration of potential age-related adverse effect dose response, given effects seen in studies on juvenile animals.

2. Fluoroquinolones - Clinical Use Perspective (Philippa McDonald)

The presentation included: a review of available evidence and guidelines on systemic fluoroquinolone efficacy/effectiveness for acute bacterial sinusitis, acute bacterial exacerbation of chronic obstructive pulmonary disease, uncomplicated acute bacterial cystitis and Neisseria gonorrhoeae infections. Optimal use of fluoroquinolones in Canada, in the context of these indications and the current benefit/harm/uncertainty profile were assessed. Conservation of fluoroquinolones for use in serious and severe infections was discussed, due to concerns related to antimicrobial resistance.

Issues raised by the panel, in questioning the presenter, included, but were not limited to,

  • Potential association between the number of fluorine atoms in the molecule and severity of side-effects.
  • Exploring potential effects of genetic polymorphism in drug metabolizing enzymes to determine patient subgroups that may be at higher risk.
  • Models of mitochondrial toxicity syndrome.
  • Differences in labelling for different fluoroquinolones, with respect to warnings.
  • Need to expand discussion to other fluoroquinolone indications as well as other antibacterial drug classes.
  • Impact of safety communications on level of prescribing.
  • Looking at actions taken by other regulatory authorities [ for example (e.g.), UK, South Africa ]
  • Using the Canadian Product Monograph to communicate on inappropriate prescribing of antibiotics in general, such as in acute bronchitis.

Deliberation on the questions posed (All panel members)

The questions posed, to the panel, by Health Canada, were as follows:

  1. Safety: Persistent Disabling Events
    1. What is the SAP-AIT’s position on how the potential persistent disability associated with various types of adverse events reported during systemic fluoroquinolone treatment should be labelled in the respective Canadian Product Monographs?
    2. Are there other risk mitigation measures that could be considered to optimally address this safety concern?
    3. Would the proposed labelling and any other proposed risk mitigation measures be applicable for all systemic fluoroquinolone products marketed in Canada?
  2. Acute Bacterial Sinusitis Indication
    • Would you support the removal of the acute bacterial sinusitis indication from all fluoroquinolone Product Monographs?
  3. Acute Bacterial Exacerbations of Chronic Bronchitis (ABECB) Indication
    1. Would you support restriction of this indication (in all fluoroquinolone Product Monographs) to use in sick/hospitalised patients with moderate to severe ABECB?
    2. If yes, would you support this indication for use for both the intravenous (IV) and the oral preparations of fluoroquinolones?
  4. Uncomplicated Acute Bacterial Cystitis Indication
    • Would you support limiting the acute cystitis indication (in all fluoroquinolone Product Monographs) to use in those patients where there is no alternative treatment option and where there is an identified pathogen that is sensitive to the fluoroquinolone in question?
  5. Acute Uncomplicated Gonorrhea Indication
    • Would you support limiting the gonorrhea indication in all fluoroquinolone Product Monographs to?
      1. Use in those patients where antimicrobial susceptibility testing is available and quinolone susceptibility is demonstrated, or
      2. Where local quinolone resistance is under 5% and a test of cure can be performed; as per the Public Health Agency of Canada Guidelines on Sexually Transmitted Infections (July 2013)?

The discussion covered a variety of areas, such as:

  • Need for consistency across Product Monographs, with caveats in exceptional cases.
  • Effective means of communication of benefit-risk information.
  • Need to discuss all indications and other serious adverse effects.
  • Misuse and overuse of antibiotics, and antibiotic resistance.
  • Safety of fluoroquinolones

The above list is by no means exhaustive and is intended only to give a sense of the type of issues discussed.

Recommendations (All panel members)

The panel’s recommendations, in response to questions posed by Health Canada, were as follows:

Question 1: Safety: Persistent Disabling Events

  1. What is the SAP-AIT’s position on how the potential persistent disability associated with various types of adverse events reported during systemic fluoroquinolone treatment should be labelled in the respective Canadian Product Monographs?
    • It is recommended that the following statement be included in Canadian Product Monographs for fluoroquinolones:
      • Fluoroquinolones have been associated with disabling and potentially irreversible persistent adverse reactions which to date include, but are not limited to: tendonitis, tendon rupture, peripheral neuropathy and neuropsychiatric effects.
    • There must be consistency with respect to safety labelling across the Product Monographs, for all systemic fluoroquinolones, with the suggested additional wording below for norfloxacin:
      • There are a limited number of reports of toxicity with norfloxacin. It is unknown if this is due to low systemic levels of norfloxacin or infrequent clinical use of norfloxacin.
  2. Are there other risk mitigation measures that could be considered to optimally address this safety concern?
    • Risk mitigation measures could include Dear Prescriber letters which summarize resistance and safety issues. Letters should be sent to all prescribing populations and their respective regulatory bodies.
    • Consideration should also be given to informing the Canadian public about ongoing safety issues associated with use of the systemic fluoroquinolone class of antimicrobials.
    • Consideration should be given to communicating safety concerns and resistance issues, for all antimicrobials, using opportunities such as the National Antibiotic Awareness Week.
    • Consideration should be given as to how recipients of fluoroquinolone prescriptions could be advised, in plain language, of known potential complications and available reporting mechanisms, should the recipient experience an adverse effect.
    • More should be done to understand the biological mechanisms underlying the safety profile of the fluoroquinolones and to gather further information at a cellular and population level. Pre-clinical and clinical studies would be required. Health Canada could explore these questions with the Drug Safety and Effectiveness Network (DSEN) and the Canadian Agency for Drugs and Technologies in Health (CADTH).
  3. Would the proposed labelling and any other proposed risk mitigation measures be applicable for all systemic fluoroquinolone products marketed in Canada?
    • Yes, the proposals should be applicable to all existing, and future, systemic fluoroquinolone products

