Levofloxacin Tablets Instructions

Date of approval.
Date of revision.
Levofloxacin Tablets Instructions
Please read the instructions carefully and use under the guidance of a physician
 Warnings
This product is strictly prohibited for food, feed processing, breeding
 WARNING: Serious adverse reactions, including tendonitis and tendon rupture, peripheral neuropathy, central nervous system effects and exacerbation of myasthenia gravis.
In all age groups, fluoroquinolones (including levofloxacin) can cause an increased risk of tendonitis and tendon rupture. This risk is further increased in elderly patients usually over 60 years of age, in patients treated with glucocorticoids, and in patients who have received a kidney transplant, heart transplant, or lung transplant.
Concurrent disabling and potentially irreversible serious adverse reactions have been reported with fluoroquinolone drugs, including levofloxacin (see [Precautions]), including
Tendonitis and tendon rupture (see [Precautions])
Peripheral neuropathy (see [Precautions])
Central nervous system effects (see [Precautions])
When these serious adverse reactions occur (see [Precautions]), levofloxacin tablets should be discontinued immediately and fluoroquinolone drugs should be avoided.
Fluoroquinolone drugs may exacerbate the symptoms of muscle weakness in patients with myasthenia gravis. Avoid levofloxacin tablets in patients with a known history of myasthenia gravis (see [Precautions]).
Because serious adverse reactions have been reported with fluoroquinolones, including levofloxacin (see [Precautions]), levofloxacin tablets should be used only in the absence of other drug therapy in patients with the following indications.
Acute bacterial sinusitis (see [Indications] and [Dosage])
Acute exacerbation of chronic bronchitis (see [Indications] and [Dosage])
Uncomplicated urinary tract infections (see [Indications] and [Dosage]) [Drug Name
Generic name: Levofloxacin tablets
English name: Levofloxacin Tablets
Hanyu Pinyin: Zuoyangfushaxing Pian
Ingredients
The main component of this product is levofloxacin.
Chemical name: (-)-(S)-3-methyl-9-fluoro-2,3-dihydro-10-(4-methyl-1-piperazinyl)-7-oxo-7H-pyrido[1,2,3-de]-1,4-benzoxazine-6-carboxylic acid hemihydrate.
Chemical structure formula.
Molecular formula: C18H20FN3O4-H2O
Molecular weight: 370.38
【Properties】.
This product is a white or off-white film-coated tablet, which appears white to light yellow after removing the coating.
Indications
To reduce the production of drug-resistant bacteria and to ensure the effectiveness of levofloxacin and other antibacterial drugs, levofloxacin is used only for the treatment or prevention of infections proven or highly suspected to be caused by sensitive bacteria. The results of bacterial culture and drug sensitivity tests should be considered when selecting or modifying an antibacterial drug regimen. If data from these tests are not available for reference, empirical treatment should be based on local epidemiology and pathogen susceptibility.
Bacterial culture and drug sensitivity tests should be performed prior to treatment to isolate and identify the infecting pathogen and determine its susceptibility to levofloxacin. Treatment with levofloxacin can be initiated until the results of these tests are available, and then the appropriate treatment can be selected after the test results are obtained.
As with other drugs in this category, some strains of P. aeruginosa can quickly develop resistance when treated with levofloxacin. Bacterial cultures and drug sensitivity tests should be performed periodically during treatment to capture the continued susceptibility of pathogenic bacteria to antimicrobial drugs and to detect the development of resistance when it occurs.
Levofloxacin oral and injectable formulations can be used to treat the following mild, moderate, and severe infections in adults (≥18 years of age) caused by susceptible strains of the bacteria listed below. Levofloxacin injection may be used if intravenous infusion is more beneficial to the patient (e.g., if the patient cannot tolerate oral administration, etc.).
1. Hospital-acquired pneumonia
Treat hospital-acquired pneumonia caused by methicillin-susceptible Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae. Other adjuvant therapeutic measures should also be taken as clinically indicated. If Pseudomonas aeruginosa infection has been demonstrated or is suspected, a combination of anti-Pseudomonas β-lactams is recommended for treatment.
2. Community-acquired pneumonia
7-14 day regimen: Treatment of community-acquired pneumonia caused by methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae [including multi-drug resistant strains (MDRSP*)], Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Catamorax, Chlamydia pneumoniae, Legionella pneumoniae, or Mycoplasma pneumoniae.
Note: MDRSP (multi-drug resistant Streptococcus pneumoniae) refers to strains resistant to two or more of the following antimicrobial drugs: penicillin (MIC ≥ 2µg/ml), second generation cephalosporins (e.g. cefuroxime), macrolides, tetracyclines and methomyl/sulfamethoxazole.
5-day regimen: Treatment of community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydia pneumoniae.
3. Acute bacterial sinusitis
Because serious adverse reactions have been reported with fluoroquinolones, including levofloxacin, and because acute bacterial sinusitis is self-limiting in some patients, levofloxacin tablets should be used only when no other drug therapy is available.
5-day regimen: Treatment of acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Catamorium.
10-14 day regimen: Treatment of acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Catamorax.
4. Acute bacterial exacerbation of chronic bronchitis
Treatment of acute bacterial exacerbations of chronic bronchitis caused by methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Catamorax.
Because serious adverse reactions have been reported with fluoroquinolones, including levofloxacin, and because for some patients, acute exacerbations of chronic bronchitis are self-limiting, levofloxacin tablets should be used only when no other drug therapy is available.
5. Complex skin and skin structure infections
Treatment of complicated skin and skin structure infections caused by methicillin-susceptible Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Streptococcus pyogenes.
6. Uncomplicated skin and skin soft tissue infections
Treatment of uncomplicated skin and skin structure infections (mild to moderate) caused by methicillin-susceptible Staphylococcus aureus or Streptococcus pyogenes, including abscesses, cellulitis, boils, impetigo, pyoderma, and wound infections.
7. Chronic bacterial prostatitis
Treatment of chronic bacterial prostatitis caused by Escherichia coli, Enterococcus faecalis, or methicillin-sensitive Staphylococcus epidermidis.
8. Complex urinary tract infection
5-day regimen: Treatment of complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae, or Aspergillus chimaera.
10-day regimen: Treatment of complicated urinary tract infections (mild to moderate) caused by Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Aspergillus chimaera or Pseudomonas aeruginosa.
9. Acute pyelonephritis
5-day regimen: Treatment of acute pyelonephritis caused by Escherichia coli, including cases of combined bacteremia.
10-day regimen: Treatment of acute pyelonephritis caused by Escherichia coli, including cases with bacteremia.
10. Uncomplicated urinary tract infections
Treatment of uncomplicated urinary tract infections (mild to moderate) caused by Escherichia coli, Klebsiella pneumoniae, or Staphylococcus putrefaciens.
Because serious adverse reactions have been reported with fluoroquinolones, including levofloxacin, and because uncomplicated urinary tract infections are self-limiting in some patients, levofloxacin tablets should be used only when no other drug therapy is available.
11. Inhalational anthrax (post-exposure)
For the treatment of inhalational anthrax (post-exposure) to reduce the onset or slow the progression of disease following exposure to Bacillus anthracis spray. The effectiveness of levofloxacin is based on the surrogate endpoint of plasma concentration in humans to predict clinical efficacy.
The prophylactic effect of levofloxacin following anthrax inhalation exposure has not been tested in humans. The safety of levofloxacin in adults beyond a 28-day course of treatment has not been studied. Long-term treatment with levofloxacin should be used only if the benefits outweigh the risks.
Specification
0.5g (based on C18H20FN3O4)
Dosage and Administration
Levofloxacin tablets are used for the treatment of the above infectious diseases (see indications). The generic dosage is shown below, but must be finalized by the clinician in relation to the severity of the disease.
Dosage and method of administration.
1. Dosage in patients with normal renal function
The usual dose of the oral formulation of levofloxacin is 250 mg or 500 mg or 750 mg administered orally every 24 hours. Take as indicated in the table below (Table 1) depending on the infection.
No dosage adjustment is required for creatinine clearance ≥ 50 ml/min. Adjustment of dosage is required when creatinine clearance is <50 ml/min.
