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European Union : Disabling and potentially permanent side effects lead to suspension or restrictions of quinolone and fluoroquinolone antibiotics
 
The European Medicines Agency (EMA) announces that it has already reviewed the serious, disabling and potentially permanent side effects with quinolone and fluoroquinolone antibiotics given by mouth, injection or inhalation. The review incorporated the views of patients, healthcare professionals and academics presented at EMA’s public hearing on fluoroquinolone and quinolone antibiotics in June 2018.

EMA’s Committee for Medicinal Products for Human Use (CHMP) has endorsed its Pharmacovigilance Risk Assessment Committee’s (PRAC) recommendations and concluded that the marketing authorization of medicines containing cinoxacin, flumequine, nalidixic acid, and pipemidic acid should be suspended.

The CHMP confirmed that the use of the remaining fluoroquinolone antibiotics should be restricted. In addition, the prescribing information for healthcare professionals and information for patients will describe the disabling and potentially permanent side effects and advise patients to stop treatment with a fluoroquinolone antibiotic at the first sign of a side effect involving muscles, tendons or joints and the nervous system.

Restrictions on the use of fluoroquinolone antibiotics will mean that they should not be used:
- to treat infections that might get better without treatment or are not severe (such as throat infections);
- to treat non-bacterial infections, e.g. non-bacterial (chronic) prostatitis;
- for preventing traveller’s diarrhoea or recurring lower urinary tract infections (urine infections that do not extend beyond the bladder);
- to treat mild or moderate bacterial infections unless other antibacterial medicines commonly recommended for these infections cannot be used.

Importantly, fluoroquinolones should generally be avoided in patients who have previously had serious side effects with a fluoroquinolone or quinolone antibiotic. They should be used with special caution in the elderly, patients with kidney disease and those who have had an organ transplantation because these patients are at a higher risk of tendon injury. Since the use of a corticosteroid with a fluoroquinolone also increases this risk, combined use of these medicines should be avoided.

Information for patients:
- Fluoroquinolone medicines (which contain ciprofloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin and rufloxacin) can cause long-lasting, disabling and potentially permanent side effects involving tendons, muscles, joints and the nervous system.
- These serious side effects include inflamed or torn tendon, muscle pain or weakness, and joint pain or swelling, walking difficulty, feeling pins and needles, burning pain, tiredness, depression, problems with memory, sleeping, vision and hearing, and altered taste and smell.
- Tendon swelling and injury may occur within 2 days of starting treatment with a fluoroquinolone but may even occur several months after stopping treatment.
- Stop taking a fluoroquinolone medicine and contact your doctor at once in the following cases:
(i) at the first sign of tendon injury, such as tendon pain or swelling – rest the painful area;
(ii) if you get pain, feel pins and needles, tingling, tickling, numbness or burning, or weakness especially in the legs or arms;
(iii) if you get swelling in the shoulder, arms or legs, have walking difficulty, feel tired or depressed or have problems with your memory or with sleeping or you notice changes with your vision, taste, smell or hearing. You and your doctor will decide if you can continue treatment or if you need to take another type of antibiotic.
- You may be more prone to joint pain or swelling or tendon damage if you are aged over 60 years, your kidneys do not work well or you have received organ transplantation.
- Speak with your doctor if you are taking a corticosteroid (medicines such as hydrocortisone and prednisolone) or need to have treatment with a corticosteroid. You may be especially prone to tendon damage if you are taking a corticosteroid and a fluoroquinolone medicine at the same time.
- You should not take a fluoroquinolone medicine if you have ever had a serious side effect with a fluoroquinolone or a quinolone medicine and you should speak with your doctor immediately.
- If you have any questions or concerns about your medicines, speak to your doctor or pharmacist.

