Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Chiesi Farmaceutici S.p.A., Via Palermo, 26/A, 43122 Parma, Italy
The use of levofloxacin should be avoided in patients who have experienced serious adverse reactions in the past when using quinolone or fluoroquinolone containing products (see section 4.8). Treatment of these patients with levofloxacin should only be initiated in the absence of alternative treatment options and after careful benefit/risk assessment (see also section 4.3).
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. including angioedema and anaphylactic shock).
Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with systemic administration of levofloxacin (see section 4.8).
Cases of hepatic necrosis up to fatal hepatic failure have been reported with systemically administered levofloxacin, primarily in patients with severe underlying diseases (e.g. sepsis, see section 4.8). Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval (see sections 4.5, 4.8 and 4.9) such as, for example:
Elderly patients and women may be more sensitive to QTc-prolonging medicinal products. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin, in these populations.
Quinolones may lower the seizure threshold and may trigger seizures (see section 4.8). Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or on concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline (see section 4.5).
Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases, these have progressed to suicidal thoughts and self-endangering behaviour – sometimes after only a single dose of levofloxacin (see section 4.8). Caution is recommended if levofloxacin is used in psychotic patients or in patients with a history of psychiatric disease.
Cases of sensory or sensorimotor polyneuropathy resulting in paraesthesia, hypaesthesia, dysesthesia, or weakness have been reported in patients receiving quinolones and fluoroquinolones. Patients under treatment with levofloxacin should be advised to inform their doctor prior to continuing treatment if symptoms of neuropathy such as pain, burning, tingling, numbness, or weakness develop in order to prevent the development of potentially irreversible condition (see section 4.8).
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post-marketing serious adverse reactions, including deaths and the requirements for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a known history of myasthenia gravis.
Tendinitis and tendon rupture (especially but not limited to Achilles tendon), sometimes bilateral, may occur as early as within 48 hours of starting treatment with quinolones and fluoroquinolones and have been reported to occur even up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in older patients, patients with renal impairment, patients with solid organ transplants, patients receiving daily doses of 1000 mg levofloxacin, and those treated concurrently with corticosteroids. Therefore, concomitant use of corticosteroids should be avoided.
At the first sign of tendinitis (e.g. painful swelling, inflammation) the treatment with levofloxacin should be discontinued and alternative treatment should be considered. The affected limb(s) should be appropriately treated (e.g. immobilisation). Corticosteroids should not be used if signs of tendinopathy occur.
Tendinitis was reported in patients with CF receiving Quinsair as an uncommon adverse reaction during clinical trials (see section 4.8).
Bronchospasm is a complication associated with inhaled therapies including Quinsair (see section 4.8). If acute, symptomatic bronchospasm occurs after receiving treatment, patients may benefit from the use of a short-acting inhaled bronchodilator prior to subsequent doses (see section 4.2).
The use of inhaled medicinal products may induce a cough reflex. Administration of Quinsair in patients with clinically significant haemoptysis should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions when treated with quinolone antibacterial agents. Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.
Due to possible increases in coagulation tests (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these active substances are given concomitantly (see section 4.5).
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported, usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. glibenclamide) or with insulin. In diabetic patients, careful monitoring of blood glucose is recommended (see section 4.8).
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin (including several weeks after treatment), may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life-threatening, the most severe form of which is pseudomembranous colitis.
The development of fluoroquinolone-resistant P. aeruginosa and superinfection with fluoroquinolone-insusceptible microorganisms represent potential risks associated with the use of Quinsair. If superinfection occurs during therapy, appropriate measures should be taken.
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
Photosensitisation has been reported with levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium) during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific methods.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
Very rare cases of prolonged (continuing months or years), disabling and potentially irreversible serious adverse drug reactions affecting different, sometimes multiple, body systems (musculoskeletal, nervous, psychiatric and senses) have been reported in patients receiving quinolones and fluoroquinolones irrespective of their age and pre-existing risk factors. Levofloxacin should be discontinued immediately at the first signs or symptoms of any serious adverse reaction and patients should be advised to contact their prescriber for advice.
