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Levofloxacin Hydrochloride Injection 5ml: 0.5g

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Levofloxacin Hydrochloride Injection 5ml: 0.5g

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Levofloxacin Hydrochloride Injection 5ml: 0.5g

[Drug Name] Generic Name: Levofloxacin Hydrochloride Injection
English name:Levofloxacin Hydrochloride Injection
Chinese Pinyin:Yansuan Zuoyangfushaxing Zhusheye
【specification】 (1)5mL:0.5g(Calculated as levofloxacin) (2)5mL:0.3g(Calculated as levofloxacin)
[Indications] In order to reduce the production of drug-resistant bacteria and ensure the effectiveness of levofloxacin hydrochloride and other antibacterial drugs, levofloxacin is only used to treat or prevent infections that have been or are highly suspected to be caused by sensitive bacteria. When selecting or modifying antimicrobial treatment regimens, the results of bacterial culture and drug susceptibility testing should be considered. If data from these trials are not available for reference, empirical treatment should be conducted based on local epidemiology and pathogen sensitivity.
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Levofloxacin Hydrochloride Injection 5ml: 0.5g
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Levofloxacin Hydrochloride Injection 5ml: 0.5g

Approval date: September 22, 2008

Modified: December 25, 2008

November 17, 2014

     July 29, 2015

     August 19, 2015

     October 09, 2015

     March 09, 2016

     August 29, 2017

Levofloxacin Hydrochloride Injection Instructions

Please read the instructions carefully and use under the guidance of a physician

caveat:

Fluoroquinolones are prone to serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathy, the effects of the central nervous system, and increased myasthenia gravis.

The use of fluoroquinolones (including levofloxacin hydrochloride injection) has been reported to cause disability and potentially irreversible serious adverse reactions (see [Notes]), including: tendonitis and tendon rupture, peripheral neuropathy, central Nervous system effects. When these serious adverse reactions occur, levofloxacin hydrochloride injection should be stopped immediately and fluoroquinolones should be avoided.

Fluoroquinolones may exacerbate muscle weakness in patients with myasthenia gravis. Patients with a known history of myasthenia gravis should avoid using levofloxacin hydrochloride injection (see [Precautions]).

As serious adverse reactions have been reported with fluoroquinolones (including levofloxacin hydrochloride injection) (see [Cautions]), patients with the following indications should be treated with levofloxacin hydrochloride without other drugs. : Acute bacterial sinusitis, acute exacerbation of chronic bronchitis, simple urinary tract infection.

In all age groups, fluoroquinolones, including levofloxacin hydrochloride, can increase the risk of tendinitis and tendon rupture. This risk is further increased in elderly patients typically over 60 years of age, patients receiving glucocorticoid therapy, and patients receiving kidney, heart or lung transplants.

Drug Name

Common name: Levofloxacin Hydrochloride Injection

English name: Levofloxacin Hydrochloride Injection

Chinese Pinyin: Yansuan Zuoyangfushaxing Zhusheye

[Ingredients]

The main ingredient of this product is levofloxacin hydrochloride. Its chemical name is: (-)-(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 hydrochloride monohydrate.

Its chemical structural formula is:

威智医药

 

 

 

 


Molecular formula: C18H20FN3O4 HCl H2O

Molecular weight: 415.85

The auxiliary materials of this product are: water for injection.

[Character] This product is a pale yellow-green or yellow-green clear liquid.

[Indications] In order to reduce the production of drug-resistant bacteria and ensure the effectiveness of levofloxacin hydrochloride and other antibacterial drugs, levofloxacin is only used to treat or prevent infections that have been proven or highly suspected to be caused by sensitive bacteria. The results of bacterial cultures and drug sensitivity tests should be considered when selecting or modifying antimicrobial treatment options. If data from these trials are not available for reference, empirical treatment should be based on local epidemiology and pathogen sensitivity.

Before treatment, bacterial culture and drug sensitivity tests should be performed to isolate and identify infectious pathogens and determine their sensitivity to levofloxacin hydrochloride. Before obtaining the above test results, you can use levofloxacin for treatment, and then select the appropriate treatment method after obtaining the test results.

As with other drugs in this class, certain strains of P. aeruginosa can quickly develop resistance when treated with levofloxacin hydrochloride. During the treatment period, bacterial culture and drug sensitivity tests should be carried out regularly to grasp whether the pathogenic bacteria are continuously sensitive to antibacterial drugs and can be detected in time after the bacteria have developed drug resistance.

Levofloxacin hydrochloride injection can be used to treat the following mild, moderate and severe infections in adults (≥ 18 years) caused by the following sensitive strains of bacteria. If intravenous drip is more beneficial to the patient (such as the patient cannot tolerate oral administration, etc.), levofloxacin hydrochloride injection can be used.

Hospital acquired pneumonia

Treatment of hospital-acquired cases caused by methicillin-sensitive Staphylococcus aureus, Pseudomonas aeruginosa, Serratia marcescens, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae, or Streptococcus pneumoniae pneumonia. At the same time, other auxiliary treatment measures should be taken according to clinical needs. If a P. aeruginosa infection has been proven or suspected, a combination of anti-Pseudomonas beta-lactams is recommended for treatment.

2. community acquired pneumonia

7-14 days treatment plan: treatment of methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae [including multi-drug resistant strains (MDRSP *)], Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae Community-acquired pneumonia caused by white bacilli, Moraxella catarrhalis, Chlamydia pneumoniae, Legionella pneumoniae, or Mycoplasma pneumoniae.

Note: MDRSP (Multidrug-resistant Streptococcus pneumoniae) refers to strains resistant to the following two or more antimicrobials: penicillin (MIC≥ 2µg / mL), second-generation cephalosporins (such as cefuroxime), macrocyclic Lactones, tetracyclines and trimethoprim / sulfamethoxazole.

5-day treatment plan: Treat community-acquired pneumonia caused by Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydia pneumoniae.

3. Acute bacterial sinusitis

5-day treatment plan: treat acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.

10-14 days treatment plan: treat acute bacterial sinusitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.

Serious adverse reactions have been reported with the use of fluoroquinolones (including levofloxacin hydrochloride injection), and for some patients, acute bacterial sinusitis is self-limiting, and levofloxacin hydrochloride injection should be used without other medications .

4. Acute bacterial attack of chronic bronchitis

Treats acute bacterial episodes of chronic bronchitis caused by methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Haemophilus parainfluenzae, or Moraxella.

As serious adverse reactions have been reported with the use of fluoroquinolones (including levofloxacin hydrochloride injection), and for some patients, the acute bacterial episodes of chronic bronchitis are self-limiting, and hydrochloric acid should be used only when no other medication is available Levofloxacin injection.

5. Complex skin and skin structure infections

Treats complex skin and skin structure infections caused by methicillin-sensitive Staphylococcus aureus, Enterococcus faecalis, Streptococcus pyogenes, or Proteus mirabilis.

6. Non-complex skin and skin soft tissue infections

Treatment of non-complex skin and skin structure infections (mild to moderate) caused by methicillin-sensitive Staphylococcus aureus or Streptococcus pyogenes, including abscesses, cellulitis, scabies, pustular disease, and pyoderma ,Wound infection.

7. Chronic bacterial prostatitis

Treats chronic bacterial prostatitis caused by Escherichia coli, Enterococcus faecalis, or methicillin-sensitive Staphylococcus epidermidis.

8. Complex urinary tract infection

5-day treatment plan: Treat complicated urinary tract infections caused by Escherichia coli, Klebsiella pneumoniae or Proteus mirabilis.

10-day treatment plan: treat complicated urinary tract infections (mild to moderate) caused by Enterococcus faecalis, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, or Pseudomonas aeruginosa.

9. Acute pyelonephritis

5-day treatment plan: treatment of acute pyelonephritis caused by Escherichia coli, including the name of comorbid bacteremia.

10-day treatment plan: treat acute pyelonephritis caused by Escherichia coli, including the name of comorbid bacteremia.

10. Non-complex urinary tract infections:

Treats non-complex urinary tract infections (mild to moderate) caused by Escherichia coli, Klebsiella pneumoniae, or Staphylococcus saprophytic.