Question 2: Acute Bacterial Sinusitis Indication

Would you support removal of the acute bacterial sinusitis indication from all fluoroquinolone Product Monographs?

  • It is recommended that the following statement be included in Canadian Product Monographs for fluoroquinolones:
    • Acute sinusitis
    • Antibiotics, including fluoroquinolones, are NOT indicated for acute sinusitis of less than 7 days duration.
  • The panel supports the removal of the acute bacterial sinusitis indication for ciprofloxacin.
  • Where no other treatment options exist, and the clinical presentation meets the diagnostic criteria for acute bacterial sinusitisFootnote *, the use of levofloxacin and moxifloxacin may be considered.

Footnotes

Footnote 1

Return to footnote * referrer [ The diagnosis of acute bacterial sinusitis is reserved for patients with:

  • Symptoms lasting 7 days or more AND
  • Purulent nasal secretions AND
  • At least one of the following:
    • Maxillary pain
    • Tenderness in the face (especially unilateral)
    • Tenderness of the teeth (especially unilateral).

(Ref: Canadian clinical practice guidelines for acute and chronic rhinosinusitis. Desrosiers et al. Allergy, Asthma & Clinical Immunology 2011, 7:2. http://www.aacijournal.com/content/7/1/2)]

Question 3: Acute Bacterial Exacerbations of Chronic Bronchitis Indication (ABECB)

  1. Would you support restriction of this indication (in all fluoroquinolone Product Monographs) to use in sick/hospitalised patients with moderate to severe ABECB?
    • It is recommended that the following statement be included in Canadian Product Monographs for fluoroquinolones:
      • Acute bronchitis
      • Antibiotics, including fluoroquinolones, are NOT indicated for acute bronchitis
      • Fluoroquinolones should not be prescribed in mild acute bacterial exacerbations of chronic obstructive pulmonary disease.
    • The panel supports limiting the use of fluoroquinolones as a therapeutic option in hospitalized patients presenting with moderate to severe acute bacterial exacerbations of chronic obstructive pulmonary disease. The panel also recognized the equivocal nature of the evidence supporting this recommendation.
  2. If yes, would you support this indication for use for both the IV and the oral preparations of fluoroquinolones?
    • Yes, the panel supports the modified indication, as outlined above, for both the intravenous and the oral preparations of fluoroquinolones.

Question 4: Uncomplicated Acute Bacterial Cystitis Indication

Would you support limiting the acute cystitis indication (in all fluoroquinolone Product Monographs) to use in those patients where there is no alternative treatment option and where there is an identified pathogen that is sensitive to the fluoroquinolone in question?

  • For all fluoroquinolone products currently indicated for acute cystitis, the panel supports limiting the indication to circumstances where no other treatment options are available. Given increasing fluoroquinolone resistance in uropathogens, a urine culture should be obtained prior to treatment to ensure fluoroquinolone susceptibility. Acute cystitis is defined by the presence of urinary symptoms, including, but not limited to: dysuria, frequency, and urgency.

Question 5: Acute Uncomplicated Gonorrhea Indication

Would you support limiting the gonorrhea indication in all fluoroquinolone Product Monographs to,

  1. use in those patients where antimicrobial susceptibility testing is available and quinolone susceptibility is demonstrated, or
  2. where local quinolone resistance is under 5% and a test of cure can be performed; as per the Public Health Agency of Canada Guidelines on Sexually Transmitted Infections (July 2013)?
    • The panel supports limiting the gonorrhea indication in all fluoroquinolone Product Monographs, where this indication is listed, to use in patients where no other treatment option exists AND
      1. where antimicrobial susceptibility testing is available, and fluoroquinolone susceptibility is demonstrated, OR
      2. fluoroquinolone susceptibility is highly likely, typically ≥ 95%, based on local susceptibility patterns.

Additional recommendations:

  • All approved indications for fluoroquinolones should be re-visited.
  • Consider evidence of other harms associated with fluoroquinolone use.
  • Communication about harms (including adverse reactions and antimicrobial resistance) associated with antibiotic use in general, not just with the use of fluoroquinolones, should be considered by Health Canada.

Closing remarks / Adjournment (Chair)

The Chair thanked the members for their participation. The meeting was adjourned.

[Note: This record of proceedings was submitted and approved in English by the Chair of the SAP-AIT.]