Chemical formula: C₁₈H₂₀FN₃O₄ Molecular mass: 361.368 g/mol PubChem compound: 149096
Levofloxacin interacts in the following cases:
Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics).
Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin, in these populations.
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.
Levofloxacin absorption is significantly reduced when iron salts, or magnesium- or aluminium-containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) are administered concomitantly with Levofloxacin Tablets. Concurrent administration of fluoroquinolones with multi-vitamins containing zinc appears to reduce their oral absorption. It is recommended that preparations containing divalent or trivalent cations such as iron salts, zinc salts or magnesium- or aluminium-containing antacids, or didanosine (only didanosine formulations with aluminium or magnesium containing buffering agents) should not be taken 2 hours before or after Levofloxacin Tablets administration. Calcium salts have a minimal effect on the oral absorption of levofloxacin.
Impaired renal function (creatinine clearance ≤50ml/min):
| Dose regimen | |||
|---|---|---|---|
| 250 mg/24 h | 500 mg/24 h | 500 mg/12 h | |
| Creatinine clearance | first dose: 250 mg | first dose: 500 mg | first dose: 500 mg |
| 50-20 ml/min | then: 125 mg/24 h | then: 250 mg/24 h | then: 250 mg/12 h |
| 19-10 ml/min | then: 125 mg/48 h | then: 125 mg/24 h | then: 125 mg/12 h |
| <10 ml/min (including haemodialysis and CAPD)1 | then: 125 mg/48 h | then: 125 mg/24 h | then: 125 mg/24 h |
1 No additional doses are required after haemodialysis or continuous ambulatory peritoneal dialysis (CAPD).
The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.
Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs 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 drugs that affect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
The bioavailability of levofloxacin is significantly reduced when administered together with sucralfate. If the patient is to receive both sucralfate and levofloxacin, it is best to administer sucralfate 2 hours after the levofloxacin administration.
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 agents which lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.
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.
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. It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with levofloxacin If CDAD is suspected or confirmed, levofloxacin should be stopped immediately and appropriate treatment initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.
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. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.
Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline. In case of convulsive seizures, treatment with levofloxacin should be discontinued.
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 requirement 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.
There are limited amount of data with respect to the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. However, in the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in pregnant women.
Levofloxacin is contraindicated in breast-feeding women. 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 due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in breast-feeding women.
Levofloxacin eye drops should be used during lactation only if the potential benefit justifies any potential risk to the nursing child.
Levofloxacin caused no impairment of fertility or reproductive performance in rats.
Some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) may impair the patient’s ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
If there are any transient effects on vision after administration of levofloxacin eye drops, the patient should be advised to wait until this clears before driving or operating machinery.
The information given below is based on data from clinical studies in more than 8300 patients and on extensive post marketing experience.