Since serious adverse reactions have been reported with fluoroquinolones (including levofloxacin hydrochloride injection), and for some patients, the onset of simple urinary tract infections is self-limiting, and levofloxacin hydrochloride injection should be used without other medications liquid.

11. Inhaled anthrax (after exposure)

It is suitable for the treatment of inhaled anthrax (post-exposure), reducing the incidence of disease or slowing the progress of the disease after exposure to anthrax spray. The effectiveness of levofloxacin is based on the surrogate endpoint of human plasma concentration to predict clinical efficacy.

The preventive effect of levofloxacin on anthrax after inhalation exposure has not been tested in humans. The safety of levofloxacin over 28 days in adults has not been studied. Long-term treatment with levofloxacin can only be used when the benefits outweigh the risks.

[Specifications] (1) 5mL: 0.5g (as levofloxacin) (2) 5mL: 0.3g (as levofloxacin)

[Usage and dosage] Levofloxacin hydrochloride injection is used for the treatment of the above infectious diseases (see the indications for details). The general usage and dosage are shown below, but it must be determined by the clinician based on the severity of the disease.

1. Dosage and method of administration

(1) Dose in patients with normal renal function

The usual dose of levofloxacin hydrochloride injection is 250mg or 500mg, slow infusion, instillation time is not less than 60 minutes, intravenous infusion every 24 hours; or 750mg, slow infusion, time is not less than 90 minutes, intravenous infusion every 24 hours once. Use according to Table 1 according to the infection situation.

No dosage adjustment is required when creatinine clearance is ≥ 50mL / min. When creatinine clearance is <50mL / min, the dosage needs to be adjusted.

Table 1: Dose in patients with normal renal function (creatinine clearance ≥50mL / min)

Infection type 1 Dose every 24 hours Course (days) 2

Hospital pneumonia 750mg 7 14

Community-acquired pneumonia 3 500mg 7 14

Community acquired pneumonia 4 750mg 5

Acute bacterial sinusitis 750mg 5

500mg 10 14

Acute bacterial exacerbation of chronic bronchitis 500mg 7

Complex skin and skin soft tissue infections (cSSSI) 750mg 7 14

Non-complicated skin and skin soft tissue infections (uSSSI) 500mg 7-10

Chronic bacterial prostatitis 500mg 28

Complex urinary tract infection (cUTI) or acute pyelonephritis (AP) 5 750mg 5

Complex urinary tract infection (cUTI) or acute pyelonephritis (AP) 6 250mg 10

Noncomplicated urinary tract infection 250mg 3

Inhaled anthracnose (after exposure), adult and pediatric patients> 50kg and ≥6 months 7,8 paediatric patients <50kg and ≥6 months 7,8 500mg

See the table below (Table 2) 608

608

Note: caused by a specific pathogen (see indications).

Physicians can use continuous treatment according to their own judgment.

Methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae [including multi-drug resistant strains (MDRSP)], Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella mucosa, Caused by Chlamydia pneumoniae, Legionella pneumophila or Mycoplasma pneumoniae (see indications).

Caused by Streptococcus pneumoniae [including multidrug-resistant strains (MDRSP)], Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydia pneumoniae (see indications).

This solution is applicable to cUTI caused by E. coli, Klebsiella pneumoniae, Proteus mirabilis, and acute pancreatitis caused by E. coli, including the names of patients with concomitant bacteremia.

This solution applies to cUTI caused by Enterococcus faecalis, Enterococcus cloacae, E. coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and acute pancreatitis caused by E. coli.

Drugs should be administered as soon as possible after a suspected or well-defined B. anthracis spray exposure. This indication is based on surrogate endpoints. Levofloxacin plasma concentrations achieved in humans may predict clinical efficacy.

The safety of levofloxacin hydrochloride in adults over 28 days and pediatric patients over 14 days 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 hydrochloride is only possible when the benefits outweigh the risks.

(2) Dose in pediatric patients (<18 years)

The doses for pediatric patients (≥6 months) are described in the table below (Table 2).

Table 2: Dose for pediatric patients (≥6 months)

Infection Type 1 Dose Frequency of each course of treatment 2

Inhaled anthrax (after exposure) 3,4

Pediatric patients> 50kg and ≥6 months 500mg 24 hours 60 days 4

Pediatric patients <50kg and ≥6 months 8mg / kg (each dose does not exceed 250mg) 12 hours 60 days 4

Note: caused by Bacillus anthracis (see indications).

Physicians can use continuous treatment according to their own judgment.

The drug should be administered as soon as possible after the suspected or clear anthrax spray exposure. This indication is based on surrogate endpoints. Plasma concentrations of levofloxacin hydrochloride achieved in humans may predict clinical efficacy.

The safety of levofloxacin hydrochloride in pediatric patients for more than 14 days 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 treatment should only be used when the benefits outweigh the risks.

(3) Dose adjustment in patients with renal insufficiency

If renal insufficiency is present, levofloxacin hydrochloride should be used with caution. Because the clearance of levofloxacin hydrochloride may decrease, careful clinical observation and appropriate laboratory research should be performed before and during treatment.

No dose adjustment is necessary for patients with creatinine clearance ≥50mL / min.

In patients with renal insufficiency (creatinine clearance <50 mL / min), the dose should be adjusted to avoid accumulation of levofloxacin hydrochloride due to decreased creatinine clearance (see Use in Specific Populations).

The following table (Table 3) shows how to adjust the dose based on creatinine clearance.

Table 3: Dose adjustment in patients with renal insufficiency (creatinine clearance <50 mL / min)

Dose every 24 hours in patients with normal renal function Creatinine clearance

20 49mL / min creatinine clearance

10 to 19 mL / min hemodialysis or continuous ambulatory peritoneal dialysis (CAPD)

750mg 750mg every 48 hours 750mg for the first dose, 500mg every 48 hours thereafter 750mg for the first dose, 500mg every 48 hours thereafter

500mg 500mg first dose, 250mg every 24 hours thereafter 500mg for the first time, 250mg every 48 hours thereafter 500mg for the first time, 250mg every 48 hours

250mg No dosage adjustment 250mg every 48 hours. No dose adjustment required for simple UTI treatment

(4) Dosing instructions

This product It is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Drug interactions with chelating agents: antacids, sucralfate, metal cations, multivitamins

Levofloxacin injection cannot be administered simultaneously with any solution containing polyvalent cations (such as magnesium ions) through the same intravenous route.

Levofloxacin injection

Caution: Levofloxacin injections iv administered quickly or intravenously may cause hypotension and should be avoided. Levofloxacin injections should be dose-dependent and slowly administered intravenously over a period of not less than 60 or 90 minutes. Levofloxacin injection can only be administered by intravenous drip, not for intramuscular, intrathecal, intraperitoneal or subcutaneous administration.

Water intake in patients receiving levofloxacin injection

Patients who receive IV injections should be hydrated enough to prevent excessive drug concentrations in the urine. There have been reports of casturia caused by quinolones.

2. Preparation of intravenous drip drugs

For non-oral pharmaceutical preparations, as long as the solution and container allow, visual inspection for particulate matter and discoloration should be performed before administration.

Since only limited information is available on the compatibility of levofloxacin hydrochloride injection and other intravenous medications, additives or other things must not be added to premixed levofloxacin hydrochloride injection in disposable flexible containers, levofloxacin hydrochloride injection in disposable vials Drugs, or infusions from the same venous access. If several different drugs are continuously infused using the same venous route, lavofloxacin hydrochloride injection and other drugs infused through the same route should be used before and after levofloxacin hydrochloride injection.

Levofloxacin hydrochloride injection (small needle) must be further diluted with an appropriate solution before intravenous infusion. Compatible intravenous solutions are shown in Table 4. The final dilution concentration of the solution before use should be 5 mg / mL.

Compatible intravenous solution: A 5 mg / mL levofloxacin hydrochloride solution of appropriate pH can be prepared with any of the following intravenous solutions.

Table 4: Compatible intravenous solutions

Liquid for intravenous drip

0.9% sodium chloride injection

5% glucose injection

Because the Pharmaceuticals does not contain preservatives or bacteriostatic agents, sterile techniques should be used when preparing intravenous solutions.