Table 1: Dosage in patients with normal renal function (creatinine clearance ≥ 50 ml/min)
Type of infection1 Dose per 24 hours Course (days)2 In-hospital pneumonia 750mg7～14 Community-acquired pneumonia 3500mg7～14 Community-acquired pneumonia 4750mg5 Acute bacterial sinusitis 750mg5500mg10～14 Acute bacterial exacerbation of chronic bronchitis 500mg7 Complex skin and skin soft tissue infection (cSSSI) 750mg7～14 uncomplicated skin and skin soft tissue infection (uSSSI) 500mg7～10 chronic bacterial prostatitis 500mg28 complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) 5750mg5 complicated urinary tract infection (cUTI) or acute pyelonephritis (AP) 6250mg10 uncomplicated urinary tract infection 250mg3 inhalational anthrax (post-exposure), adult and pediatric patients >50kg and ≥6 months7,8
Pediatric patients <50kg and ≥6 months7,8500mg
See the table below
(Table 2) 608
608 Note: ① Caused by specific pathogens (see indications).
②Physicians may use continuous therapy (intravenous or oral) according to their judgment.
③ Caused by methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae [including multi-drug resistant strains (MDRSP)], Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella mucosae, Chlamydia pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae (see indications).
④ Caused by Streptococcus pneumoniae [including multi-drug resistant strains (MDRSP)], Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydia pneumoniae (see indications).
⑤ This regimen is indicated for cUTI caused by E. coli, Klebsiella pneumoniae, and Aspergillus chimaera and for acute pancreatitis caused by E. coli, including cases with concurrent bacteremia.
(6) This protocol applies to cUTI caused by Enterococcus faecalis, Enterococcus gutterus, Escherichia coli, Klebsiella pneumoniae, Aspergillus chimaera, Pseudomonas aeruginosa, and acute pancreatitis caused by Escherichia coli.
(7) The drug should be administered as soon as possible after suspected or definite B. anthracis spray exposure. This indication is based on surrogate endpoints. The levofloxacin plasma concentration achieved in humans may predict clinical efficacy.
(8) The safety of levofloxacin treatment beyond 28 days in adults and beyond 14 days in pediatric patients has not been studied. An increased incidence of musculoskeletal adverse reactions was observed in pediatric patients compared to controls (see Warnings and Precautions for details). Long-term treatment with levofloxacin should be used only if the benefits outweigh the risks.
2. Dosing in pediatric patients (<18 years)
The doses in pediatric patients (≥6 months) are described in the following table (Table 2).
Table 2: Doses in pediatric patients (≥6 months)
Type of infection1 Dose Frequency of each dose2 Inhalational anthrax (post-exposure)3,4 Pediatric patients >50 kg and ≥6 months 500 mg for 24 hours and 60 days4 Pediatric patients <50 kg and ≥6 months 8 mg/kg (no more than 250 mg per dose) for 12 hours and 60 days4 Note: ① Caused by Bacillus anthracis (see indications).
②Physicians may use continuous therapy (intravenous or oral) at their discretion.
(iii) The drug should be administered as soon as possible after suspected or definite Bacillus anthracis spray exposure. This indication is based on surrogate endpoints. The levofloxacin plasma concentration achieved in humans may predict clinical efficacy.
④ The safety of levofloxacin treatment beyond 14 days in pediatric patients has not been studied. An increased incidence of musculoskeletal adverse reactions was observed in pediatric patients compared to controls (see Warnings and Precautions). Long-term levofloxacin therapy should be used only if the benefits outweigh the risks.
3. Dose adjustment in patients with renal insufficiency
If renal insufficiency is present, levofloxacin should be used with caution. Because of the potential for decreased clearance of levofloxacin, careful clinical observation and appropriate laboratory studies should be performed before and during initiation of therapy.
Dose adjustment is not necessary in patients with creatinine clearance ≥50 ml/min.
In patients with renal insufficiency (creatinine clearance <50 ml/min), dose adjustment is required to avoid accumulation of levofloxacin due to decreased creatinine clearance (see Use in Special Populations).
The following table (Table 3) shows how to adjust the dose according to creatinine clearance.
Table 3: Dose adjustment in patients with renal insufficiency (creatinine clearance <50 ml/min)
Dose creatinine clearance per 24 hours in patients with normal renal function
20～49ml/min creatinine clearance
10 to 19 ml/min Hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) 750 mg every 48 hours 750 mg first dose 750 mg every 48 hours thereafter 500 mg every 48 hours first dose 750 mg every 48 hours thereafter 500 mg 500 mg first dose 500 mg every 48 hours thereafter 250 mg every 24 hours first dose 500 mg every 24 hours thereafter Thereafter every 48 hours 250mg first dose 500mg, thereafter every 48 hours 250mg 250mg no dose adjustment required every 48 hours 250mg. for simple UTI therapy no dose adjustment required no dose adjustment information 4. dosing instructions
Drug interactions with chelating agents: antacids, aluminum thioglycollate, metal cations, multivitamins
Oral formulations of levofloxacin should be taken at least 2 hours before or after the administration of: magnesium-containing antacids, aluminum, aluminum thioglycollate, metal cations such as iron ions, zinc-containing multivitamin preparations, dehydroinositide chewable/dispersible tablets, or pediatric flush.
Food and oral levofloxacin preparations
Levofloxacin oral preparations may be administered without regard to the effects of eating. It is recommended that levofloxacin oral formulations be taken 1 hour before or 2 hours after eating.
Water intake in patients receiving oral formulations of levofloxacin and injections
Patients receiving oral or intravenous formulations and injections should be adequately hydrated to stop excessive drug concentrations in the urine. Crystalluria and tubular urine caused by quinolones have been reported.
[Adverse reactions].
1.
Serious and other important adverse reactions
Disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathy, central nervous system effects.
Tendinopathy and tendon rupture
Prolonged QT interval
Allergic reactions
Other serious and sometimes fatal reactions
Central nervous system effects
Clostridium difficile-associated diarrhea (C. difficile-associated diarrhea)
Peripheral neuropathy
Interference with blood glucose
Photosensitivity/phototoxicity
Worsening of myasthenia gravis
Hepatotoxicity
Musculoskeletal disorders in pediatric patients
Drug-resistant bacteria production.
The above adverse reactions are described in detail under [Precautions].
Cardiovascular system: QT interval prolongation, tip-twisting ventricular tachycardia, ventricular arrhythmias
Central nervous system: Convulsions, toxic psychosis, tremor, agitation, anxiety, dizziness, confusion, hallucinations, delusions, depression, nightmares, insomnia, seizures, and in rare cases, suicidal thoughts or actions.
Peripheral neuropathy: sensory confusion, sensory dullness, pain to touch, pain, burning, tingling, numbness, weakness, or abnormalities in light touch, pain, temperature, position, and vibration, polyneuritis
Skeletal muscle system: arthralgia, myalgia, muscle weakness, hypertonic tendonitis, tendon rupture, worsening of myasthenia gravis
Hypersensitivity reactions: urticaria, pruritus and other severe skin reactions (e.g., toxic epidermolysis bullosa, erythema multiforme), dyspnea, angioneurotic edema (including edema/swelling of the tongue, throat, pharynx, or face), cardiovascular collapse, hypotension, loss of consciousness, airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), allergic pneumonia, anaphylaxis
Hepatobiliary system: hepatitis, jaundice, acute hepatic necrosis or liver failure
Urological system: acute renal insufficiency or renal failure
Hematologic system: anemia, including hemolytic anemia and aplastic anemia, thrombocytopenia, including thrombotic thrombocytopenic purpura, leukopenia, granulocytopenia, holocytopenia, and/or other hematologic disorders
Other: fever, vasculitis, serum sickness, Clostridium difficile-associated diarrhea, dysglycemia, photosensitivity/phototoxicity
The use of quinolones (including levofloxacin) has been reported to cause crystalluria and tubuluria. Therefore, appropriate hydration should be maintained in patients treated with levofloxacin to prevent the formation of highly concentrated urine.
2. Clinical trial experience
Because clinical trials are completed under different conditions, the rate of adverse reactions observed for one drug in clinical trials cannot be directly compared with the rate of adverse reactions for other drugs in clinical trials and may not reflect the rate of adverse reactions in actual application.