Levofloxacin is primarily excreted unchanged in the urine and metabolism is minimal (see section 5.2). Interactions with CYP inhibitors or inducers are thus not expected.
No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However, a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other substances which lower the seizure threshold. Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.
The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both active substances are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance. Caution should be exercised when levofloxacin is coadministered with active substances that affect the tubular renal secretion such as probenecid and cimetidine, especially in patients with renal impairment.
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following active substances: calcium carbonate, digoxin, glibenclamide and ranitidine.
In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2) indicating that levofloxacin is not a CYP1A2 inhibitor.
An in vitro study indicated a low potential for interaction between levofloxacin and CYP2C9 substrates.
In vitro studies demonstrated that inhibition of the key transporters associated with drug disposition in the kidney (organic anion-transporting polypeptide-1B1 (OATP1B1), OATP1B3, organic anion transporter-1 (OAT1), OAT3 and organic cationic transporter-2 (OCT2)) at exposures following inhalation of 240 mg levofloxacin twice daily is low.
Furthermore, clinical data do not suggest interaction with P-glycoprotein (P-gp) substrates such as digoxin.
The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin).
Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists (see section 4.4).
Levofloxacin should be used with caution in patients receiving active substances known to prolong the QT interval (e.g. Class IA and III antiarrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
There is a limited amount of data from the use of levofloxacin in pregnant women. Animal studies with levofloxacin do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
However, in the absence of human data and findings in non-clinical studies suggesting a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, use of Quinsair is contraindicated during pregnancy (see sections 4.3 and 5.3).
There is insufficient information on the excretion of levofloxacin in human milk; however, other fluoroquinolones are excreted in breast milk.
In the absence of human data and findings in non-clinical studies suggesting a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, use of Quinsair is contraindicated in breast-feeding women (see sections 4.3 and 5.3).
Levofloxacin caused no impairment of fertility or reproductive performance in rats (see section 5.3).
Some adverse reactions (e.g. fatigue, asthenia, visual disturbances, dizziness) may impair patient’s ability to concentrate and react. Patients who experience such symptoms should be advised not to drive or use machines.
The safety of the recommended dose of Quinsair was evaluated in 472 patients with CF from two double-blind, single-cycle, placebo-controlled trials and from an active-comparator study with an optional uncontrolled extension.
The most frequently reported adverse reactions were cough/productive cough (54%), dysgeusia (30%) and fatigue/asthenia (25%).
The adverse reactions with at least a reasonable possibility of a causal relationship with Quinsair are presented according to the MedDRA System Organ Classification. The adverse drug reactions are ranked by frequency with the most frequent reactions first. The frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
Common: Vulvovaginal mycotic infection
Uncommon: Oral fungal infection
Uncommon: Anaemia*, Neutropenia*
Hypersensitivity*
Very common: Anorexia*
Common: Insomnia*
Uncommon: Anxiety*, Depression*
Very common: Dysgeusia
Common: Headache, Dizziness*
Uncommon: Hyposmia*, Somnolence*
Uncommon: Visual disturbance*
Common: Tinnitus*
Uncommon: Hearing loss*
Uncommon: Tachycardia*
Very common: Cough/productive cough, Dyspnoea, Changes in bronchial secretions (volume and viscosity), Haemoptysis
Common: Dysphonia
Uncommon: Bronchospasm**, Bronchial hyper-reactivity, Obstructive airways disorder
Common: Nausea, Vomiting, Abdominal pain*, Diarrhoea* Constipation*
Uncommon: Retching, Dyspepsia*, Flatulence*
Uncommon: Hepatitis*, Hyperbilirubinaemia*
Common: Rash
Uncommon: Urticaria*, Pruritus*
Common: Arthralgia, Myalgia*
Uncommon: Tendinitis, Costochondritis, Joint stiffness
Uncommon: Renal failure*
Very common: Fatigue/asthenia, Exercise tolerance decreased
Common: Pyrexia
Very common: Weight decreased**, Forced expiratory volume decreased*
Common: Alanine aminotransferase increased, Aspartate aminotransferase increased, Pulmonary function test decreased*, Blood glucose increased and decreased*, Blood creatinine increased* Breath sounds abnormal*
Uncommon: Liver function test abnormal, Blood alkaline phosphatase increased*, Electrocardiogram QT prolonged*, Eosinophil count increased*, Platelet count decreased*
1 Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4).