Information for healthcare professionals:
- Fluoroquinolones are associated with prolonged (up to months or years), serious, disabling and potentially irreversible drug reactions affecting several, sometimes multiple, systems, organ classes and senses.
- The serious side effects include tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impaired hearing, vision, taste and smell.
- Tendon damage (especially to Achilles tendon but also other tendons) can occur within 48 hours of starting fluoroquinolone treatment but the damage may be delayed several months after stopping treatment.
- Patients who are older, have renal impairment or have had solid organ transplantation and those being treated with a corticosteroid are at higher risk of tendon damage. Concomitant treatment with a fluoroquinolone and a corticosteroid should be avoided.
- Fluoroquinolone treatment should be discontinued at the first sign of tendon pain or inflammation and patients should be advised to stop treatment with a fluoroquinolone and speak with the doctor in case of symptoms of neuropathy such as pain, burning, tingling, numbness or weakness so as to prevent development of potentially irreversible condition.
- Fluoroquinolones should generally not be used in patients who have had serious adverse reactions associated with the use of quinolone or fluoroquinolone medicines.
- Up-to-date summary of product characteristics should be consulted for authorized indications when considering treatment with a fluoroquinolone medicine. This is because the indications for these medicines have been restricted.
- The benefits and risks of fluoroquinolones will be monitored continuously and a drug utilization study will evaluate the effectiveness of the new measures to reduce inappropriate use of fluoroquinolones by investigating changes in prescribing behaviour.

Fluoroquinolones and quinolones are a class of broad-spectrum antibiotics that are active against bacteria of both Gram-negative and Gram-positive classes. Fluoroquinolones are of value in certain infections, including some life-threatening ones, where alternative antibiotics are not sufficiently effective.

The review covered medicines containing the following fluoroquinolone and quinolone antibiotics: cinoxacin, ciprofloxacin, flumequine, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, pefloxacin, pipemidic acid, prulifloxacin and rufloxacin.

The review concerned only medicines given systemically (by mouth or injection) and inhaled medicines. The CHMP opinion will now be forwarded to the European Commission, which will issue a final legally binding decision applicable in all countries of the European Union. In Europe, national authorities will enforce this decision for the fluoroquinolone and quinolone medicines and they will also take other appropriate measures to promote the correct use of these antibiotics.

Please refer to the following website in EMA for details: http://www.ema.europa.eu/en/news/disabling-potentially-permanent-side-effects-lead-suspension-restrictions-quinolone-fluoroquinolone

In Hong Kong, there are 190 registered pharmaceutical products for systemic administration containing fluoroquinolones and quinolones, including ciprofloxacin (81 products), levofloxacin (62), moxifloxacin (6), norfloxacin (7), ofloxacin (30), sparfloxacin (1), prulifloxacin (1), nalidixic acid (1) and pipemidic acid (1). All products are prescription-only medicines.

Drug safety news related to fluoroquinolones had previously been reported by overseas drug regulatory authorities, and posted on the Drug Office website since 8 Nov 2011, with the last update on 6 October 2018. Letters to inform local healthcare professionals on the above safety news had been issued in 2011, 2013, 2016 and 2018. In 2013, the Registration Committee of the Pharmacy and Poisons Board (the Registration Committee) discussed the safety of fluoroquinolones with peripheral neuropathy, and decided that the relevant warnings should be included in the sales packs and/or package inserts of the products. In 2016, the Registration Committee further discussed the safety of fluoroquinolones with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system, and subsequently decided to remain vigilant on further updates by other overseas drug regulatory authorities.

So far, the Department of Health (DH) has received 4 cases of adverse drug reaction related to levofloxacin and 1 case related to moxifloxacin; and of these 5 cases, one case (of the levofloxacin) was related to tendinitis and neuropathy, while the other 4 cases were not related to adverse effects mentioned in EMA's announcement. The DH has not received any cases of the adverse drug reaction related to the other fluoroquinolones and quinolones. In light of the EMA’s announcement in Feb 2017 and Oct 2018, letters to local healthcare professionals to draw their attention were issued on 8 October 2018, and the matter will be further discussed by the Registration Committee of the Pharmacy and Poisons Board. The DH will maintain vigilant on any further update from the EMA and other health authorities for consideration of any action deemed necessary.

Ends/ Saturday, Nov 17, 2018
Issued at HKT 12:00

 
Related Information:
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China: Announcement by China Food and Drug Administration (CFDA) on amendment of... Posted 2017-07-06
European Union: European Medicines Agency (EMA) reviews persistence of side effe... Posted 2017-02-11
Canada: FLUOROQUINOLONES - Risk of disabling and persistent serious adverse reac... Posted 2017-01-24
The United States: FDA Drug Safety Communication: FDA updates warnings for oral ... Posted 2016-07-27
The United States: FDA Drug Safety Communication: FDA advises restricting fluoro... Posted 2016-05-13
Fluoroquinolones: restricting use for certain uncomplicated infections (Letter t... Posted 2016-05-13
 
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