The data described below reflect the combined exposure of 7537 patients to levofloxacin from 29 phase III clinical trials. The mean age of the study population was 50 years (approximately 74% of the population was <65 years), of which 50% were male, 71% were Caucasian, and 17% were Black. Patients were treated with levofloxacin for a wide range of infectious diseases (see Indications). Patients received levofloxacin at a dose of 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily, with a duration of therapy usually ranging from 3 to 14 days, with a mean duration of therapy of 10 days.
The overall incidence, type, and distribution of adverse reactions were similar in patients treated with levofloxacin 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. In total, 4.3% of patients discontinued levofloxacin due to adverse drug reactions, compared with 3.8% of patients receiving 250 mg and 500 mg daily doses and 5.4% of patients receiving 750 mg daily doses. The most common adverse drug reactions leading to discontinuation in patients receiving 250 mg and 500 mg daily doses were gastrointestinal reactions (1.4%), primarily nausea (0.6%), vomiting (0.4%), dizziness (0.3%), and headache (0.2%). The most common adverse drug reactions leading to discontinuation in patients receiving the 750 mg daily dose were gastrointestinal reactions (1.2%), primarily nausea (0.6%), vomiting (0.5%), dizziness (0.3%), and headache (0.3%).
In the following tables (Tables 4 and 5), adverse reactions in patients treated with levofloxacin with an incidence of ≥1% and in patients treated with levofloxacin with an incidence of 0.1 to <1% are presented, respectively. The most common adverse reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation, and dizziness.
Table 4: Common (≥1%) adverse reactions reported in levofloxacin clinical trials
System/Organ Classification Adverse Reactions % (N=7537) Infectious and Infectious Diseases Candidiasis1 Psychiatric Insomnia4a Various Neurological Diseases Headache6 Dizziness3 Respiratory, Thoracic and Mediastinal Diseases Dyspnea1 Gastrointestinal Diseases Nausea7 Diarrhea5 Constipation3 Abdominal Pain2 Vomiting2 Dyspepsia2 Skin and Subcutaneous Tissue Diseases Rash
Pruritus2
1 Reproductive system and breast diseasesVaginitis1b Systemic diseases and various reactions at the drug administration siteOedema
Injection site reactions
Chest pain1
1
1 Note: a. N=7274; b. N=3758 (female).
Table 5: Less common (0.1 to 1%) adverse reactions reported in clinical trials of levofloxacin (N=7537)
System/Organ Classification Adverse Reactions Infection and Infestation Genital Candidiasis Blood and Lymphatic System Disorders Anemia, thrombocytopenia, granulocytopenia Immune System Disorders Allergic Reactions Metabolic and Nutritional Disorders Hyperglycemia, hypoglycemia, hyperkalemia Psychiatric Disorders Anxiety, agitation, confusion, depression, hallucinations, nightmares
sleep disordersa, anorexia various neurological disorders tremors, convulsions, sensory confusion, vertigo, hypertonia, hyperkinesia, gait abnormalities, drowsinessa, syncope respiratory, thoracic and mediastinal disorders epistaxis cardiac organ disorders cardiac arrest, palpitations, ventricular tachycardia, ventricular arrhythmias vascular disorders phlebitis gastrointestinal system disorders gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, tongue inflammation, pseudomembranous/unidentifiable Clostridial colitisHepatobiliary system disordersAbnormal liver function, increased liver enzymes, increased alkaline phosphataseDermal and skin soft tissue disordersUrticariaVarious musculoskeletal and connective tissue disordersArthralgia, tendonitis, myalgia, bone painRenal and urinary system disordersAbnormal renal function, acute renal failureNote: a. N=7274.
Adverse reactions collected after levofloxacin injection in a clinical study enrolling 586 patients and a post-marketing study of 1138 patients in Japan are shown below
Common: abnormal liver function
Uncommon: severe liver function abnormalities
Ophthalmic abnormalities, including cataracts and multiple punctate patches of the lens, have been noted in patients treated with quinolone antimicrobials, including levofloxacin, in clinical trials using multiple doses of treatment. A link between the drug and these events has not been established.
3. Post-marketing surveillance
The following table (Table 6) lists the adverse reactions identified in use after levofloxacin received marketing approval. Because these reactions were spontaneously reported from a variable number of people, it is sometimes not possible to reliably evaluate the incidence of these events or to establish a causal relationship between drug exposure and these events.
Table 6: Postmarketing adverse drug reaction reports
System/Organ Classification Adverse Reactions Hematologic and Lymphatic System Disorders Allogeneic cytopenia, aplastic anemia, leukopenia, hemolytic anemia, eosinophilia Immune System Disorders Allergic reactions, sometimes fatal, including: anaphylaxis/anaphylaxis-like reactions, anaphylaxis, angioneurotic edema, serum sickness Psychosis-like psychosis, paranoia, isolated reports of suicide attempts and suicidal ideation Various neurologic disorders worsening myasthenia gravis, loss of smell, loss of taste, olfactory abnormalities, taste disorders, peripheral neuropathies, isolated reports of encephalopathy, electroencephalogram (EEG) abnormalities, vocal difficulties eye organ disorders visual disturbances including diplopia, reduced visual acuity, blurred vision, dark spots ear and vagus disorders hearing loss, tinnitus heart organ disorders isolated reports of tip-twist ventricular Tachycardia, prolonged ECG QT interval, tachycardia vascular disease vasodilation respiratory, thoracic and mediastinal disease isolated reports of allergic pneumonia hepatobiliary system disease liver failure (including fatal cases), hepatitis, jaundice skin and soft tissue skin disease maculopapular rash (including: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme), photosensitivity/phototoxicity Reaction, leukocyte rupture vasculitis various musculoskeletal and connective tissue disorders tendon rupture, muscle injury (including rupture), rhabdomyolysis renal and urinary disorders interstitial nephritis systemic diseases and administration site conditions multi-organ failure, fever various types of tests prolonged prothrombin time, increased muscle enzymes [contraindicated
Allergic to quinolones, pregnant and lactating women, patients under 18 years of age are prohibited.
Precautions]
1. Disabling and potentially irreversible serious adverse reactions, including tendonitis and tendon rupture, peripheral neuropathy, central nervous system effects
Disabling and potentially irreversible serious adverse reactions have been reported with fluoroquinolones in different organ systems of the body in the same patient, usually including: tendonitis, tendon rupture, arthralgia, myalgia, peripheral neuropathy and central nervous system reactions (hallucinations, anxiety, depression, insomnia, severe headache and confusion). These adverse reactions can occur hours to weeks after levofloxacin administration. These adverse reactions have been reported in patients of any age with no prior associated risk factors.
2. Tendonitis and tendon rupture
Fluoroquinolones, including levofloxacin, increase the risk of tendonitis and tendon rupture in patients of all ages. This adverse reaction occurs most often in the Achilles tendon, including Achilles tendon, and Achilles tendon requires surgical repair and Achilles tendon rupture may require surgical repair. Tendonitis and tendon rupture have also been reported in the shoulder, hand, biceps, thumb, and other tendon points. Tendonitis and tendon rupture can occur hours or days after starting levofloxacin tablets, or months after finishing treatment. Tendonitis and tendon rupture can occur bilaterally. This risk is further increased in older patients over 60 years of age, in patients taking corticosteroid drugs and in patients who have had kidney, heart or lung transplants. In addition to age and corticosteroid use, other factors that may independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon disease such as rheumatoid arthritis. Tendonitis and tendon rupture also occur in patients using fluoroquinolones without these risk factors. Tendon ruptures can occur during or after the end of treatment; they have also been reported several months after the end of treatment. This product should be discontinued after a patient develops tendon pain, swelling including edema, inflammation, or rupture. After signs of tendonitis or tendon rupture, patients should be advised to rest and contact their physician to switch to a non-quinolone drug. Patients with a history of tendon disease or who have experienced tendonitis and tendon rupture should avoid fluoroquinolone drugs.
3. Exacerbation of myasthenia gravis
Fluoroquinolone drugs, including levofloxacin, have neuromuscular blocking activity and may exacerbate symptoms of myasthenia gravis in patients with myasthenia gravis. Post-marketing serious adverse events, including death and need for ventilatory support, and patients with myasthenia gravis have been associated with the use of fluoroquinolone drugs. Levofloxacin tablets should be avoided in patients with myasthenia gravis.
