Response from Lindsay A. Slowiczek, PharmD Medical writer, Slowiczek Communications, LLC, Portland, Oregon In July 2018, the US Food and Drug Administration (FDA) issued a Drug Safety Communication to alert healthcare professionals and patients about the increased risks for hypoglycemic coma and adverse psychiatric events associated with the use of fluoroquinolone (FQ) antibiotics.[1] Prior to this safety announcement, labeling for individual fluoroquinolone agents differed in regard to warnings and precautions for blood sugar– or mental health–related side effects. The FDA's intention is to make information pertaining to such side effects more prominent and consistent across the drug class so that healthcare providers and patients can make informed risk-benefit decisions. The updated labeling for all systemic (oral and injectable) fluoroquinolones resulted from analyses of postmarketing adverse events identified through both the voluntary FDA Adverse Event Reporting System (FAERS) and published medical literature. The FDA's analyses included safety reports for five FQs: ciprofloxacin, gemifloxacin, levofloxacin, moxifloxacin, and ofloxacin. Delafloxacin, approved in June 2017, was not included, although it is expected to exhibit a similar adverse effect profile and is included in the required labeling updates.[1] Hypoglycemic Coma Between October 1987 and April 2017, FAERS received 56 reports of hypoglycemic coma following fluoroquinolone use. Additionally, investigators identified 11 published case reports linking the drug class to hypoglycemic coma. Most cases involved elderly patients or those with renal impairment or diabetes. Among the 47 patients who were receiving concomitant hypoglycemic therapy for diabetes, 35 were receiving a sulfonylurea. However, nearly one third of the reported cases involved patients who were neither diagnosed with diabetes nor receiving hypoglycemic therapy. Of the 67 total cases, the FDA reports that nine patients experienced permanent disability and 13 patients ultimately died as a result of severe hypoglycemia. The FDA investigators noted that renal insufficiency may have complicated these more severe cases. On the basis of the FDA's review, manufacturer labeling of fluoroquinolones will now include strengthened warnings in the Warnings and Precautions section to explicitly describe the risk for coma due to hypoglycemia. [1] Adverse Psychiatric Effects Postmarketing analyses using FAERS and published medical literature related to adverse psychiatric effects also warranted updated fluoroquinolone labeling, according to the FDA. While warning labels for central nervous system (CNS) effects differed across the class, many already included warnings for anxiety, confusion, depression, hallucination, and psychoses. To standardize class-wide labeling, the following six adverse effects will now be included separately in the Warnings and Precautions section: agitation, delirium, disorientation, disturbance in attention, memory impairment, and nervousness.[1] The FDA does not provide qualitative evidence from their analyses but states that these effects have been observed after as little as one fluoroquinolone dose. Recently published evidence supports the FDA's safety alert. A meta-analysis[2]of 28 randomized controlled trials evaluating adverse effects from oral fluoroquinolone use in primary care settings identified an increased risk of CNS effects. Compared with a combined group of studies that evaluated macrolides, trimethoprim/sulfamethoxazole (TMP/SMX), cefuroxime, amoxicillin/clavulanic acid, or placebo as comparators, oral fluoroquinolones were associated with 40% greater odds of adverse CNS effects (odds ratio, 1.40; 95% confidence interval, 1.12-1.75). Adverse effects described in the included studies were less severe in nature (eg, tremor, dizziness, insomnia, asthenia) than those being added to the drug labels but provide supporting evidence for an association between fluoroquinolone and CNS outcomes nonetheless. The risks for serious hypoglycemic or psychiatric adverse effects should be carefully weighed against the therapeutic benefits of fluoroquinolones for all patients. Oral and injectable fluoroquinolones should be used cautiously in elderly patients and those with renal impairment owing to an increased risk for drug accumulation, and in patients with diabetes or those who are taking hypoglycemic agents owing to the risk for severe hypoglycemia. Alternative treatment options should be used, when available, for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, or uncomplicated urinary tract infections. For example, amoxicillin/clavulanate is preferred over respiratory fluoroquinolones by the Infectious Diseases Society of America (IDSA) as first-line therapy of acute bacterial sinusitis [3] Amoxicillin-clavulanate, TMP/SMX, or nitrofurantoin are acceptable options for uncomplicated urinary tract infections, per the IDSA and European Society for Microbiology and Infectious Diseases. [4] Preserving fluoroquinolone use for clinical scenarios without appropriate alternatives will reduce the incidence of severe adverse effects and subsequent risk for collateral damage. In cases where no alternative to fluoroquinolone therapy is available, patients should be educated on how they can mitigate the risks for serious adverse effects. All patients who receive a systemic fluoroquinolone should be made aware of the potential for changes in memory, attention span, and other psychiatric functions, and should report signs of alarming CNS effects to a healthcare professional. Healthcare professionals should educate patients on the risk for blood glucose fluctuations and the need for more frequent monitoring in patients with diabetes. Patients should be aware of the signs and symptoms of low blood sugar, including anxiety, confusion, elevated heart rate, headache, and sweating, which can progress to seizures or coma if not treated appropriately. Patients should be told to consider keeping glucose tablets or gel, hard candy, or raisins on hand during fluoroquinolone therapy. Patients with a very high hypoglycemia risk and a prescription for glucagon should keep glucagon with them at all times, and their family members and friends should be comfortable with its administration. If serious hypoglycemic or CNS adverse effects occur during fluoroquinolone therapy, the drug should be immediately discontinued, and an alternative agent should be initiated. The FDA encourages healthcare professionals and patients to report any adverse effects to MedWatch and FAERS.[1] The Bottom Line Rare but serious disturbances in blood glucose and CNS adverse effects are the latest additions to the developing fluoroquinolone safety profile, following warnings for potentially permanent, disabling tendon, muscle, joint, or nerve damage; rare, but serious peripheral neuropathy; and QT interval prolongation. As available evidence of severe adverse effects continues to develop, healthcare providers should use this information to inform safe fluoroquinolone prescribing. References Food and Drug Administration. Safety Announcement: FDA reinforces safety information about serious low blood sugar levels and mental health side effects with fluoroquinolone antibiotics; requires label changes. July 10, 2018. Source Accessed October 13, 2018. Tandan M, Cormican M, Vellinga A. Adverse events of fluoroquinolones vs other antimicrobials prescribed in primary care: a systematic review and meta-analysis of randomized controlled trials. Int J Antimicrob Agents. 2018;52:529-540. Abstract Chow AW, Benninger MS, Brook I, et al; Infectious Diseases Society of America. IDSA clinical practice guideline for acute bacterial rhinosinusitis in children and adults. Clin Infect Dis. 2012;54:e72-e112. Abstract Gupta K, Hooton TM, Naber KG, et al; Infectious Diseases Society of America; European Society for Microbiology and Infectious Diseases. International clinical practice guidelines for the treatment of acute uncomplicated cystitis and pyelonephritis in women: a 2010 update by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases. Clin Infect Dis. 2011;52:e103-e120. Abstract Source