You should carefully observe the solution for particulate impurities before use. Pharmaceuticalss containing visible particles should be discarded.

Stability of levofloxacin hydrochloride injection after dilution: Levofloxacin hydrochloride injection is diluted to a concentration of 5mg / mL with a compatible intravenous injection solution, and can be stored at 25 ° C (77 ° F) or below 25 ° C In a 5 ° C (41 ° F) refrigerator, it can be stored in a plastic container for intravenous drip for 14 days. The solution diluted with a compatible intravenous solution is frozen in a glass bottle or a plastic container for intravenous drip, stored at -20 ° C (-4 ° F), and can be stable for 6 months. Thaw frozen solutions at 25 ° C (77 ° F) at room temperature or in an 8 ° C (46 ° F) refrigerator. Do not use a microwave or water bath to accelerate its dissolution. Do not freeze or thaw repeatedly after thawing once.

Instructions for use of injection: Before use, check the container for slight leaks. If there is a leak or the seal is incomplete, the solution should be discarded, as the solution may no longer be sterile. It should not be used if the solution is cloudy or precipitated. Use sterile equipment.

Caution: Do not chain containers together. This may cause air embolism due to the suction of residual air in the primary container before the liquid in the secondary container is completely dispensed.

Adverse reactions

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

1. Serious and other important adverse reactions

The following serious and other important adverse reactions have been detailed in [Precautions]: disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathy, effects of the central nervous system, and myasthenia Deterioration of weakness, allergic reactions, other severe and sometimes fatal reactions, liver toxicity, Clostridium difficile-associated diarrhea, prolonged QT interval, musculoskeletal diseases in pediatric patients, interference with blood glucose, light sensitivity / phototoxicity and tolerance Drug bacteria are produced.

The above adverse reactions are described in detail under [Precautions].

Cardiovascular system: prolonged QT interval, apical torsional ventricular tachycardia, ventricular arrhythmia.

Central nervous system: convulsions, toxic psychosis, tremor, restlessness, anxiety, dizziness, confusion, hallucinations, delusions, depression, nightmares, insomnia, seizures, and rare cases can cause suicidal thoughts or actions in patients.

Peripheral neuropathy: sensory confusion, dullness, touching pain, pain, burning, tingling, numbness, weakness, or abnormalities of lightness, pain, temperature, position and vibration, and polyneuritis.

Skeletal muscle system: joint pain, myalgia, muscle weakness, hypertonic tendonitis, tendon rupture, and myasthenia gravis worsen.

Hypersensitivity: urticaria, pruritus and other severe skin reactions (such as toxic epidermal necrolysis, erythema polymorphism), dyspnea, angioedema (including edema / swelling of the tongue, throat, pharynx, or facial), Cardiovascular prolapse, hypotension, loss of consciousness, airway obstruction (including bronchospasm, shortness of breath, and acute respiratory distress), allergic pneumonia, and anaphylactic shock.

Hepatobiliary system: hepatitis, jaundice, acute liver necrosis or liver failure.

Urinary system: Acute renal insufficiency or renal failure.

Blood system: Anemia, including hemolytic anemia and aplastic anemia, thrombocytopenia, including thrombotic thrombocytopenic purpura, leukocytopenia, granulocytopenia, pancytopenia, and / or other blood disorders.

Others: fever, vasculitis, serum disease, Clostridium difficile-associated diarrhea, blood sugar disorders, light sensitivity / phototoxicity.

Rapid intravenous infusion or bolus of levofloxacin may cause hypotension. According to the dose, intravenous drip is not less than 60 to 90 minutes.

The use of quinolone drugs, including levofloxacin, has been reported to cause crystalline urine and cast urine. Therefore, for patients receiving levofloxacin treatment, proper hydration should be maintained to prevent the formation of highly concentrated urine.

2. Clinical trial experience

Because clinical trials are completed under different conditions, the adverse reaction rates of one drug observed in clinical trials cannot be directly compared with the adverse reaction rates of other drugs in clinical trials, and may not reflect the adverse reactions in practical applications. rate.

The data described below reflect the combined exposure of levofloxacin to 7,537 patients in 29 phase III clinical trials. The average age of the study population was 50 years (about 74% of the population was <65 years), 50% of whom were male, 71% were white, and 17% were black. The patient was 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. The course of treatment is usually 3 to 14 days, with an average course of 10 days.

The overall incidence, type, and distribution of adverse reactions were similar in patients using levofloxacin 750 mg once daily, 250 mg once daily, or 500 mg once or twice daily. A total of 4.3% of patients discontinued levofloxacin due to adverse drug reactions. Among patients receiving daily doses of 250mg and 500mg, this ratio was 3.8%; among patients receiving daily doses of 750mg, this ratio was 5.4%. . The most common adverse drug reactions that led to discontinuation in patients receiving daily doses of 250 mg and 500 mg were gastrointestinal reactions (1.4%), mainly nausea (0.6%), vomiting (0.4%), dizziness (0.3%) , And headache (0.2%). The most common adverse drug reactions that led to discontinuation in patients receiving a daily dose of 750 mg were gastrointestinal reactions (1.2%), mainly nausea (0.6%) and vomiting (0.5%), dizziness (0.3%), and Headache (0.3%).

The following table (Table 5 and Table 6) lists the adverse reactions that occurred in ≥1% of patients receiving levofloxacin and the adverse reactions that occurred in 0.1 to <1% of patients receiving levofloxacin. The most common adverse reactions (≥3%) were nausea, headache, diarrhea, insomnia, constipation, and dizziness.

Table 5: Common (≥1%) adverse reactions reported in levofloxacin clinical trials

System / organ classification Adverse reactions% (N = 7537)

Infections and infectious diseases Candidiasis 1

Insomnia 4 a

Various neurological diseases headache 6

Dizziness 3

Respiratory, chest and mediastinal disorders Dyspnea 1

Gastrointestinal disorders nausea 7

Diarrhea 5

Constipation 3

Abdominal pain 2

Vomiting 2

Indigestion 2

Skin and subcutaneous diseases

Itching 2

1

Reproductive system and breast diseases Vaginitis 1b

Systemic diseases and various reactions at the site of administration

Various reactions at the injection site

Chest pain 1

1

1

Note: a. N = 7274; b. N = 3758 (female).

Table 6: Less common (0.1 to 1%) adverse reactions reported in clinical trials of levofloxacin (N = 7537)

System / organ classification

Infection and Infection Genital Candidiasis

Diseases of the blood and lymphatic system Anemia, thrombocytopenia, granulocytopenia

Diseases of the immune system

Metabolic and nutritional diseases Hyperglycemia, hypoglycemia, hyperkalemia

Anxiety, agitation, confusion, depression, hallucinations, nightmares, sleep disordersa, anorexia

Various neurological disorders Shivering, convulsions, disturbed feelings, dizziness, high tension, excessive exercise, gait

Abnormal, lethargy, syncope

Respiratory, chest and mediastinal diseases

Cardiac organ disease Cardiac arrest, palpitations, ventricular tachycardia, ventricular arrhythmia

Vascular disease phlebitis

Gastrointestinal diseases gastritis, stomatitis, pancreatitis, esophagitis, gastroenteritis, glossitis, pseudomembranous / difficile Clostridium colitis

Hepatobiliary system disorders: abnormal liver function, increased liver enzymes, increased alkaline phosphatase

Diseases of the skin and soft tissues of the skin

Various musculoskeletal and connective tissue disorders arthralgia, tendonitis, myalgia, bone pain

Kidney and urinary system disorders Renal dysfunction, acute renal failure

Note: a. N = 7274

In clinical trials using multiple-dose treatments, ophthalmic abnormalities, including cataracts and lenticular plaques, were noted in patients receiving quinolone antibiotics, including levofloxacin. No link between the drug and these events has been established.

3. Post-market monitoring

The following table (Table 7) lists the adverse reactions identified in use after levofloxacin was approved for marketing. Because these reactions are reported spontaneously from an uncertain number of people, it is sometimes not possible to reliably assess the incidence of these events or to establish a causal relationship between drug exposure and these events.

