FDA Updates Warnings for Fluoroquinolone

Kathryn G. Smith, PharmD PGY1 Pharmacy Resident Via Christi Hospitals Wichita, Inc  Kathryn G. Smith: Nothing to disclose  Describe the new updates and rationale for them

 Relay safety concerns with use of fluoroquinolones (FQ)

 List appropriate alternatives to FQ  July 26, 2016 - FDA approved label changes • Boxed Warning • Warnings and Precautions • Indications and Usage

 Updated Medication Guides for patients

FDA Drug Safety Communication. 2016. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm FDA Briefing Document 2015. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm467383.pdf  Associated with disabling and potentially permanent side effects • Tendons, muscles, and peripheral and central nervous systems

 Risk outweighs the benefit • Acute bacterial sinusitis (ABS) • Acute bacterial exacerbation of chronic bronchitis (ABECB) • Uncomplicated urinary tract infections (uUTI)

FDA Drug Safety Communication. 2016. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm511530.htm FDA Briefing Document 2015. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm467383.pdf  Black Box Warnings • Tendinitis and tendon ruptures • Central nervous system effects • Peripheral neuropathy • Exacerbation of Myasthenia Gravis

 Warnings and Precautions • Clostridium difficile-associated diarrhea • Photosensitivity • Prolongation of QT interval

Daily Med. “Levofloxacin”. Available at: https://dailymed.nlm.nih.gov/dailymed/drugInfo FDA Briefing Document 2015. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm467383.pdf  Use of antibacterial agents inhibits normal flora  Risk with nearly all antibacterial agents  Mild diarrhea to fatal colitis  Modifiable risk factor

Antibiotic Class Hazard Ratio Fluoroquinolones 4.0 3rd and 4th generation cephalosporins 3.1 1st and 2nd generation cephalosporins 2.4 β-lactamase inhibitor combinations 2.3 Sulfas 1.9 Penicillins 1.9 Metronidazole 0.3

Stevens, et al. Clin Infect Dis. 2011  FDA Adverse Event Reporting System

 Identified 178 U.S. cases • November 1997-May 2015 • Previously healthy individuals • FQ to treat ABS, ABECB, or uncomplicated UTI • Lasting longer than a month • Involving two or more body systems

FDA Briefing Document 2015. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm467383.pdf FQAD = Fluoroquinolone-associated disability

 Sex: 78% were female

 Reported Indication: 47% for cystitis/UTI

 Onset of AE: 48% within 1-2 days

 Mean: 14 months

 Longest: 9 years

592

358

136 91 65 19

Levofloxacin Ciprofloxacin Moxifloxacin

Azithromycin 1.2 Cephalexin 2.7 Amox/Clav 5.1 Doxycycline 6 Amoxicillin 6 Nitrofurantoin 6.7 Cefdinir 6.9 Moxifloxacin 9.9 Gemifloxacin 10.5 Levofloxacin 26.9 Ciprofloxacin 29.3 Ofloxacin 31.1

Musculoskeletal 98% 94% 95%

Peripheral 52% 78% 79% Nervous System 38%

Neuropsychiatric 74% 66% 65%

Senses 30% 31% 30%

Cardiovascular 10% 12% 10%

Skin 10% 15% 15%

FDA Briefing Document 2015. Available at: https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-infectivedrugsadvisorycommittee/ucm467383.pdf

Duration ≤4 weeks

Bacterial infection suspected: Nasal purulence + severe/persistent symptoms + ≥7-10 days

Watchful waiting with symptomatic relief

Treatment Prescribe antibiotic failure?

-Amoxicillin-Clavulanate 875/125 mg PO BID x 10-14 days*

-Azithromycin 2 g x 1 dose or 500 mg PO daily x 3 days -Doxycycline 100 mg PO BID x 10-14 days* -TMP-SMX DS 1 tab BID x 10-14 days* *5-7 day duration may be appropriate for adults

Chow AW, et al. Clin Infect Dis. 2012;54(8):e72-e112 Rosenfeld RM, et al. Otolaryng Head Neck. 2015; 152(4) Bartlett JG, et al. (2012). ABX Guide. Burlington, MA: Jones & Bartlett Learning Assess for cardinal symptoms: -Increased dyspnea -Increased sputum volume -Increased sputum purulence

Amoxicillin- Age >65 or cardiac clavulanate disease or ≥3 875/125 mg PO exacerbations/year BID x 7 days

Doxycycline 100 mg Cefdinir 300 mg PO PO BID x 7 days BID x 7 days

Cefuroxime 500 mg Azithromycin 500 mg PO BID x 10 days PO x 1 day, then 250 x 4 days

Lee H, Am Fam Physician. 2013 Nov 15;88(10):655-63 -100 mg PO BID x 5 days -Do not use: CrCl <40mL/min -DS 1 tab PO BID x 3 days -Avoid use in ≥65 yo -CrCl >30 mL/min -40% unchanged in urine -40% unchanged in urine

-500 mg PO q6-8h x 5-7 days -3 g PO x 1 dose -CrCl >30 mL/min -30-40% bioavailability -80% unchanged in urine -100% unchanged in urine

-875/125 mg PO BID x 5-7 days -CrCl >30 mL/min -60% unchanged in urine

*Beta-lactams can be considered if other agents cannot be used.

Treatment with antibiotics is only indicated if patient is symptomatic or pregnant

Gupta K, et al. Clin Infect Dis. 2011;52(5):e103–e120 Bartlett JG, et al. (2012). ABX Guide. Burlington, MA: Jones & Bartlett Learning  FQ are associated with severe disabling events

 Can involve several body systems at once

 High risk of C. difficile-associated diarrhea

 Variety of alternative antibacterial options available

 Education to patients and physicians can be beneficial Kathryn G. Smith, PharmD PGY1 Pharmacy Resident Via Christi Hospitals Wichita, Inc