4. Prolonged QT interval
Certain fluoroquinolone drugs can prolong the QT interval of the electrocardiogram, and a small number of patients can develop arrhythmias. Spontaneous reports of tip-twist ventricular tachycardia in patients treated with fluoroquinolones during postmarketing surveillance are rare. Levofloxacin tablets should be avoided in patients with known QT interval prolongation, in patients with uncorrected hypokalemia, and in patients using Class IA (quinidine, procainamide) and Class III (amiodarone, sotalol) antiarrhythmic drugs and in patients using delamanid. Elderly patients are more susceptible to drug-related QT intervals.
5. Allergic reactions
Serious and sometimes fatal hypersensitivity and/or allergic reactions have been reported with treatment with fluoroquinolone antibacterial drugs, including levofloxacin. Some reactions occur in some patients after the first dose and some may be associated with cardiovascular system failure, hypotension/shock, seizures, loss of consciousness, tingling, paresthesia, angioneurotic edema (including edema/swelling of the tongue, throat, pharynx, or face), airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), dyspnea, urticaria, pruritus, and other severe skin reactions. Severe allergic reactions require emergency treatment with epinephrine. Levofloxacin tablets should be discontinued at the first sign of rash or any other signs of allergy. Oxygen administration, intravenous rehydration, antihistamines, intravenous steroids, antihypertensive amines, and airway management, including intubation, may be indicated if necessary.
6. Other serious and potentially fatal adverse reactions
Other serious and potentially fatal events have been reported with the use of fluoroquinolones, including levofloxacin. Some of these events are due to allergy and others are of unknown etiology. These events may be severe and usually occur after multiple dose administration. Clinical manifestations may include one or more of the following: fever, rash, severe skin reactions (e.g., toxic epidermolysis bullosa, Stevens-Johnson syndrome, erythema multiforme; vasculitis; arthralgia; myalgia; serum sickness; allergic pneumonia; interstitial nephritis; acute renal insufficiency or renal failure; hepatitis, jaundice, acute hepatic necrosis, or hepatic failure; anemia including hemolytic anemia and aplastic anemia; thrombocytopenia, including thrombotic thrombocytopenic purpura; leukopenia; granulocyte deficiency; holocytopenia and/or other hematologic abnormalities. The drug should be discontinued and action taken immediately at the first appearance of rash, jaundice, or any other manifestation of allergy.
7. Central nervous system effects
The use of fluoroquinolones, including levofloxacin tablets, has been reported to increase the risk of central nervous system adverse reactions, including convulsions and increased intracranial pressure (including pseudotumor cerebri) and psychosis due to toxicity. The use of fluoroquinolones may cause CNS reactions including agitation, restlessness, confusion, delusions, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or behaviors. These reactions may occur after the first dose of the drug. If these reactions occur while the patient is using levofloxacin tablets, administration should be discontinued and appropriate action taken. As with all fluoroquinolones, levofloxacin tablets should be used when the benefit outweighs the risk in patients with known or suspected central nervous system disease (epilepsy or lowered seizure threshold) (e.g., severe cerebral atherosclerosis, epilepsy) or in patients with other risk factors (e.g., propensity to seizures or lowered seizure threshold, e.g., treatment with certain drugs, renal insufficiency).
8. Peripheral neuropathy
Rare sensory or sensorimotor axonal neuropathy affecting small and/or large axons, resulting in abnormal skin sensation, sensory confusion, sensory dullness, painful sensation to touch, and debilitation (weakness) has been reported in patients using fluoroquinolones. In some patients, symptoms may occur soon after levofloxacin tablets are administered and may be irreversible. If patients develop peripheral neuropathy (neuronopathy) symptoms, including pain, burning, tingling, numbness and/or weakness, or other sensory disturbances, including changes in light touch, pain, warmth, position and vibration, the drug should be discontinued immediately. Patients with a history of peripheral neuropathy should avoid fluoroquinolone antimicrobials.
9. Clostridium difficile-associated diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with almost all antimicrobial drugs, including levofloxacin tablets, ranging in severity from mild diarrhea to severe colitis. Antimicrobial drug therapy alters the normal flora of the colon, leading to C. difficile overgrowth.
Toxins A and B produced by C. difficile are responsible for C. difficile-associated diarrhea. High virulence includes elevated morbidity and mortality caused by hyper-toxin-producing Clostridium difficile, and these infections are ineffective with antimicrobial therapy and may require colectomy. The possibility of CDAD should be considered in all cases of diarrhea following antimicrobial therapy. Because CDAD may occur up to two months after treatment with antimicrobial drugs, a careful history is necessary.
If C. difficile-associated diarrhea is suspected or confirmed, it may be necessary to discontinue the current use of antimicrobial drugs that do not target C. difficile. Appropriate fluid and electrolyte replacement, protein supplementation, treatment with antimicrobial agents directed against C. difficile, and surgical evaluation should be performed when clinical indications arise.
10. Interference with blood glucose
Fluoroquinolone antimicrobials have been reported to cause dysglycemia (e.g., symptomatic hyperglycemia and hypoglycemia), which mostly occurs in diabetic patients who are also taking oral hypoglycemic agents (e.g., euglycemia/glibenclamide) or using insulin. Therefore, for such patients, it is recommended that they should be closely monitored for changes in blood glucose. If a patient develops hypoglycemic reactions while receiving levofloxacin tablets, the drug should be discontinued immediately and appropriate therapeutic measures should be taken.
11. Photosensitivity/phototoxicity
Moderate to severe photosensitivity/phototoxicity can occur after exposure to sunlight (daylight) or UV radiation following the use of fluoroquinolone antimicrobials. The latter may manifest as excessive sunburn reactions (e.g., burning sensation, erythema, blistering, blistering, oozing, edema), often at the site of exposure to light (usually the “V” area of the neck, the surface of the extensor muscles of the forearm, the back of the hand). Therefore, overexposure to light sources should be avoided. The drug should be discontinued in the event of photosensitivity/phototoxicity reactions.
12. Musculoskeletal Disorders in Pediatric Patients and Arthropathy Effects in Animals
In pediatric patients (≥6 months), levofloxacin is indicated only for protection from anthrax inhalation (post-exposure). An increased incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, and gait abnormalities) was observed in pediatric patients receiving levofloxacin compared to controls.
In immature rats and dogs, oral and intravenous administration of levofloxacin resulted in an increase in osteochondrosis. Histopathological examination of weight-bearing joints in immature dogs receiving levofloxacin revealed the presence of persistent damage to cartilage. Other quinolones can also produce similar erosions in weight-bearing joints, as well as other signs of arthropathy, in several species of immature animals.
13. Hepatotoxicity
Post-marketing reports of serious hepatotoxicity, including acute hepatitis and fatal events, have been received from patients treated with levofloxacin. No evidence of serious drug-related hepatotoxicity was found in clinical trials of more than 7,000 patients. Severe hepatotoxicity usually appeared within 14 days of starting treatment and in most cases within 6 days of starting treatment. Most cases of severe hepatotoxicity were not related to allergy. Most reports of fatal hepatotoxicity were seen in patients aged ≥65 years and most were not related to hypersensitivity. Levofloxacin should be discontinued immediately if the patient develops signs and symptoms of hepatitis.
14. Development of drug-resistant bacteria
Prescribing levofloxacin when bacterial infection has not been diagnosed or is highly suspected and when it is not indicated for prophylaxis does not provide benefit to the patient and may increase the risk of development of drug-resistant organisms.
For Pregnant and Lactating Women
Pregnancy
Pregnancy Dosage Classification C. Levofloxacin is not teratogenic in rats at oral doses up to 810 mg/kg/day, a dose equivalent to 9.4 times the maximum recommended human dose for the same relative body surface area. Levofloxacin was also not teratogenic at an intravenous dose of 160 mg/kg/day, which is 1.9 times the maximum recommended human dose for the same relative body surface area. Oral doses of 810 mg/kg/day in rats resulted in decreased fetal body weight and increased mortality. No teratogenic effects of levofloxacin were observed in rabbits at an oral dose of 50 mg/kg/day, which is 1.1 times the maximum recommended human dose for the same relative body surface area. No teratogenic effect of levofloxacin was observed at an intravenous dose of 25 mg/kg/day, which is 0.5 times the maximum recommended human dose for the same relative body surface area.
