07 January 2019 IMPORTANT MEDICINE SAFETY INFORMATION Dear Healthcare Professional RE: SYSTEMIC AND INHALED QUINOLONE AND FLUOROQUINOLONE ANTIBIOTICS - RISK OF DISABLING AND POTENTIALLY LONG-LASTING SIDE EFFECTS AND THE INCREASED RISK OF AORTIC ANEURYSM AND DISSECTION In collaboration with the South African Health Products Regulatory Authority (SAHPRA), the companies listed below would like to inform you that the prescribing information of oral, parenteral and inhaled quinolones/fluoroquinolones are to be amended in view of new safety information that has become available. Patients may experience adverse reactions that may be disabling, long-lasting and potentially irreversible. The majority of these adverse reactions relate to the muscles, tendons, joints and nervous system including psychiatry disorders. As a consequence, the benefits and risks of all oral, parenteral and inhaled quinolone and fluoroquinolone antibiotics and their indications are being reviewed. Healthcare professionals are therefore advised that for the indications listed below, only to prescribe quinolone/fluoroquinolone antibiotics where other antimicrobials are considered not to be an appropriate treatment option, have failed, are contraindicated or not tolerated: for treating non-severe or self-limiting infections (such as pharyngitis, tonsillitis and acute bronchitis) for preventing travellers' diarrhoea or recurrent lower urinary tract infections for non-bacterial infections, e.g. non-bacterial (chronic) prostatitis and for mild to moderate infections (including uncomplicated cystitis, acute exacerbation of chronic bronchitis and chronic obstructive pulmonary disease (COPD), acute bacterial rhinosinusitis and acute otitis media). Caution is advised when prescribing for the elderly, patients with renal impairment, patients with solid organ transplants, and those concurrently treated with corticosteroids, as the risk of fluoroquinolone-induced tendinitis and tendon rupture may be exacerbated in these patients. Healthcare professionals should advise patients to stop treatment immediately at the first signs of a serious adverse reaction, such as tendinitis and tendon rupture, muscle pain, muscle weakness, joint pain, joint swelling, peripheral neuropathy and central nervous system effects and to contact their doctor for further advice. DHCPL draft 3 to SAHPRA Quinolones/fluoroquinolones Group 1 P a g e 1
There is some evidence of an association of quinolone/fluoroquinolone use and the risk of aortic aneurysm and dissection particularly in the elderly population. Therefore, in patients at risk for aortic aneurysm and dissection, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic option. The conditions predisposing to aortic aneurysm and dissection include a family history of aneurysm disease, pre-existing aortic aneurysm or aortic dissection, Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behçet's disease, hypertension, and atherosclerosis. Patients should be advised about risk of aortic aneurysm and dissection and told to seek immediate medical attention in the emergency department in case of sudden severe abdominal, chest or back pain. Therefore, quinolones/ fluoroquinolones should only be prescribed to patients with a preexisting dilated aorta, aortic aneurysm or dissection, or the presence of other risk factors predisposing to aortic aneurysm/dissection, where other antimicrobials have been considered not to be an appropriate treatment option, have failed, are contraindicated or cannot be tolerated. Background to safety concern The European Medicines Agency (EMA) have reviewed systemic and inhaled quinolone and fluoroquinolone antibiotics to evaluate the risk of serious and persistent (lasting months or years), disabling and potentially irreversible adverse reactions mainly affecting the musculoskeletal and nervous systems. Serious adverse reactions of the musculoskeletal system include tendinitis, tendon rupture, myalgia, muscle weakness, arthralgia and joint swelling. Serious peripheral and central nervous system effects include peripheral neuropathy, psychosis, anxiety, insomnia, depression, hallucinations, suicidal thoughts, confusion, as well as impairment of vision, hearing, smell and taste. Due to the seriousness of these reactions in previously healthy persons, any decision to prescribe quinolones and fluoroquinolones should be taken after a careful assessment of the benefits and risk and other