Fluoroquinolone Adverse Reactions

A new boxed warning is being added to the product information and consumer medicine information documents of systemic fluoroquinolone products. This warning advises that “fluoroquinolones… have been associated with disabling and potentially irreversible serious adverse reactions involving different body systems that have occurred together in the same patient.”

Fluoroquinolones are broad-spectrum antibiotics. Medications in this class that are currently available for systemic use include:

• Ciprofloxacin (oral, parenteral);
• Moxifloxacin (oral, parenteral); and
• Norfloxacin (oral).

In the majority of cases, fluoroquinolones are not first-line antibiotics. They are typically reserved for infections where alternative agents are ineffective or contraindicated. This is due to the rising level of resistance to this antibiotic class around the world. Judicious use is recommended to extend their clinical life. Another reason to be cautious about the use of these medicines is the potential for serious and long-lasting adverse reactions.

The European Medicines Agency (EMA) conducted a review of this issue in 2018. This review found that fluoroquinolones are associated with prolonged, serious, and disabling reactions. These reactions may affect several systems, organ classes and senses and may, in some cases, be irreversible.

These reactions include:

• Tendonitis;
• Tendon rupture;
• Arthralgia;
• Pain in the extremities;
• Gait disturbance;
• Neuropathies associated with paraesthesia;
• Depression;
• Fatigue;
• Memory impairment;
• Sleep disorders; and
• Impaired hearing, vision, taste, and smell.

These reactions have been associated with the use of fluoroquinolones via the oral, parenteral, and inhalation routes.

Effects on tendons

Tendonitis and tendon rupture are known adverse events associated with fluoroquinolones. Any tendon can be affected, but the Achilles tendon is most commonly implicated. The estimated incidence is between 0.14% and 2%. Onset can occur within days of initiating a fluoroquinolone, and almost all reported cases have occurred with one month. However, a longer latency of up to six months has been reported.

Risk factors for tendon effects may include older age, obesity, and physical exertion. As long-term use of glucocorticoids is independently implicated in tendinopathies, the concomitant use of a glucocorticoid may potentiate the risk with fluoroquinolones.

Adverse events affecting tendons can lead to prolonged disability or the need for surgical repair. If a patient develops tendon pain or inflammation, it is recommended that the fluoroquinolone be discontinued, and the affected limb rested.

Nervous system effects

Mononeuropathies and polyneuropathy have been reported in association with fluoroquinolone use. The resultant sensory disturbances can have a significant impact on functional ability and quality of life.

A large nested case-control study evaluated the risk of peripheral neuropathy with fluoroquinolones compared to amoxicillin + clavulanic acid. This study found that current fluoroquinolone use was associated with a significantly higher risk of peripheral neuropathy (adjusted incidence rate ratio [aIRR]: 1.47; 95% CI: 1.13-1.92). The risk was found to increase with increasing duration of fluoroquinolone use. There was no significant association with amoxicillin + clavulanic acid (aIRR: 1.10; 95% CI: 0.86-1.40).

Peripheral neuropathy is likely a rare adverse event. Risk factors may include high body mass index, alcohol abuse, amyloidosis, Sjögren syndrome, and shingles. For patients who develop symptoms of neuropathy during fluoroquinolone therapy, discontinuation of the fluoroquinolone is recommended to avoid the development of an irreversible condition. Symptoms that could indicate neuropathy include burning, tingling, numbness, and weakness.

Psychiatric adverse effects

Fluoroquinolones are associated with psychiatric adverse effects. These may be mild and include confusion, restlessness, and insomnia. Severe events such as catatonia, psychosis, and suicidal depression have also been reported. The usual reported incidence is 1% to 4.4%. However, one study reported an incidence of 13.6% in patients over 80 years with a history of neurologic or psychiatric disorders.

The potential for fluoroquinolones to cause these effects is thought to be related to their structural similarity to gamma-aminobutyric acid (GABA) and their high permeability across the blood-brain barrier. This allows access to the central nervous system (CNS) where these drugs may inhibit GABAergic neurotransmission.

A recent retrospective analysis of US data found that the class is associated with a range of psychiatric effects, although there are some key differences for the individual drugs. Ciprofloxacin was more frequently associated with adverse events of anxiety, depression, and suicidal ideation compared to other fluoroquinolones. Moxifloxacin may have a lower risk of depression and suicidal ideation but was more strongly associated with delirium. The study authors suggest that moxifloxacin may be preferred over ciprofloxacin for patients with pre-existing depression.

Risk factors for psychiatric adverse events appear to include high fluoroquinolone dose and a history of neurological or psychiatric disorders. However, it should be noted that psychiatric adverse events have been reported in patients with no relevant psychiatric history. Patient age may also be a significant variable with patients under 65 years experiencing more adverse events related to affective disorders, and older adults more likely to experience psychosis and delirium.

Recommendations:

The potential for fluoroquinolones to cause severe and long-lasting adverse events, combined with increasing levels of resistance, means that the use of this class should be restricted. These antibiotics are reserved for infections where alternative therapies are ineffective or contraindicated. In general, fluoroquinolones should not be used to treat infections that are non-severe or self-limiting. Their use should also be avoided in patients who have previously experienced severe adverse effects with a fluoroquinolone, unless there are no other appropriate alternatives.

Prior to initiating a fluoroquinolone, individual risk factors should be considered. As fluoroquinolones are cleared via the kidneys, renal impairment may increase the risk of adverse effects. Dose alteration is required for ciprofloxacin and norfloxacin when used in renal impairment.

Treatment with a fluoroquinolone be discontinued at the first signs of musculoskeletal, neurological, or psychiatric adverse effects.