However, there have not been sufficient well-controlled trials in pregnant women to ensure safe administration in pregnant women, so it is contraindicated in women who are pregnant or at risk of pregnancy. Levofloxacin should be used in pregnant women only if the potential benefit to the fetus outweighs the potential risk.
Lactating Women
Based on the limited data available for other fluoroquinolones and levofloxacin, it is presumed that levofloxacin should be secreted into human breast milk. Because levofloxacin may cause serious adverse reactions in breastfed infants, it is contraindicated in nursing women. Levofloxacin should be used in nursing women only when the potential benefit to the nursing mother outweighs the potential risk, but breastfeeding should be suspended.
Pediatric Use]
Quinolones, including levofloxacin, can cause arthropathy and bone/chondral lesions in juveniles of certain species of animals. Safety in children has not been established and is therefore contraindicated in patients younger than 18 years of age, except for protection from anthrax inhalation (post-exposure).
Inhalational Anthrax (Post-Exposure)
Levofloxacin is indicated for use in pediatric patients with inhalational anthrax (post-exposure). The risk-benefit assessment suggests that levofloxacin is appropriate for administration in pediatric patients. The safety of levofloxacin treatment over a 14-day period has not been studied in pediatric patients. The pharmacokinetics of a single intravenous dose of levofloxacin have been studied in pediatric patients aged 6 months to 16 years. In pediatric patients, levofloxacin was cleared more rapidly than in adult patients, so that the resulting plasma exposure levels were lower than in adults at specific mg/kg doses.
Adverse Reactions
In clinical trials, 1534 children (aged 6 months to 16 years) received oral and intravenous levofloxacin. Children aged 6 months to 5 years received levofloxacin at 10 mg/kg twice daily, and children older than 5 years received levofloxacin at 10 mg/kg once daily (maximum dose of 500 mg daily) for a total duration of 10 days.
A subgroup of children in the clinical trial (1340 treated with levofloxacin and 893 treated with non-fluoroquinolones) participated in a prospective long-term monitoring study to assess the incidence of musculoskeletal disorders (arthralgia, arthritis, tendinopathy, gait abnormalities) as defined by the trial protocol at 60 days and 1 year after the first administration of the study drug. The incidence of musculoskeletal disorders was significantly higher in children treated with levofloxacin than in children treated with non-fluoroquinolones, as shown in the table below (Table 7).
Table 7: Incidence of musculoskeletal disorders in pediatric clinical trials
Follow-up period Levofloxacin
N=1340 Non-fluoroquinolonesa
N=893p valueb 60 days 28 (2.1%) 8 (0.9%) p=0.0381 yearsc 46 (3.4%) 16 (1.8%) p=0.025 Note: a. Non-fluoroquinolones: ceftriaxone, amoxicillin/clavulanic acid, clarithromycin.
b.Bilateral Fisher’s exactness test.
c.A 1-year evaluation visit was conducted in 1199 levofloxacin-treated children and 804 non-fluoroquinolone-treated children. The incidence of musculoskeletal disorders, however, was calculated using all reported events for all children participating in the trial during the specified period, regardless of whether they completed the 1-year evaluation visit.
In both treatment groups, arthralgia was the most frequent musculoskeletal disorder. In both groups, the vast majority of musculoskeletal disorders involved multiple weight-bearing joints. Disease was moderate in 8/46 (17%) levofloxacin-treated children and mild in 35/46 (76%) levofloxacin-treated children, most of whom received analgesic therapy. The median time to remission was 7 days in the levofloxacin-treated group and 9 days in the non-fluoroquinolone-treated group (in both groups, approximately 80% of patients remitted within 2 months). No children developed severe or significant disease, and all skeletal muscle disease remissions left no sequelae.
Vomiting and diarrhea were the most frequently reported adverse events and occurred at similar rates in the levofloxacin-treated and non-fluoroquinolone-treated groups.
In addition to events reported in clinical trials in pediatric patients, events reported in clinical trials or post-sales monitoring in adult patients may also occur in pediatric patients.
Geriatric Use]
Geriatric patients are at increased risk of serious adverse reactions (tendinopathy including tendon rupture) while receiving fluoroquinolones, such as levofloxacin. This risk is further increased in patients receiving glucocorticoid combination therapy. Tendonitis or tendon rupture can involve the heel, hand, shoulder, or other tendon sites and can occur during or after the end of treatment. Cases have been reported that occurred several months after the end of fluoroquinolone therapy. Levofloxacin must be used with caution in elderly patients, especially those receiving glucocorticoids. Patients must be informed of these potential side effects, and if any symptoms of tendonitis or tendon rupture occur, it is recommended that levofloxacin therapy be discontinued and that health care personnel be contacted.
In the phase III clinical trial, 1945 patients (26%) treated with levofloxacin were ≥65 years of age, 1081 (14%) were between 65 and 74 years of age, and 864 (12%) were equal to or greater than 75 years of age. The safety and efficacy of the drug did not differ significantly between these patients and younger patients, but it does not exclude the possibility that some older patients may have a higher sensitivity.
Serious, even fatal, hepatotoxicity associated with levofloxacin has been reported in marketing reports. The major reports of fatal hepatotoxicity occurred in patients 65 years of age or older and were mostly without anaphylactic reactions. Levofloxacin should be discontinued immediately if a patient has signs or indications of hepatitis.
Elderly patients may be more sensitive to the drug-related effects of the QT interval. Therefore caution should be exercised when using levofloxacin concomitantly with certain drugs that can cause prolongation of the QT interval (e.g., class IA or III antiarrhythmics) or in patients with risk factors for tip-turn ventricular tachycardia (e.g., known QT interval prolongation, intractable hypokalemia).
If differences in creatinine clearance are considered, there is no significant difference in the pharmacokinetic profile of levofloxacin in young and elderly subjects. However, since the majority of levofloxacin is excreted from the kidneys, patients with renal impairment are at higher risk of drug toxicity reactions. Elderly patients are more likely to have reduced renal function, so special care should be taken when selecting the dose, and renal function needs to be monitored at the same time.
Drug Interactions]
1. Chelating agents: antacids, aluminum thioglycollate, metal cations, multivitamin preparations
Levofloxacin oral formulation
Although the chelation of levofloxacin with divalent cations is weaker than that of other fluoroquinolone antibacterial drugs, the concomitant use of levofloxacin tablets and antacids such as magnesium or aluminum, as well as aluminum thiosaccharides, metal cations such as iron and zinc-containing multivitamin preparations can still affect the gastrointestinal absorption of levofloxacin, resulting in systemic drug concentrations significantly lower than expected. Drugs containing antacids such as magnesium or aluminum and aluminum thioglycollate, metal cations such as iron and zinc-containing multivitamin preparations, or desoxifloxacin can significantly affect the gastrointestinal absorption of levofloxacin, resulting in significantly lower systemic drug concentrations than expected. These drugs should be taken at least two hours before or two hours after levofloxacin administration.
2. Warfarin
A clinical trial in healthy volunteers showed no significant effect of levofloxacin on peak plasma concentrations, AUC and other metabolic parameters of R- and S-warfarin. Similarly, no significant effect of warfarin on the absorption and metabolism of levofloxacin was observed. There have been post-marketing surveillance reports indicating that levofloxacin enhances the efficacy of warfarin. Concomitant application of warfarin and levofloxacin prolongs prothrombin time, which leads to prolonged bleeding time. Close monitoring of prothrombin time, international normalized ratio (INR) or other anticoagulation tests should be performed when levofloxacin and warfarin are applied simultaneously, and patients should be noted for signs of bleeding.
3. Anti-diabetic drugs
Patients who combine quinolone antibacterial drugs and antidiabetic drugs may experience dysglycemia such as hyperglycemia and hypoglycemia. Therefore, the blood glucose level should be closely monitored when these drugs are applied simultaneously.