Table 7: Report of adverse drug reactions after marketing

System / organ classification

Hematological and Lymphatic System Diseases Hemocytopenia, Aplastic Anemia, Leukopenia, Hemolytic Anemia, Eosinophilia

Diseases of the immune system Allergic reactions, sometimes fatal, including: allergic / anaphylaxis, anaphylactic shock, angioedema, serum disease

Psychiatric psychiatry, paranoia, individual reported suicide attempts, and suicidal thoughts

Various neurological diseases Deterioration of myasthenia gravis, loss of smell, loss of taste, abnormal smell, taste disorder, peripheral neuropathy, individually reported encephalopathy, abnormal electroencephalogram (EEG), difficulty speaking

Diseases of the eye organs Visual disorders, including diplopia, reduced visual acuity, blurred vision, dark spots

Ear and labyrinth disorders Hearing loss, tinnitus

Cardiac organ diseases Individually reported apical torsional ventricular tachycardia, ECG QT interval prolongation, tachycardia

Vascular disease vasodilation

Respiratory, chest and mediastinal diseases Individually reported allergic pneumonia

Hepatobiliary system diseases Liver failure (including fatal disease name), hepatitis, jaundice

Skin and skin and soft tissue disorders Bullous rash, including: Stevens-Johnson syndrome, toxic epidermal necrosis, erythema polymorphism, photosensitivity / phototoxic reaction, leukocyte rupture vasculitis

Various musculoskeletal and connective tissue disorders Tendon rupture, muscle damage, including rupture, rhabdomyolysis

Kidney and urinary system diseases interstitial nephritis

Systemic diseases and site of administration Multiple organ failure, fever

Various tests prolonged prothrombin time and increased muscle enzymes

[Contraindications] Those who are allergic to quinolone drugs, pregnant and lactating women, and patients under 18 years of age are contraindicated.

Precautions

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

1. Disabling and potentially irreversible serious adverse reactions, including tendinitis and tendon rupture, peripheral neuropathy, central nervous system effects

The use of fluoroquinolones has been reported to cause disability and potentially irreversible serious adverse reactions in different organ systems of the same patient, usually including: tendonitis, tendon rupture, joint pain, myalgia, muscle weakness, surrounding Neuropathy and central nervous system reactions (hallucinations, anxiety, depression, insomnia, severe headaches and disorders). These adverse reactions can occur from hours to weeks after using levofloxacin hydrochloride injection. These adverse reactions have been reported in patients of any age without previous risk factors.

2. Tendon disease and tendon rupture

Fluoroquinolones increase the risk of tendinitis and tendon rupture in patients of all ages. This adverse reaction most often occurs in the Achilles tendon, which may require surgical repair. Tendonitis and tendon rupture have also been reported in the shoulders, hands, biceps, thumb and other tendon points. Tendonitis and tendon rupture can occur hours or days after the start of levofloxacin hydrochloride injection, or months after the end of treatment. Tendonitis and tendon rupture can occur on both sides. This risk is further increased in elderly patients over the age of 60, patients taking corticosteroids, and patients undergoing kidney, heart or lung transplants. In addition to factors such as age and corticosteroid use, factors that can independently increase the risk of tendon rupture include strenuous physical activity, renal failure, and previous tendon diseases such as rheumatoid arthritis. Tendonitis and tendon rupture also occur in patients who use fluoroquinolones without these risk factors. Tendon rupture can occur during or after treatment; there are also reports of tendon rupture months after treatment has ended. After patients with tendon pain, swelling, inflammation or rupture, the use of this product should be stopped. After showing signs of tendinitis or tendon rupture, the patient should be advised to rest and contact a doctor to switch to non-quinolones. Patients with a history of tendon disease or having tendinitis and tendon rupture should avoid using fluoroquinolones.

3. Myasthenia gravis worsens

Fluoroquinolones have neuromuscular blocking activity and may exacerbate muscle weakness symptoms in patients with myasthenia gravis. Post-marketing serious adverse events, including death and need for ventilation support, and the use of fluoroquinolones in patients with myasthenia gravis. Patients with myasthenia gravis should avoid using levofloxacin hydrochloride injection.

4.QT interval extended

Certain fluoroquinolones can prolong the QT interval of the electrocardiogram, and a few patients can develop arrhythmia. It is rare to report spontaneous VT in patients receiving fluoroquinolones during postmarketing surveillance. Patients with known QT interval extension, patients with uncorrected hypokalemia, and patients using class IA (quinidine, procainamide) and class III (amiodarone, sotalol) antiarrhythmic drugs Levofloxacin hydrochloride injection should be avoided. Elderly patients are more susceptible to drug-related QT intervals.

5. Allergic reactions

With fluoroquinolones, severe allergic reactions have been reported. Some patients develop after the first dose, and some reactions may be accompanied by cardiovascular failure, loss of consciousness, stinging, swelling of the throat or face, dyspnea, urticaria, pruritus, etc. Severe allergic reactions require urgent treatment with adrenaline. Levofloxacin hydrochloride injection should be discontinued at the first appearance of a rash or any other sign of allergy. If necessary, oxygen can be administered, intravenous steroids, airway management, including intubation and other measures.

6. Other serious and potentially fatal reactions

Other serious and potentially fatal incidents have been reported with the use of fluoroquinolones. Some of these events were due to allergies, and some were unknown. These events can be severe and usually occur after multiple doses. Clinical manifestations may include one or more of the following symptoms: fever, rash, severe skin reactions (eg, toxic epidermal necrolysis, Stevens-Johnson syndrome); vasculitis; joint pain; myalgia; serum disease; Allergic pneumonia; interstitial nephritis; acute renal insufficiency or renal failure; hepatitis, jaundice, acute liver necrosis or liver failure; anemia, including hemolytic anemia and aplastic anemia; thrombocytopenia, including thrombotic thrombocytopenia Purpura; leukopenia; agranulocytosis; pancytopenia and / or other hematological abnormalities. The drug should be discontinued and action taken immediately upon the first appearance of a rash, jaundice, or any other allergic manifestation.

7. Central nervous system effects

The use of fluoroquinolones, including levofloxacin hydrochloride injections, has been reported to increase the risk of adverse reactions in the central nervous system, including convulsions and increased intracranial pressure (including pseudo brain tumors), as well as psychosis caused by poisoning. Use of fluoroquinolones may cause central nervous system reactions including anxiety, agitation, insomnia, anxiety, nightmares, paranoia, dizziness, confusion, tremors, hallucinations, depression, and suicidal thoughts or behaviors. These reactions may occur after the first dose. If these reactions occur when the patient is using levofloxacin hydrochloride injection, stop the administration and take appropriate measures. As with all fluoroquinolones, patients with known or suspected central nervous system disease (such as severe cerebral arteriosclerosis, epilepsy) or patients with other risk factors (such as seizure tendency or reduced seizure threshold) should The benefits outweigh the risks when using levofloxacin hydrochloride injection.

8. Peripheral neuropathy

Patients have been reported to use fluoroquinolones to produce rare sensory or sensorimotor axonal neuropathies that affect small and / or large axons, causing abnormal skin sensation, dullness, pain and weakness. In some patients, symptoms may occur soon after levofloxacin hydrochloride injection and may be irreversible. If the patient develops symptoms of peripheral neuropathy, including pain, burning, tingling, numbness and / or weakness, or other sensations, including changes in touch, pain, temperature, position, and vibration, the drug should be discontinued immediately. Patients with a history of peripheral neuropathy should avoid the use of fluoroquinolones.

9. Clostridium difficile-associated diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported in almost all antibacterials, including levofloxacin hydrochloride injection, with severity ranging from mild diarrhea to severe colitis. Antimicrobial treatment alters the normal flora of the colon, which leads to excessive growth of Clostridium difficile.

Toxins A and B produced by C. difficile are responsible for C. difficile-associated diarrhea. Highly toxic Clostridium causes increased morbidity and mortality, antibacterial treatments for these infections are ineffective, and colectomy may be required. After receiving antibiotic treatment, the possibility of CDAD should be considered in the occurrence of diarrhea. Because CDAD can occur two months after treatment with antimicrobials, a careful medical history is necessary.