Frequencies are defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data)
In the following list, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Fungal infection including Candida infection, Pathogen resistance
Uncommon: Leukopenia, Eosinophilia
Rare: Thrombocytopenia, Neutropenia
Not known: Pancytopenia, Agranulocytosis, Haemolytic anaemia
Rare: Angioedema, Hypersensitivity
Not known: Anaphylactic shocka, Anaphylactoid shocka,
Uncommon: Anorexia
Rare: Hypoglycaemia particularly in diabetic patients
Not known: Hyperglycaemia, Hypoglycaemic coma
Common: Insomnia
Uncommon: Anxiety, Confusional state, Nervousness
Rare: Psychotic reactions (with e.g. hallucination, paranoia), Depression, Agitation, Abnormal dreams, Nightmares
Not known: Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt
Common: Headache, Dizziness
Uncommon: Somnolence, Tremor, Dysgeusia
Rare: Convulsion, Paraesthesia
Not known: Peripheral sensory neuropathy, Peripheral sensory motor neuropathy, Parosmia including anosmia, Dyskinesia, Extrapyramidal disorder, Ageusia, Syncope, Benign intracranial hypertension
Rare: Visual disturbances such as blurred vision
Not known: Transient vision loss
Uncommon: Vertigo
Rare: Tinnitus
Not known: Hearing loss, Hearing impaired
Rare: Tachycardia, Palpitation
Not known: Ventricular tachycardia, which may result in cardiac arrest, Ventricular arrhythmia and torsade de pointes (reported predominantly in patients with risk factors of QT prolongation), Electrocardiogram QT prolonged
Common: Phlebitis
Rare: Hypotension
Uncommon: Dyspnoea
Not known: Bronchospasm, Pneumonitis allergic
Common: Diarrhoea, Vomiting, Nausea
Uncommon: Abdominal pain, Dyspepsia, Flatulence, Constipation
Not known: Diarrhoea–haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis, Pancreatitis
Common: Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)
Uncommon: Blood bilirubin increased
Not known: Jaundice and severe liver injury, including fatal cases with acute liver failure, primarily in patients with severe underlying diseases, Hepatitis
Uncommon: Rash, Pruritus, Urticaria, Hyperhidrosis
Not known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, Photosensitivity reaction, Leukocytoclastic vasculitis, Stomatitis
Uncommon: Arthralgia, Myalgia
Rare: Tendon disorder including tendinitis (e.g. Achilles tendon), Muscular weakness which may be of special importance in patients with myasthenia gravis
Not known: Rhabdomyolysis, Tendon rupture (e.g. Achilles tendon), Ligament rupture, Muscle rupture, Arthritis
Uncommon: Blood creatinine increased
Rare: Renal failure acute (e.g. due to interstitial nephritis)
Common: Infusion site reaction (pain, reddening)
Uncommon: Asthenia
Rare: Pyrexia
Not known: Pain (including pain in back, chest, and extremities)
Not known: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.
b Mucocutaneous reactions may sometimes occur even after the first dose
Other undesirable effects which have been associated with fluoroquinolone administration include attacks of porphyria in patients with porphyria.
The safety of the recommended dose of levofloxacin 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 levofloxacin 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.
* Adverse events with uncertain relatedness to levofloxacin but which are known to be associated with systemic administration of levofloxacin and/or are plausibly associated with levofloxacin 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.
If acute, symptomatic bronchoconstriction occurs after receiving levofloxacin, patients may benefit from the use of a short-acting inhaled bronchodilator prior to subsequent doses.
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 levofloxacin 240 mg twice daily and 6 adolescents with CF received levofloxacin 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 levofloxacin 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 levofloxacin in these subsets of the paediatric population compared to adults. However, two cases of arthralgia have been observed in children in clinical studies with levofloxacin and long-term safety data are missing especially considering the effects on cartilage observed in animals.
Approximately 10% of patients can be expected to experience adverse reactions. The reactions are usually graded as mild or moderate, are transient, and are generally restricted to the eye.
As the product contains benzalkonium chloride, contact eczema and/or irritation may be due to the active component or to this preservative.
The following undesirable effects assessed as definitely, probably or possibly related to treatment were reported during clinical trials and post-marketing experience with levofloxacin eye drops:
Rare (≥1/10,000 to <1/1,000): extra-ocular allergic reactions, including skin rash
Very rare (<1/10,000), not known (cannot be estimated from the available data): anaphylaxis
Uncommon (≥1/1,000 to <1/100): headache
Common (≥1/100 to <1/10): Ocular burning, decreased vision and mucous strand.
Uncommon (≥1/1,000 to <1/100): Lid matting, chemosis, conjunctival papillary reaction, lid oedema, ocular discomfort, ocular itching, ocular pain, conjunctival injection, conjunctival follicles, ocular dryness, lid erythema, and photophobia.
No corneal precipitates were observed in clinical studies.
Uncommon (≥1/1,000 to <1/100): rhinitis
Very rare (<1/10,000), Not known (cannot be estimated from the available data): Laryngeal oedema
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
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