appropriate treatment options that are available. The epidemiological studies [1-3] report an increase in risk of aortic aneurysm and dissection in patients taking systemic fluoroquinolones compared with patients taking no antibiotics or other antibiotics (amoxicillin); with older people being at higher risk. A non-clinical study [4] reported that ciprofloxacin increases the susceptibility to aortic dissection and rupture in a mouse model. This finding is likely to be a class effect similar to that of fluoroquinolones being harmful to tendon tissue. The product information for fluoroquinolones-containing medicines will be updated accordingly. For further information, please contact the respective companies indicated in the table below: Aspen Puromylon Nalidixic acid K/18.5/247 Tel: 0800 118 088 Pharmacare Tafloc 200 mg Ofloxacin 35/20.1.1/0174 Fax: 011 239 6306 drugsafety@aspenpharma.com Tafloc 400 mg Ofloxacin 35/20.1.1/0175 Factive 320 mg Gemifloxacin 35/20.1.1/0058 mesylate Litares Moxifloxacin HCl 42/20.1.1/0142 DHCPL draft 3 to SAHPRA Quinolones/fluoroquinolones Group 1 P a g e 2
Bayer (Pty) Ltd Ciprobay 250 mg Ciprofloxacin U/20.1.1/126 Tel: 011 921 5067 Ciprobay 500 mg Ciprofloxacin U/20.1.1/127 Ciprobay 750 mg Ciprofloxacin U/20.1.1/128 Ciprobay IV Ciprofloxacin Y/20.1.1/311 Ciprobay IV Flexibag Ciprobay Suspension 5 % Ciprobay Suspension 10 % Ciprofloxacin 32/20.1.1/0574 Ciprofloxacin 31/20.1.1/0111 Ciprofloxacin 31/20.1.1/0112 Ciprobay XR 500 Ciprofloxacin 37/20.1.1/0250 Ciprobay XR 1000 Ciprofloxacin 38/20.1.1/0024 Avelon Moxifloxacin 34/20.1.1/0008 Avelon IV Moxifloxacin 36/20.1.1/0052 Bayquin Tablets Moxifloxacin 42/20.1.1/0594 Bayquin IV Moxifloxacin 42/20.1.1/0595 Moxibay Tablets Moxifloxacin 42/20.1.1/0593 Moxibay IV Moxifloxacin 42/20.1.1/0592 Fresenius Kabi Ciprofloxacin Ciprofloxacin 45/20.1.1/0798 Tel: 011 545 0154 (Pty) Ltd Fresenius 2 hydrogen mg/ml 100 ml sulphate safety.fksa@fresenius-kabi.com Ciprofloxacin Ciprofloxacin 45/20.1.1/0799 Fresenius 2 hydrogen mg/ml 200 ml sulphate 45/20.1.1/0139 100ml levofloxacin. DHCPL draft 3 to SAHPRA Quinolones/fluoroquinolones Group 1 P a g e 3
Ranbaxy (SA) (Pty) Ltd Tavanic 500 32/20.1.1/0124 Tel: 012 643 2033/ 011 495 0117 Fax:012 643 2001/3 Tavanic I.V. 500 32/20.1.1/0125 Tavanic I.V. 750 43/20.1.1/0948 Ranbaxy Pharmaceuticals (Pty) Ltd Floxin Norfloxacin 400 mg Cifran 250 Tablets Ciprofloxacin 33/20.1.1/0365 32/20.1.1/0377 Tel: 011 495 0181/ 011 495 0117 Fax: 011 495 0150 Cifran 500 Tablets Ciprofloxacin 33/20.1.1/0366 Avebact 400 Moxifloxacin 41/20.1.1.1/077 8 Tavanic 250 32/20.1.1/0123 Tavanic I.V. 250 32/20.1.1/0002 Tavanic 750 43/20.1.1/0947 Zentiva South Africa (Pty) Ltd Winthrop I.V. 500 Winthrop I.V. 750 Winthrop 500 Winthrop 750 500 mg 750 mg 500 mg 750 mg A39/20.1.1/0578 Tel: 082 828 0291 Fax: 086 686 3635 or 011 256 3721 za.drugsafety@sanofi.com 43/20.1.1/ 0579 A40/20.1.1/0310 43/20.1.1/1058 Healthcare professionals should report all suspected adverse effects associated with the use of all quinolones and fluoroquinolones containing medicines to the applicable company indicated above or to the NADEMC (National Drug Event Monitoring Centre) - Tel: 021 447 1618 or Fax: 021 448 6181 or SAHPRA Pharmacovigilance Office adr@health.gov.za Tel: 012 395 9133/8197/8811/9696. DHCPL draft 3 to SAHPRA Quinolones/fluoroquinolones Group 1 P a g e 4
Yours faithfully Lorraine Hill Eric Chauke Group Operating Officer/ Regulatory Affairs & Country Quality Head / Aspen Pharmacare Ltd Bayer (Pty) Ltd Sharon Davis Fresenius Kabi (Pty) Ltd Geeta Ghela QA Head/ Ranbaxy Pharmaceuticals (Pty) Ltd Penny Slabbert Zentiva South Africa (Pty) Ltd References [1] Daneman N, Lu H, Redelmeier DA. Fluoroquinolones and collagen associated severe adverse events: a longitudinal cohort study. BMJ Open. 2015 Nov 18; 5(11):e010077 [2] Lee CC, Lee MT, Chen YS, Lee SH, Chen YS, Chen SC, Chang SC. Risk of Aortic Dissection and Aortic Aneurysm in Patients Taking Oral Fluoroquinolone. JAMA Intern Med. 2015 Nov;175(11):1839-47. [3] Pasternak B, lnghammar M and Svanstrom H. Fluoroquinolone use and risk of aortic aneurysm and dissection: nationwide cohort study. BMJ 2018; 360: k678. [4] LeMaire SA, Zhang L, Luo W, Ren P, Azares AR, Wang Y, Zhang C, Caselli JS, Shen YH. Effect of Ciprofloxacin on Susceptibility to Aortic Dissection and Rupture in Mice. JAMA Surg. 2018 Jul 25:e181804. [Epub ahead of print] DHCPL draft 3 to SAHPRA Quinolones/fluoroquinolones Group 1 P a g e 5