If C. difficile-associated diarrhea is suspected or confirmed, antibiotics not currently used against C. difficile may need to be discontinued. Fluids and electrolytes should be supplemented appropriately, protein should be supplemented, antibiotic therapy against C. difficile should be used, and surgical evaluation should be performed when clinical indications appear.

10. Interference with blood sugar

Glucose disorders (such as symptomatic hyperglycemia and hypoglycemia) have been reported by fluoroquinolone antibiotics, and this often occurs in patients with diabetes taking oral hypoglycemic agents (such as hypoglycemic / glibenclamide) or using insulin . Therefore, for such patients, it is recommended that their blood glucose changes should be closely monitored. If the patient develops a hypoglycemic response when receiving levofloxacin hydrochloride injection, the drug should be discontinued immediately and appropriate treatment measures taken.

11. Light sensitivity / phototoxicity

Moderate to severe photosensitivity / phototoxic reactions occur when exposed to sunlight or ultraviolet radiation after using fluoroquinolone antibiotics, which may show excessive sunburn reactions (such as burning sensation, erythema, blisters, exudation, Edema), often in areas exposed to light (usually the "V" area of ​​the neck, the surface of the forearm extensor, the back of the hand). Therefore, excessive exposure to light sources should be avoided. The drug should be discontinued when a phototoxic reaction occurs.

12. Liver toxicity

Post-market reports of severe liver toxicity, including acute hepatitis and fatal events, have been received in patients receiving levofloxacin. No evidence of severe drug-related liver toxicity was found in clinical trials in more than 7,000 patients. Severe hepatotoxicity usually occurs within 14 days of starting treatment and, in most cases, within 6 days of starting treatment. Most severe hepatotoxic diseases are not associated with allergies. Most fatal hepatotoxicity reports are seen in patients ≥65 years of age, and most are not related to hypersensitivity. If patients have signs and symptoms of hepatitis, levofloxacin should be stopped immediately.

13. Musculoskeletal diseases in pediatric patients and joint disease effects in animals

In pediatric patients (≥ 6 months), levofloxacin is only suitable for protection against anthrax inhalation (after exposure). An increase in the incidence of musculoskeletal disorders (joint pain, arthritis, tendon disorders, and gait abnormalities) was observed in pediatric patients receiving levofloxacin compared to controls.

In young rats and dogs, oral and intravenous levofloxacin causes an increase in osteochondrosis. Histopathological examination of the load-bearing joints of juvenile dogs receiving levofloxacin revealed the presence of persistent cartilage damage. Other quinolone drugs can also produce similar erosions of load-bearing joints in juvenile animals of multiple species, as well as other signs of joint disease.

14. Production of drug-resistant bacteria

Prescribing levofloxacin without an undiagnosed or highly suspected bacterial infection and not meeting preventive indications will not benefit patients and increase the risk of developing resistant bacteria.

[Medication for pregnant and lactating women]

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Pregnancy

Pregnancy medication grade C. Levofloxacin has no teratogenic effect when the oral dose in rats is as high as 810 mg / kg / day, which is equivalent to 9.4 times the maximum recommended human dose when the relative body surface area is the same. Levofloxacin did not have teratogenic effects when the intravenous infusion dose was 160 mg / kg / day, which was equivalent to 1.9 times the maximum recommended human dose when the relative body surface area was the same. The oral dose of 810 mg / kg / day in rats can reduce fetal rat weight and increase mortality. When the rabbit oral dose reached 50 mg / kg / day, no teratogenic effect of levofloxacin was observed. This dose is equivalent to 1.1 times the maximum recommended human dose when the relative body surface area is the same. When the intravenous infusion dose was 25 mg / kg / day, levofloxacin had no teratogenic effect. This dose was equivalent to 0.5 times the maximum recommended human dose when the relative body surface area was the same.

However, sufficient well-controlled trials have not yet been conducted on pregnant women, and medication safety for pregnant women cannot be ensured. Therefore, women who are pregnant or are likely to become pregnant are contraindicated. Levofloxacin should be used in pregnant women only if the potential benefits to the fetus outweigh the potential risks.

 Lactating women

Based on limited data from other fluoroquinolones and levofloxacin, it is speculated that levofloxacin should be secreted into human breast milk. Levofloxacin may be severely contraindicated in breast-fed infants and is therefore contraindicated in lactating women. Levofloxacin should be used in lactating women only if the potential benefits outweigh the potential risks for lactating women, but breastfeeding should be suspended.

[Children's medication] This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Quinolone antibiotics, including levofloxacin, can cause joint disease and bone / chondropathy in larvae of certain species of animals. The safety of children has not been established and is contraindicated in patients younger than 18 years of age except for protection for anthrax inhalation (after exposure).

Inhaled anthrax (after exposure)

Levofloxacin is suitable for pediatric inhaled anthrax (after exposure). A risk-benefit assessment suggests that levofloxacin is appropriate in pediatric patients. The safety of levofloxacin treatment for more than 14 days has not been studied in pediatric patients. The pharmacokinetics of a single intravenous injection of levofloxacin was studied in pediatric patients aged 6 months to 16 years. In pediatric patients, levofloxacin is cleared faster than in adult patients, so the resulting plasma exposure levels are lower than in adults at specific mg / kg doses.

Adverse reactions

In clinical trials, 1,534 children (aged 6 months to 16 years) received oral and intravenous levofloxacin. Children aged 6 months to 5 years receive 10 mg / kg of levofloxacin twice daily, and children over 5 years of age receive 10 mg / kg of levofloxacin once daily (maximum dose is 500 mg daily) for a total duration of 10 days .

A subgroup of children in clinical trials (1340 received levofloxacin and 893 received non-fluoroquinolones) participated in a prospective long-term monitoring study to assess 60 days and 1 year of first study drug administration Later trials defined the incidence of musculoskeletal disorders (arthralgia, arthritis, tendon disorders, gait abnormalities). The incidence of musculoskeletal diseases in children treated with levofloxacin was significantly higher than in children treated with non-fluoroquinolones, as shown in the following table (Table 8).

Table 8: Rate of musculoskeletal diseases in pediatric clinical trials

Follow-up period Levofloxacin

N = 1340 non-fluoroquinolones

N = 893 p-value b

60 days 28 (2.1%) 8 (0.9%) p = 0.038

1 year c 46 (3.4%) 16 (1.8%) p = 0.025

Note: a. Non-fluoroquinolones: ceftriaxone, amoxicillin / clavulanic acid, clarithromycin

b. Two-sided Fisher ’s accuracy test

c. A 1-year evaluation visit was conducted on 1199 children treated with levofloxacin and 804 children treated with non-fluoroquinolones. However, the incidence of musculoskeletal disorders was calculated using all reported events for all participating children in the trial, regardless of whether they completed a 1-year evaluation visit.

Joint pain was the most common musculoskeletal disease in both treatment groups. In both groups, the vast majority of musculoskeletal disorders involve multiple load-bearing joints. The disease was moderate in 8/46 (17%) children treated with levofloxacin, mild in 35/46 (76%) children treated with levofloxacin, and most were treated with analgesics. The median response time in the levofloxacin-treated group was 7 days, and the median response time in the non-fluoroquinolone-treated group was 9 days (in both groups, approximately 80% of patients responded within 2 months). No child had a serious or major illness, and all skeletal and muscle disorders alleviated no sequelae.

Vomiting and diarrhea were the most commonly reported adverse events, with 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 aftermarket monitoring in adult patients may also occur in pediatric patients.

[Pharmaceuticals for the elderly]

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Elderly patients are at increased risk for serious adverse reactions, including tendon rupture, while receiving fluoroquinolones, such as levofloxacin. This risk is further increased in patients receiving glucocorticoid therapy. Tendonitis or tendon rupture can affect the crotch, hands, shoulders, or other tendon areas and can occur during or after treatment. The names of illnesses that have occurred several months after the end of fluoroquinolone treatment have been reported. Levofloxacin must be used with caution in elderly patients, especially those receiving glucocorticoid therapy. Patients must be informed of these potential side effects, and if any symptoms of tendinitis or tendon rupture occur, it is recommended to discontinue levofloxacin treatment and contact a health care provider.