4. Non-steroidal anti-inflammatory drugs
Concomitant use of NSAIDs and quinolone antibacterial drugs including levofloxacin can increase the risk of CNS stimulation and convulsive episodes.
5. Theophylline
No significant effects of levofloxacin on plasma concentrations, AUC and other metabolic parameters of theophylline were found in a clinical trial involving 14 healthy volunteers. Similarly, no significant effect of theophylline on the absorption and metabolism of levofloxacin was observed. However, concomitant application of other quinolone antibacterial drugs and theophylline may result in prolonged clearance half-life and increased blood concentrations of theophylline in patients, thereby increasing the incidence of theophylline-related adverse reactions. Therefore, when used concomitantly with levofloxacin, theophylline levels should be closely monitored and the drug dose should be adjusted appropriately. Adverse reactions such as seizures may occur regardless of whether the blood levels of theophylline are elevated.
6. Cyclosporine
A clinical trial in healthy volunteers showed no significant effect of levofloxacin on peak plasma concentrations, AUC and other metabolic parameters of ciclosporin. However, elevated cyclosporine blood levels have been reported in patients when administered concomitantly with certain other quinolone antimicrobials. Compared with other trials without concomitant dosing, concomitant use of ciclosporin mildly reduced Cmax and ke of levofloxacin, while Tmax and t1/2 were slightly prolonged, but this difference was not clinically significant. Therefore, no dose adjustment of levofloxacin and ciclosporin is required for concomitant use.
7. Digoxin
A clinical trial in healthy volunteers showed no significant effect of levofloxacin on peak plasma concentrations, AUC and other metabolic parameters of digoxin. Digoxin also had no significant effect on the absorption and metabolic kinetics of levofloxacin. Therefore, no dose adjustment of levofloxacin and digoxin is required for concomitant use.
8. Propofol and cimetidine
A clinical trial in healthy volunteers showed no significant effect of probenecid or cimetidine on the rate or extent of absorption of levofloxacin. The AUC and t1/2 of levofloxacin were 27% to 38% and 30% higher, respectively, and the CL/F and CLR were 21% to 35% lower when coadministered with propofol or cimetidine compared with levofloxacin alone. Although this difference was statistically significant, no dose adjustment of levofloxacin was required when co-administered with propofol or cimetidine.
9. Interactions with laboratory or diagnostic tests
Fluoroquinolones including levofloxacin, urine screening for opioid preparations with commercially available kits may produce false positive results, necessitating more specific methods to determine positive opioid results.
[Drug Overdose].
The acute toxicity of levofloxacin is low. The following clinical signs can occur in mice, rats, dogs and monkeys after a single high dose of levofloxacin: ataxia, ptosis, decreased spontaneous activity, respiratory distress, failure, tremor and convulsions. Oral doses exceeding 1500 mg/kg and injectable doses exceeding 250 mg/kg can result in significantly increased mortality in rodents.
The following symptoms can occur in quinolone overdose: nausea, vomiting, stomach pain, heartburn, diarrhea, thirst, stomatitis, hobbling, dizziness, headache, generalized lethargy, numbness, chills, fever, extrapyramidal symptoms, euphoria, hallucinations, convulsions, delirium, cerebellar ataxia, elevated intracranial pressure (headache, vomiting, optic nerve papilla edema), metabolic acidosis, increased blood glucose, GOT/ GPT/ALP, leukopenia, increased eosinophilia, thrombocytopenia, hemolytic anemia, hematuria, cartilage/joint disorders, cataracts, visual disturbances, abnormal color vision, and diplopia.
In acute overdose, gastric lavage should be performed (only when taking oral preparations), observed and given hydration and electro-mediated support therapy. Hemodialysis or peritoneal dialysis does not effectively remove levofloxacin.
First aid measures and antidotes.
(1) Infusion (plus hepatoprotective drugs): give sodium bicarbonate injection for metabolic acidosis and sodium bicarbonate injection for urinary alkalinization to increase excretion of the product by the kidneys.
(2) Forced diuresis: give furanophanic acid injection.
(3) Allopathic treatment: give Valium intravenous injection repeatedly in case of convulsions.
Pharmacology and Toxicology
1. Pharmacological action
Mechanism of action: Levofloxacin is the left-hand side of ofloxacin (racemic), which is an antibacterial drug of quinolone class. The antibacterial effect of ofloxacin is mainly produced by the levofloxacin. The mechanism of action of levofloxacin and other fluoroquinolone antibacterial drugs is the inhibition of topoisomerase IV and DNA rotamase (for topoisomerase II) required for bacterial DNA replication, transcription, repair and recombination.
Resistance: Fluoroquinolone resistance is produced by mutations in specific regions of DNA rotase or topoisomerase IV, also known as quinolone resistance determining regions (ORDRs), or altered drug efflux systems.
Fluoroquinolone antibacterial drugs, including levofloxacin, have a different chemical structure and mode of action than aminoglycosides, macrolides and β-lactam antibacterial drugs (including penicillin). Therefore, fluoroquinolones may still be effective against bacteria resistant to the above antibacterial drugs.
Resistance to levofloxacin due to spontaneous mutation under in vitro conditions is less common (range: 10-9 to 10-10). Although cross-resistance between levofloxacin and some other fluoroquinolones has been observed, bacteria resistant to other fluoroquinolone species may still be susceptible to levofloxacin.
In vitro and in vivo antibacterial activity:
Levofloxacin has in vitro antimicrobial activity against a wide range of Gram-negative and Gram-positive bacteria at concentrations equal to or slightly higher than the inhibitory concentration.
In vitro studies and clinical infections have demonstrated the antibacterial activity of levofloxacin against the following microorganisms.
Gram-positive aerobic bacteria: Enterococcus faecalis (several strains only moderately sensitive), Staphylococcus aureus (methicillin-sensitive strains), Staphylococcus epidermidis (methicillin-sensitive strains), Staphylococcus saprophyticus, Streptococcus pneumoniae (including multi-drug resistant strains [MDRSP]*), Streptococcus pyogenes.
Note*: MDRSP (multi-drug resistant Streptococcus pneumoniae) refers to strains resistant to two or more of the following antimicrobial drugs: penicillin (MIC ≥ 2µg/ml), second generation cephalosporins (e.g. cefuroxime), macrolides, tetracyclines and methomyl/sulfamethoxazole.
Gram-negative aerobic bacteria: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumoniae, Catamorax, Aspergillus chimaerae, Pseudomonas aeruginosa*, Serratia marcescens.
Note*: As with other drugs in this category, some strains of Pseudomonas aeruginosa can quickly develop resistance when treated with levofloxacin.
Other microorganisms: Chlamydia pneumoniae, Mycoplasma pneumoniae.
Levofloxacin was shown to be antimicrobial against B. anthracis both in the macaque anthrax fever (post-exposure) model and under in vitro conditions when plasma concentrations were applied as surrogate markers.
The following data are the results of in vitro tests, but their clinical significance is unknown.
The minimum inhibitory concentration (MIC) of levofloxacin under in vitro conditions was 2 µg/ml or less for most strains (≥90%) of the following microorganisms; however, the safety and efficacy of levofloxacin for the treatment of clinical infections caused by these microorganisms has not been studied in adequate, well-controlled trials.
Gram-positive aerobic bacteria: Staphylococcus haemolyticus, β-haemolytic streptococci (group C/F), β-haemolytic streptococci (group G), non-lactating streptococci, Streptococcus miller, Streptococcus grass green.
Gram-negative aerobic bacteria: Acinetobacter baumannii, Acinetobacter rouxii, Acinetobacter perfringens, Citrobacter coxiella (Citrobacter differential), Citrobacter fowleri, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella acidophilus, Morgan’s bacillus, Enterobacter agglomerans, Proteus mirabilis, Proteus mirabilis, Proteus mirabilis, Pseudomonas fluorescens.
Gram-positive anaerobic bacteria: Clostridium perfringens.