* Adverse events with uncertain relatedness to Quinsair but which are known to be associated with systemic administration of levofloxacin and/or are plausibly associated with Quinsair and were reported more frequently than with placebo in clinical studies.
** See paragraph below for further details.
The adverse reactions with at least a reasonable possibility of a causal relationship with levofloxacin are presented according to the MedDRA System Organ Classification. The adverse drug reactions are ranked by frequency with the most serious reactions first. The frequency categories are defined using the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from the available data).
Not known: Pancytopenia*, Agranulocytosis*, Haemolytic anaemia*
Rare: Angioedema
Not known: Anaphylactic shock, Anaphylactoid shock
Not known: Hypoglycaemic coma
Uncommon: Confusional state, Nervousness
Rare: Psychotic reactions (e.g. hallucination, paranoia), Agitation, Abnormal dreams, Nightmares
Rare: Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt
Uncommon: Tremor
Rare: Convulsion, Paraesthesia
Not known: Peripheral sensory neuropathy, Peripheral sensory motor neuropathy, Dyskinesia, Extrapyramidal disorder, Syncope, Benign intracranial hypertension
Not known: Transient vision loss
Uncommon: Vertigo
Rare: Palpitation
Not known: Ventricular tachycardia, Ventricular arrhythmia and torsade de pointes
Rare: Hypotension
Not known: Pneumonitis allergic
Not known: Jaundice and severe liver injury, including cases with fatal acute liver failure
Uncommon: Hyperhidrosis
Not known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, Photosensitivity reaction, Leukocytoclastic vasculitis, Stomatitis
Rare: Muscular weakness
Not known: Rhabdomyolysis, Tendon rupture, Ligament rupture, Muscle rupture, Arthritis
Not known: Pain (including pain in back, chest and extremities)
* See paragraph below for further details.
1 Very rare cases of prolonged (up to months or years), disabling and potentially irreversible serious drug reactions affecting several, sometimes multiple, system organ classes and senses (including reactions such as tendonitis, tendon rupture, arthralgia, pain in extremities, gait disturbance, neuropathies associated with paraesthesia, depression, fatigue, memory impairment, sleep disorders, and impairment of hearing, vision, taste and smell) have been reported in association with the use of quinolones and fluoroquinolones in some cases irrespective of pre-existing risk factors (see section 4.4).
If acute, symptomatic bronchoconstriction occurs after receiving Quinsair, patients may benefit from the use of a short-acting inhaled bronchodilator prior to subsequent doses (see sections 4.2 and 4.4).
Weight decrease was reported as an adverse event during clinical studies, but was primarily thought to be disease rather than drug-related.
Serious haematological adverse reactions such as pancytopenia, agranulocytosis and haemolytic anaemia have been reported following systemic administration of levofloxacin. Their frequency cannot be estimated from available data.
In clinical trials, 51 adolescents with CF (≥12 to <18 years old) received Quinsair 240 mg twice daily and 6 adolescents with CF received Quinsair 120 mg (n=3) or 240 mg (n=3) once daily. In addition, 14 children with CF (≥6 to <12 years old) and 13 adolescents with CF (≥12 to <17 years old) received Quinsair 180 mg or 240 mg once daily for 14 days. Based on these limited data, there does not appear to be any clinically relevant difference in the safety profile of Quinsair in these subsets of the paediatric population compared to adults. However, two cases of arthralgia have been observed in children in clinical studies with Quinsair and long-term safety data are missing especially considering the effects on cartilage observed in animals (See sections 4.2 and 5.3).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