In phase III clinical trials, 1,945 patients (26%) receiving levofloxacin were 65 years of age or older, 1081 (14%) were between 65 and 74 years old, and 864 (12%) were 75 or older year old. There is no significant difference in the safety and effectiveness of the drug between these patients and younger patients, but it cannot be ruled out that some elderly patients may be more sensitive.

In the marketing report, there have been severe and even fatal liver toxicity related to levofloxacin. The main reports of fatal hepatotoxicity occur at the age of 65 years and older, and most have no allergic reactions. Levofloxacin should be discontinued immediately if the patient has symptoms or signs of hepatitis.

Older patients may be more sensitive to the drug-related effects of the QT interval. Therefore, the simultaneous use of levofloxacin and certain drugs that can cause QT interval prolongation (such as IA or III antiarrhythmic drugs) or the risk factors of tip torsional ventricular tachycardia (such as known extended QT interval and refractory hypokalemia) Caution in using levofloxacin in all patients.

If differences in creatinine clearance are taken into account, there is no significant difference in the pharmacokinetic characteristics of levofloxacin between young subjects and older subjects. However, since most of levofloxacin is excreted from the kidney, patients with impaired renal function are at higher risk of drug toxicity. Elderly patients are more likely to have impaired renal function, so care should be taken when choosing a dose, and renal function needs to be monitored at the same time.

Pharmaceuticals interactions

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

1. Chelating agents: antacids, sucralfate, metal cations, multivitamin preparations

Levofloxacin injection

There is no information about the interaction between intravenous quinolone antibiotics and oral antacids, sucralfate, multivitamin preparations, didanosine or metal cations The data. However, quinolone antibiotics should not be instilled through the same intravenous infusion channel with any solution containing polyvalent cations such as magnesium.

2. Warfarin

A clinical trial in healthy volunteers showed that levofloxacin had no significant effect 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 monitoring reports that levofloxacin can enhance the efficacy of warfarin. The simultaneous application of warfarin and levofloxacin can prolong prothrombin time, which leads to prolonged bleeding time. When using levofloxacin and warfarin at the same time, the prothrombin time, the international normalized ratio (INR) or other anticoagulation tests should be closely monitored, and the patient should be monitored for signs of bleeding.

3. Antidiabetic drugs:

Patients who use a combination of quinolone antibiotics and antidiabetic drugs may experience blood sugar disorders such as high blood sugar and low blood sugar. Therefore, blood glucose levels should be closely monitored when these drugs are used simultaneously.

4. Non-steroidal anti-inflammatory drugs

Concomitant use of non-steroidal anti-inflammatory drugs and quinolone antibiotics, including levofloxacin, can increase the risk of CNS irritation and seizures.

5. Theophylline

In a clinical trial involving 14 healthy volunteers, no significant effects of levofloxacin on theophylline plasma concentration, AUC, and other metabolic parameters were found. Similarly, no significant effect of theophylline on the absorption and metabolism of levofloxacin was observed. However, the simultaneous application of other quinolone antibiotics and theophylline can lead to prolonged elimination half-life of theophylline and increase of plasma concentration in patients, thereby increasing the incidence of theophylline-related adverse reactions. Therefore, when used concurrently with levofloxacin, the theophylline levels should be closely monitored and the drug dose adjusted appropriately. Regardless of whether the theophylline plasma concentration is elevated, adverse reactions such as epilepsy may occur.

6. Cyclosporine

A clinical trial in healthy volunteers showed that levofloxacin had no significant effect on peak plasma concentrations, AUC, and other metabolic parameters of cyclosporine. However, it has been reported that cyclosporine blood levels of patients are increased when used concurrently with certain other quinolone antibiotics. Compared with other trials without concomitant medication, the concurrent use of cyclosporine can slightly reduce the Cmax and ke of levofloxacin, while the Tmax and t1 / 2 are slightly extended, but this difference is not of clinical significance. Therefore, there is no need to adjust the dose of levofloxacin and cyclosporine when used simultaneously.

7. Digoxin

A clinical trial in healthy volunteers showed that levofloxacin had no significant effect on peak plasma concentrations, AUC, and other metabolic parameters of digoxin. Digoxin did not significantly affect the absorption and metabolic kinetics of levofloxacin. Therefore, it is not necessary to adjust the dosage of levofloxacin and digoxin when used simultaneously.

8. Probenecid and Cimetidine

A clinical trial in healthy volunteers showed that probenecid or cimetidine had no significant effect on the rate and extent of levofloxacin absorption. Compared with levofloxacin alone, when combined with probenecid or cimetidine, AUC and t1 / 2 of levofloxacin increased by 27% to 38% and 30%, and CL / F and CLR decreased by 21% to 35. %. Although this difference is statistically significant, no adjustment to the dose of levofloxacin is necessary when combined with probenecid or cimetidine.

9. Interaction with laboratory or diagnostic tests

Fluoroquinolones, including levofloxacin, can be screened for opiate preparations with commercially available kits, which may produce false positive results. More specific methods are needed to determine opiate positive results.

[Drug overdose]

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Levofloxacin has very low acute toxicity. After a single large dose of levofloxacin, mice, rats, dogs, and monkeys can show the following clinical signs: ataxia, ptosis, decreased spontaneous activity, dyspnea, failure, tremor, and convulsions. Oral doses exceeding 1500 mg / kg and injection doses exceeding 250 mg / kg can significantly increase rodent mortality.

When quinolone is overdose, the following symptoms may occur: nausea, vomiting, stomach pain, heartburn, diarrhea, thirst, stomatitis, staggering, dizziness, headache, general burnout, numbness, chills, fever, extrapyramidal symptoms, Excitation, hallucinations, convulsions, madness, cerebellar ataxia, increased intracranial pressure (headache, vomiting, optic papillary edema), metabolic acidosis, increased blood glucose, increased GOT / GPT / ALP, decreased white blood cells, eosinophil Increased cells, thrombocytopenia, hemolytic anemia, hematuria, cartilage / joint disorders, cataracts, visual impairment, abnormal color vision, and diplopia.

For acute overdose, gastric lavage should be performed (only when taking oral preparations), and water and dielectric support therapy should be observed and given. Hemodialysis or peritoneal dialysis cannot effectively remove levofloxacin.

First aid measures and antidote:

(2) Infusion (plus liver protection drugs): sodium bicarbonate injection is given for metabolic acidosis, and sodium bicarbonate injection is given for alkalization of urine to increase excretion of this product from the kidney.

(2) Mandatory diuresis: furan phenyline injection.

(3) Symptomatic therapy: Diazepam should be given repeatedly during convulsions.

[Pharmacology and Toxicology]

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The related situation of levofloxacin reported in the literature is as follows:

Pharmacological action

Mechanism of action: Levofloxacin is the L-body of ofloxacin (racemate), a quinolone antibacterial drug. The antibacterial effect of ofloxacin is mainly produced by L-body. The mechanism of action of levofloxacin and other fluoroquinolones are antitopoisomerase IV and DNA gyrase (topoisomerase II) required to inhibit bacterial DNA replication, transcription, repair, and recombination.

Drug resistance: Fluoroquinolones are caused by mutations in specific regions of DNA rotase or topoisomerase IV, also known as quinolone resistance determining regions (ORDRs), or changes in the drug efflux system.

Fluoroquinolone antibiotics, including levofloxacin, have different chemical structures and modes of action than aminoglycosides, macrolides, and β-lactam antibiotics (including penicillin). Therefore, fluoroquinolones may still be effective against the above-mentioned antimicrobial resistant bacteria.

Levofloxacin resistance in vitro due to spontaneous mutations is rare (range: 10-9 to 10-10). Although cross-resistance has been observed between levofloxacin and some other fluoroquinolones, bacteria resistant to other fluoroquinolones may still be sensitive to levofloxacin.

Antibacterial activity in vitro and in vivo:

Levofloxacin has antibacterial effect on a variety of Gram-negative and Gram-positive bacteria in vitro, and has bactericidal activity when the concentration is equal to or slightly higher than the inhibitory concentration.