2. Non-clinical toxicology
Carcinogenic effects, mutagenic effects, reproductive function impairment: Bioassay results on rats throughout their lives showed that levofloxacin given daily for 2 years did not exhibit any carcinogenic effects. The highest dose used (100 mg/kg/day) was 1.4 times the recommended maximum dose (750 mg) for humans (based on relative body surface area). Levofloxacin at any dose did not shorten the time to progression of UV-induced skin tumors in albino nude mice (Skh-1) and therefore was not photocarcinogenic under the conditions of this test. In the photocarcinogenicity test, the range of dermal levofloxacin concentrations in nude mice at the maximum levofloxacin dose (300 mg/kg/day) was 25 to 42 µg/g, while the mean Cmax of dermal levofloxacin concentrations in human subjects at a dose of 750 mg was approximately 11.8 µg/g.
The following tests demonstrated that levofloxacin is not mutagenic: Ames bacterial mutation analysis (Salmonella typhimurium and Escherichia coli), CHO/HGPRT forward mutation assay, mouse micronucleus test, mouse dominant lethal assay, rat non-programmed DNA synthesis assay, and mouse sister chromatid swap assay. Positive in vitro chromosomal aberrations (CHL cell line) and sister chromatid swap assay (CHL/IU cell line).
Levofloxacin did not impair reproduction in rats at oral doses up to 360 mg/kg/day, a dose equivalent to 4.2 times the maximum recommended human dose for the same relative body surface area. Levofloxacin also did not impair reproduction at an intravenous dose of 100 mg/kg/day, which is 1.2 times the maximum recommended human dose for the same relative body surface area.
Animal toxicology and/or pharmacodynamics: Levofloxacin and other quinolone antimicrobials have been shown to cause arthropathy in immature laboratory animals of most species. Levofloxacin administered orally at a dose of 10 mg/kg/day for 7 days or intravenously at a dose of 4 mg/kg/day for 14 days in immature dogs (4 to 5 months of age) can cause joint damage. In young rats, oral doses of 300 mg/kg/day for 7 days or intravenous doses of 60 mg/kg/day for 4 weeks caused joint lesions. 3-month-old beagles given the usual oral dose of 40 mg/kg/day of levofloxacin for 14 days showed severe joint toxicity on day 8 and discontinued the drug. At dose levels ≥2.5 mg/kg (approximately 0.2 times the pediatric dose based on comparative plasma AUC), clinical manifestations of mild musculoskeletal injury may occur, but no gross pathological or histopathological damage has been observed. Synovitis and articular cartilage damage can be induced at doses of 10 and 40 mg/kg (approximately 0.7 and 2.4 times the pediatric dose, respectively). After 18 weeks of recovery, articular cartilage gross pathology and histopathology were still present.
Ear swelling tests in mice showed levofloxacin to have similar phototoxicity to that of of ofloxacin but weaker compared to other quinolones.
Although crystalluria was found in some intravenously administered rat tests, the crystals did not form in the bladder but after urination and therefore do not imply that levofloxacin is nephrotoxic.
Concomitant use with NSAIDs can exacerbate the stimulatory effect of quinolones on the CNS in mice.
Rapid intravenous administration of levofloxacin at doses of 6 mg/kg or higher can produce hypotension in dogs. This effect may be related to the release of histamine.
In vitro and in vivo tests in animals have shown that levofloxacin is neither an enzyme inducer nor an enzyme inhibitor in the range of therapeutic plasma concentrations in humans, and therefore, there are no drug-metabolizing enzyme-related interactions with other drugs or agents.
[Pharmacokinetics].
The pharmacokinetic parameters of levofloxacin after a single oral administration of levofloxacin tablets, oral solution or intravenous administration and after reaching steady state were determined and expressed as Mean±SD and summarized in the following table (Table 8).
Table 8: Mean±SD of levofloxacin PK parameters
Treatment regimen Cmax
(μg/ml) Tmax (h) AUC
(μg-h/ml)CL/F1
(ml/min)Vd/F2
(L)t1/2
(h)CLR
(ml/min) Single dose 250 mg p.o. tablet 32.8 ± 0.41.6 ± 1.027.2 ± 3.9156 ± 20ND7.3 ± 0.9142 ± 21500 mg p.o. tablet 3*5.1 ± 0.81.3 ± 0.647.9 ± 6.8178 ± 28ND6.3 ± 0.6103 ± 30500 mg Oral liquid 125.8 ± 1.80.8 ± 0.747.8 ± 10.8183 ± 40112 ± 37.27.0 ± 1.4ND500 mg i.v.36.2 ± 1.01.0 ± 0.148.3 ± 5.4175 ± 2090 ± 116.4 ± 0.7112 ± 25750 mg p.o. Tablets 5*9.3 ± 1.61.6 ± 0.8101 ± 20129 ± 2483 ± 177.5 ± 0.9ND750 mg i.v.511.5 ± 4.04ND110 ± 40126 ± 3975 ± 137.5 ± 1.6ND multiple doses of 500 mg q24h p.o. tablets 35.7 ± 1.41.1 ± 0.447.5 ± 6.7175 ± 25102 ± 227.6 ± 1.6116 ± 31500 mg q24h i.v. 36.4 ± 0.8ND54.6 ± 11.1158 ± 2991 ± 127.0 ± 0.899 ± 28500 mg or 250 mg q24h i.v.
Patients with bacterial infection 68.7 ± 4.07ND72.5 ± 51.27154 ± 72111 ± 58NDND750 mg q24h p.o. tablets 58.6 ± 1.91.4 ± 0.590.7 ± 17.6143 ± 29100 ± 168.8 ± 1.5116 ± 28750 mg q24h i.v. 512.1 ± 4.14 ND108 ± 34126 ± 3780 ± 277.9 ± 1.9 ND500 mg p.o. tablet, single dose, gender and age factors: male 85.5 ± 1.11.2 ± 0.454.4 ± 18.9166 ± 4489 ± 137.5 ± 2.1126 ± 38 female 97.0 ± 1.61.7 ± 0.567.7 ± 24.2136 ± 4462 ± 166.1 ± 0.8106 ± 40 young people 105.5 ± 1.01.5 ± 0.647.5 ± 9.8182 ± 3583 ± 186.0 ± 0.9140 ± 33 elderly 117.0 ± 1.61.4 ± 0.574.7 ± 23.3121 ± 3367 ± 197.6 ± 2.091 ± 29500 mg p.o. Single dose, tablets, patients with renal insufficiency: CLCR50-80 ml/min7.5 ± 1.81.5 ± 0.595.6 ± 11.888 ± 10ND9.1 ± 0.957 ± 8CLCR20-49 ml/min7.1 ± 3.12.1 ± 1.3182.1 ± 62.651 ± 19ND27 ± 1026 ± 13CLCR<20ml/min8.2 ± 2.61.1 ± 1.0263.5 ± 72.533 ± 8ND35 ± 513 ± 3Hemodialysis5.7 ± 1.02.8 ± 2.2NDNDND76 ± 42NDCAPD6.9 ± 2.31.4 ± 1.1NDNDND51 ± 24ND Note: ①
Clearance/bioavailability.
②
Distribution volume/bioavailability.
③
Healthy male, age 18 to 53 years.
④
Dose of 250 mg and 500 mg in a 60-minute titration and 750 mg in a 90-minute titration.
⑤
Healthy male and female subjects, age 18 to 54 years.
⑥
Patients with moderate renal impairment and respiratory or skin infections, 500 mg every 48 h (CLCR 20-50 ml/min).
(vii)
Dose standard values (500 mg dose) estimated from population pharmacokinetic models.
⑧
Healthy males, age 22 to 75 years.
⑨
Healthy females, age 18 to 80 years.
⑩Healthy young male and female subjects, age 18 to 36 years.
⑪ Healthy elderly male and female subjects, age 66 to 80 years.
⑫Healthy male and female subjects, age 19 to 55 years.
3* Absolute bioavailability; 500 mg tablet, F = 0.99 ± 0.08; 750 mg tablet, F = 0.99 ± 0.06; ND = not tested.
Absorption
Absorption of levofloxacin was rapid and complete after oral administration, with peak plasma drug concentrations usually occurring 1 to 2 hours after oral administration. The absolute bioavailability of both levofloxacin 500 mg tablets and 750 mg tablets was approximately 99%, indicating complete absorption of levofloxacin after oral administration. The Mean±SD of peak plasma concentration was 6.2±1.0 µg/ml for a single intravenous dose of 500 mg administered over 60 minutes of drip time in healthy volunteers and 11.5±4.0 µg/ml for a dose of 750 mg administered over 90 minutes of drip time. levofloxacin oral solution and tablets were bioequivalent.
The pharmacokinetics of levofloxacin after single and multiple oral or injectable administrations showed a linear curve, which allowed predicting the pharmacokinetic changes. Steady state was reached after 48 hours when dosed once daily at 500 mg or 750 mg. The Mean±SD of plasma peak and trough concentrations after multiple doses were 5.7 ± 1.4 and 0.5 ± 0.2 µg/ml, respectively, for once-daily transoral dosing of 500 mg, while the Mean±SD of plasma peak and trough concentrations after multiple doses were 8.6 ± 1.9 and 1.1 ± 0.4 µg/ml, respectively, for once-daily transoral dosing of 750 mg. The Mean±SD of peak and trough plasma concentrations were 6.4 ± 0.8 and 0.6 ± 0.2 µg/ml, respectively, after multiple doses of 500 mg administered intravenously once daily, and 12.1 ± 4.1 and 1.3 ± 0.71 µg/ml, respectively, after multiple doses of 750 mg.
Oral administration of levofloxacin 500 mg at the same time as eating would delay the time to peak by approximately 1 hour and reduce peak concentrations by approximately 14% for tablets and 25% for oral solution. Therefore, the administration of levofloxacin tablets is not related to eating or not. However, it is recommended that levofloxacin oral solution should be taken 1 hour before or 2 hours after a meal. The time profile (AUC) of the change in plasma drug concentration following levofloxacin injectable administration is similar to that following oral administration of an equivalent dose (mg/mg) of tablets. Therefore, the two routes of administration, oral and injectable, are interchangeable.
Distribution
The mean volume of distribution for levofloxacin administered as a single or multiple doses of 500 mg or 750 mg is typically 74 to 112 L. This indicates that levofloxacin is widely distributed to various tissues in the body. Peak drug concentrations in the skin and body fluids of healthy subjects are reached approximately 3 hours after dosing.
After multiple doses of 750 mg and 500 mg administered orally once daily to healthy subjects, the ratio of skin to plasma AUC was approximately 2 and the ratio of body fluid to plasma AUC was approximately 1. Levofloxacin also has good permeability to lung tissue. When administered orally in a single dose of 500 mg, the drug concentration in the lungs after 24 hours is usually 2 to 5 times higher than the plasma concentration, with a concentration range of approximately 2.4 to 11.3 µg/g.
In isolated cases, approximately 24 to 38% of levofloxacin was measured to be bound to serum proteins in the clinically appropriate serum/plasma concentration range of levofloxacin (1 to to 10 µg/ml) in the various animals studied by applying equilibrium dialysis. In humans, levofloxacin binds primarily to serum albumin. The binding of levofloxacin to serum proteins is independent of the drug concentration.
Metabolism
Levofloxacin is stereochemically stable in plasma and urine and is not metabolized to its rotameric isomer, D-oxofloxacin. The human metabolism of levofloxacin is very low and it is excreted mainly in its original form in the urine. After oral administration, approximately 87% of the drug is excreted in the urine in its original form within 48 hours, and less than 4% is excreted in the feces within 72 hours. Less than 5% of the drug is excreted in the urine as a demethylated metabolite and as an N-oxidized metabolite, the only two metabolites found in humans. The pharmacological activity of these two metabolites is very weak.
Excretion
Levofloxacin is excreted in the urine mainly in its original form. The mean terminal plasma clearance half-life after single or multiple oral or intravenous doses is approximately 6 to 8 hours. The mean apparent clearance and renal clearance are approximately 144 to 226 ml/min and 96 to 142 ml/min, respectively.
The renal clearance exceeded the glomerular filtration rate indicating that levofloxacin is not only filtered through the glomerulus but also secreted through the renal tubules. Concomitant administration of cimetidine or probenecid reduced the renal clearance of levofloxacin by approximately 24% and 35%, respectively, suggesting that levofloxacin secretion occurs primarily in the proximal tubule of the kidney. No levofloxacin crystals were found in any of the fresh urine samples collected from subjects using levofloxacin.
Older subjects
There were no significant differences in the pharmacokinetics of levofloxacin between young and elderly subjects when differences in creatinine clearance of the subjects were considered. The mean terminal plasma clearance half-life of levofloxacin administered orally at a dose of 500 mg to healthy elderly subjects (aged 66 to 80 years) was approximately 7.6 hours compared to approximately 6 hours in young adults. The reason for this difference is the different renal functional status of the subjects and is not considered clinically significant. Age also has no effect on the absorption of the drug. Therefore there is no need to adjust the dose of levofloxacin based on age alone.
Children
The pharmacokinetics of a single intravenous dose of 7 mg/kg of levofloxacin given to children aged 6 months to 16 years were studied. Levofloxacin was cleared more rapidly in pediatric patients than in adults. This resulted in lower plasma exposure than in adults at corresponding doses. 8 mg/kg administered every 12 hours (no more than 250 mg per dose) fully achieved steady-state plasma exposure (AUC0-24 and Cmax) in pediatric patients 6 months to 17 years of age, whereas adults required 500 mg every 24 hours to achieve steady-state plasma exposure.
Gender
There were no significant differences in the pharmacokinetics of levofloxacin between male and female subjects when differences in creatinine clearance of the subjects were considered. The mean terminal plasma clearance half-life of oral levofloxacin at a dose of 500 mg was approximately 7.5 hours in healthy male subjects compared to approximately 6.1 hours in females. The reason for this difference was the different renal functional status of male and female subjects, which was not considered clinically significant. The gender of the subject has no effect on the absorption of the drug. There is no need to adjust the dose of levofloxacin based on gender alone.
Race
Data from 72 subjects, including 48 Caucasians and 24 non-Caucasians, were analyzed by analysis of covariance to investigate the effect of race on levofloxacin pharmacokinetics. Subjects’ race had no effect on apparent clearance or apparent volume of distribution.
Renal impairment
In patients with renal impairment (creatinine clearance <50 ml/min) levofloxacin clearance was significantly reduced and plasma clearance half-life was significantly prolonged, thus requiring dose adjustment in these patients to avoid drug accumulation.
Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) is effective in removing levofloxacin from the body, indicating that neither hemodialysis nor CAPD requires supplemental levofloxacin.
Hepatic impairment
Pharmacokinetics in patients with hepatic impairment have not been studied. Because levofloxacin is metabolized in small amounts, hepatic impairment may not affect the pharmacokinetics of levofloxacin.
Bacterial Infections
The pharmacokinetic profile of levofloxacin in patients with severe community-acquired bacterial infections was similar to that of healthy subjects.
Drug Interactions
Interactions between levofloxacin and the pharmacokinetics of theophylline, warfarin, cyclosporine, digoxin, probenecid, cimetidine, aluminum thioglycollate, and antacids have been studied (see Drug Interactions).
Storage
Store under shade and seal.
Packaging
Packed in aluminum-plastic blister (PVC solid pharmaceutical hard tablets and pharmaceutical aluminum foil).
Package specification: 4 tablets/plate×1 plate/box; 4 tablets/plate×2 plate/box; 6 tablets/plate×1 plate/box; 6 tablets/plate×2 plate/box; 7 tablets/plate×1 plate/box; 7 tablets/plate×2 plate/box; 8 tablets/plate×1 plate/box; 8 tablets/plate×2 plate/box; 10 tablets/plate×1 plate/box; 10 tablets/plate×2 plate/box.
[Expiration date
24 months
【Execution standard
【Approval number】
【Drug marketing license holder
Name
Name: Zhejiang Sapience Pharmaceutical Co.
Registered Address: No. 1588 Xinming Road, Economic Development Zone, Pinghu City, Zhejiang Province
Manufacturer
Company Name: Zhejiang Sapience Pharmaceutical Co.
Production Address: No. 1588 Xinming Road, Economic Development Zone, Pinghu City, Zhejiang Province
Postal code: 314200
Telephone number: 0573-85035601
Fax number: 0573-85035602
Web
Address: http://www.zjspas.com
 If you have questions, you can contact directly with the drug marketing license holder and/or manufacturer.