Levofloxacin has been shown to have antibacterial effects on the following microorganisms in in vitro studies and clinical infections:

Gram-positive aerobic bacteria: Enterococcus faecalis (multiple strains are 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 (Multidrug-resistant Streptococcus pneumoniae) refers to strains resistant to the following two or more antimicrobials: penicillin (MIC ≥ 2µg / mL), second-generation cephalosporins (such as cefuroxime), macrocyclic Lactones, tetracyclines and trimethoprim / sulfamethoxazole.

Gram negative aerobic bacteria: Enterobacter cloacae, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Legionella pneumoniae, Moraxella catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa Cell bacteria *, Serratia marcescens.

Note: * Same as other drugs in this class, certain strains of Pseudomonas aeruginosa can quickly develop resistance when treated with levofloxacin.

Other microorganisms: Chlamydia pneumoniae, Mycoplasma pneumoniae.

Levofloxacin has an antibacterial effect on Bacillus anthracis when the plasma concentration is used as a surrogate marker in the rhesus monkey anthrax model (after exposure) and in vitro conditions.

The following data are the results of in vitro tests, but their clinical significance is unknown:

The minimum inhibitory concentration (MIC value) of levofloxacin against most of the following microorganisms (≥90%) is 2µg / mL or lower under in vitro conditions; however, levofloxacin is safe and effective in treating clinical infections caused by these microorganisms Adequate, well-controlled experimental studies have not been performed.

Gram-positive aerobic bacteria: Staphylococcus hemolyticus, β-hemolytic streptococcus (group C / F), β-hemolytic streptococcus (group G), Streptococcus agalactiae, Streptococcus miller, Streptococcus grass green.

Gram-negative aerobic bacteria: Acinetobacter baumannii, Acinetobacter reuteri, Pertussis bacillus, Citrobacter colii (differential citrate), Citrobacter freundii, Enterobacter aerogenes, Enterobacter sakazakii, Klebsiella acidigenes, Morganella, Enterobacter agglomerans, Proteus commona, Providence lei, Providence s., Pseudomonas fluorescens.

Gram-positive anaerobic bacteria: Clostridium perfringens.

2. Non-clinical toxicology

Carcinogenicity, mutagenicity, and impaired reproductive function: The results of bioassays throughout the life of the rats showed that taking levofloxacin daily for 2 consecutive years did not show any carcinogenic effects. The highest dose used (100mg / kg / day) is 1.4 times the maximum recommended human dose (750mg) (based on relative body surface area). Levofloxacin at any dose could not shorten the progression time of UV-induced albino nude mice (Skh-1) skin tumors, so it was not photocarcinogenic under the conditions of this test. In the photocarcinogenicity test, at the maximum dose of levofloxacin (300 mg / kg / day), the concentration of levofloxacin in the skin of nude mice ranged from 25 to 42 µg / g. At a dose of 750mg, the average Cmax of levofloxacin skin concentration in human subjects was about 11.8µg / g.

The following tests show that levofloxacin does not have mutagenic effects: Ames bacterial mutation analysis (S. typhimurium and Escherichia coli), CHO / HGPRT forward mutation detection, mouse micronucleus test, mouse dominant lethal test, rat non-program Sex DNA synthesis test, mouse sister chromatid exchange test. Positive in vitro chromosome aberration (CHL cell line) and sister chromatid exchange test (CHL / IU cell line).

When the oral dose in rats is as high as 360 mg / kg / day, levofloxacin does not impair its reproductive ability, which is equivalent to 4.2 times the maximum recommended human dose when the relative body surface area is the same. At an intravenous infusion dose of 100 mg / kg / day, levofloxacin did not impair its reproductive capacity, which was equivalent to 1.2 times the maximum recommended human dose when the relative body surface area was the same.

Animal Toxicology and / or Pharmacodynamics: Levofloxacin and other quinolones have been shown to cause joint disease in juvenile experimental animals of most species. Underage dogs (4 to 5 months of age) take levofloxacin orally at a dose of 10 mg / kg / day for 7 consecutive days or intravenously at a dose of 4 mg / kg / day for 14 consecutive days, which can cause joints damage. The oral dose of juvenile rats is 300mg / kg / day, continuous administration for 7 days, or intravenous administration, the dose is 60mg / kg / day, continuous administration for 4 weeks, can cause joint disease. For 3 months, the beagle was given oral levofloxacin at a dose of 40 mg / kg / day for 14 consecutive days. On the 8th day, severe joint toxicity occurred and the drug was discontinued. At a dose of ≥2.5mg / kg (based on the comparison of plasma AUC, about 0.2 times the dosage of children), the clinical manifestations of minor musculoskeletal injuries can occur, but there is no general pathological and histopathological damage. At doses of 10 and 40 mg / kg (approximately 0.7 and 2.4 times the dosage of children, respectively), it can cause synovitis and articular cartilage damage. After 18 weeks of recovery, the gross pathology and histopathology of articular cartilage remained.

Ear swelling tests in mice have shown that levofloxacin has similar phototoxicity to ofloxacin but is weaker than other quinolone drugs.

Although crystalline urine was found in some intravenously administered rats, crystals did not form in the bladder, but formed after urination, so it does not imply that levofloxacin is nephrotoxic.

Simultaneous use with non-steroidal anti-inflammatory drugs can aggravate the stimulating effect of quinolone drugs on CNS in mice.

When the dose of levofloxacin is 6 mg / kg or higher, rapid intravenous injection can cause hypotension in dogs. This effect may be related to the release of histamine.

In vitro and in vivo tests on animals have shown that levofloxacin is neither an enzyme inducer nor an enzyme inhibitor within the range of human plasma concentrations for treatment, and therefore, there are no drug-metabolizing enzyme-related interactions with other drugs or agents.

Pharmacokinetics

This product is levofloxacin hydrochloride and its active ingredient is levofloxacin. The pharmacokinetics of levofloxacin reported in the literature are as follows:

The pharmacokinetic parameters of levofloxacin after a single oral administration of levofloxacin tablets, oral solution or intravenous injection and after reaching steady state were expressed as Mean ± SD and summarized in the table below (Table 9).

Table 9: Mean ± SD of levofloxacin PK parameters

Treatment options 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. tablets 3 2.8 ± 0.4 1.6 ± 1.0 27.2 ± 3.9 156 ± 20 ND 7.3 ± 0.9 142 ± 21

500 mg p.o. tablets 3 * 5.1 ± 0.8 1.3 ± 0.6 47.9 ± 6.8 178 ± 28 ND 6.3 ± 0.6 103 ± 30

500 mg oral liquid 12 5.8 ± 1.8 0.8 ± 0.7 47.8 ± 10.8 183 ± 40 112 ± 37.2 7.0 ± 1.4 ND

500 mg i.v. 3 6.2 ± 1.0 1.0 ± 0.1 48.3 ± 5.4 175 ± 20 90 ± 11 6.4 ± 0.7 112 ± 25

750 mg p.o. tablets 5 * 9.3 ± 1.6 1.6 ± 0.8 101 ± 20 129 ± 24 83 ± 17 7.5 ± 0.9 ND

750 mg i.v. 5 11.5 ± 4.04 ND 110 ± 40 126 ± 39 75 ± 13 7.5 ± 1.6 ND

Multiple doses

500 mg q24h p.o. tablets 3 5.7 ± 1.4 1.1 ± 0.4 47.5 ± 6.7 175 ± 25 102 ± 22 7.6 ± 1.6 116 ± 31

500 mg q24h i.v. 3 6.4 ± 0.8 ND

54.6 ± 11.1 158 ± 29 91 ± 12 7.0 ± 0.8 99 ± 28

500 mg or 250 mg q24h i.v. 8.7 ± 4.07 ND 72.5 ± 51.27 154 ± 72 111 ± 58 ND ND

Patients with bacterial infection 6

750 mg q24h p.o. tablets 5 8.6 ± 1.9 1.4 ± 0.5 90.7 ± 17.6 143 ± 29 100 ± 16 8.8 ± 1.5 116 ± 28

750 mg q24h i.v. 5 12.1 ± 4.14 ND 108 ± 34 126 ± 37 80 ± 27 7.9 ± 1.9 ND

500 mg p.o. tablet, single-dose, sex and age factors:

Male 8 5.5 ± 1.1 1.2 ± 0.4 54.4 ± 18.9 166 ± 44 89 ± 13 7.5 ± 2.1 126 ± 38

Female 9 7.0 ± 1.6 1.7 ± 0.5 67.7 ± 24.2 136 ± 44 62 ± 16 6.1 ± 0.8 106 ± 40

Young people 10 5.5 ± 1.0 1.5 ± 0.6 47.5 ± 9.8 182 ± 35 83 ± 18 6.0 ± 0.9 140 ± 33

Senior 11 7.0 ± 1.6 1.4 ± 0.5 74.7 ± 23.3 121 ± 33 67 ± 19 7.6 ± 2.0 91 ± 29

500 mg p.o. Single dose, tablet, for patients with renal insufficiency:

CLCR50-80 mL / min 7.5 ± 1.8 1.5 ± 0.5 95.6 ± 11.8 88 ± 10 ND 9.1 ± 0.9 57 ± 8

CLCR20-49 mL / min 7.1 ± 3.1 2.1 ± 1.3 182.1 ± 62.6 51 ± 19 ND 27 ± 10 26 ± 13

CLCR <20 mL / min 8.2 ± 2.6 1.1 ± 1.0 263.5 ± 72.5 33 ± 8 ND 35 ± 5 13 ± 3

Hemodialysis 5.7 ± 1.0 2.8 ± 2.2 ND ND ND 76 ± 42 ND

CAPD 6.9 ± 2.3 1.4 ± 1.1 ND ND ND 51 ± 24 ND

 

Note: clearance rate / bioavailability.

Distribution volume / bioavailability.

Healthy male, aged 18 to 53 years.

When the dosage is 250mg and 500mg, drip for 60 minutes, and when the dosage is 750mg, drip for 90 minutes.

Healthy male and female subjects, aged 18 to 54 years.

For patients with moderate renal impairment and patients with respiratory or skin infections, 500 mg (CLCR 20-50 mL / min) is administered every 48 hours.

标准Standard dose estimates (500 mg dose) based on population pharmacokinetic models.

Healthy males, aged 22 to 75 years.

Healthy women, aged 18 to 80 years.

Healthy young male and female subjects, aged 18 to 36 years.

Healthy elderly male and female subjects, aged 66 to 80 years.

Healthy men and women, aged 19 to 55 years.

Absolute bioavailability; 500mg tablets, F = 0.99 ± 0.08; 750mg tablets, F = 0.99 ± 0.06;

ND = not detected.

absorb

Levofloxacin is absorbed rapidly and completely after oral administration, and usually peaks in plasma drug concentration within 1 to 2 hours after oral administration. The absolute bioavailability of levofloxacin 500mg tablet and 750mg tablet were both about 99%, indicating that levofloxacin was completely absorbed after oral administration. Healthy volunteers received a single intravenous injection at a dose of 500 mg and a mean plasma concentration of Mean ± SD of 6.2 ± 1.0 µg / mL when the instillation time was greater than 60 minutes; at a dose of 750 mg and an infusion time greater than 90 minutes, the peak plasma The Mean ± SD concentration was 11.5 ± 4.0 µg / mL. Levofloxacin oral solution and tablets are bioequivalent.

After single or multiple oral or injection administration of levofloxacin, its pharmacokinetics show a linear curve, which can predict its pharmacokinetic changes. When taken once a day at a dose of 500 mg or 750 mg, a steady state was reached after 48 hours. After oral administration, once daily, 500 mg, Mean ± SD of peak and trough plasma concentrations after multiple administrations were 5.7 ± 1.4 and 0.5 ± 0.2 µg / mL, respectively; and oral administration once daily, 750 mg, Mean ± SD of peak and trough plasma concentrations after multiple administrations were 8.6 ± 1.9 and 1.1 ± 0.4 µg / mL, respectively. Intravenous infusion, once a day, at a dose of 500 mg, Mean ± SD of peak and trough plasma concentrations after multiple doses were 6.4 ± 0.8 and 0.6 ± 0.2µg / mL, respectively. Mean ± SD of peak and trough plasma concentrations after the first administration were 12.1 ± 4.1 and 1.3 ± 0.71 µg / mL, respectively.

Levofloxacin 500mg orally while eating will delay the peak time by about 1 hour, and reduce the peak concentration, the tablet will be reduced by about 14%, and the oral solution will be reduced by about 25%. Therefore, taking levofloxacin tablets has nothing to do with eating or not. However, levofloxacin oral solution is recommended to be taken 1 hour before or 2 hours after a meal. The time curve (AUC) of plasma drug concentration changes after levofloxacin injection was similar to the time curve after taking tablets of the same dose (mg / mg). Therefore, the two routes of administration, oral and injection, can be substituted for each other.

distributed

Levofloxacin is administered in single or multiple doses at a dose of 500 mg or 750 mg, and its average distribution volume is usually 74 to 112 L, which means that levofloxacin can be widely distributed in various tissues of the body. Healthy subjects reached peak drug and skin fluid concentrations approximately 3 hours after administration.

Healthy subjects were administered orally once daily at 750 mg and 500 mg doses. After multiple administrations, the skin-to-plasma AUC ratio was approximately 2 and the body fluid to plasma AUC ratio was approximately 1. Levofloxacin is also very permeable to lung tissue. For a single oral dose of 500 mg, the drug concentration in the lungs after 24 hours is usually 2 to 5 times higher than the plasma concentration, and the concentration range is about 2.4 to 11.3 μg / g.

In vitro, using equilibrium dialysis, it was determined that the levofloxacin and serum proteins in the various animals studied were within the clinically relevant serum / plasma concentration range (1-10 μg / mL) of levofloxacin. Combine. In humans, levofloxacin is mainly associated with serum albumin. The binding of levofloxacin to serum proteins was independent of drug concentration.

metabolism

The stereochemical structure of levofloxacin in plasma and urine is stable, and it will not be metabolized to its optical isomer, D-ofloxacin. The human body has a low metabolism of levofloxacin, which is mainly excreted from the urine in its original form. After oral administration, about 87% of the drug is excreted from the urine in its original form within 48 hours, and less than 4% of the drug is excreted from the feces within 72 hours. Less than 5% of the drug is excreted from the urine in the form of demethyl metabolites and N-oxidative metabolites, which are the only two metabolites in humans. The pharmacological activity of these two metabolites is weak.

excretion

Levofloxacin is mainly excreted from the urine in its original form. After oral or intravenous single or multiple administrations, the average terminal plasma clearance half-life is about 6 to 8 hours. The mean apparent clearance and renal clearance were approximately 144 to 226 mL / min and 96 to 142 mL / min, respectively.

The renal clearance rate exceeds the glomerular filtration rate, indicating that levofloxacin is not only filtered through the glomerulus, but also secreted through the renal tubules. Simultaneous administration of cimetidine or probenecid can reduce renal clearance of levofloxacin by about 24% and 35%, respectively, which indicates that levofloxacin secretion mainly occurs in the proximal tubules of the kidney. Levofloxacin crystals were not found in fresh urine samples collected from subjects using levofloxacin.

Seniors

If the differences in creatinine clearance of the subjects are considered, there is no significant difference in the pharmacokinetics of levofloxacin between young subjects and older subjects. Leachofloxacin was administered orally to healthy elderly subjects (aged 66 to 80 years) at a dose of 500 mg. The mean terminal plasma clearance half-life was approximately 7.6 hours, compared with approximately 6 hours for young adults. The reason for this difference is that the renal function status of the subjects is different, which is not considered to be clinically significant. Age also has no effect on drug absorption. Therefore, there is no need to adjust the dosage of levofloxacin based on age alone.

child

The pharmacokinetics of levofloxacin at a single intravenous administration of 7 mg / kg was studied in children 6 months to 16 years of age. Levofloxacin is cleared faster in children than in adults. As a result, plasma exposure is lower than the corresponding dose for adults. For children from 6 months to 17 years old, 8 mg / kg, once every 12 hours (not more than 250 mg each time) can completely reach steady-state plasma exposure (AUC0-24 and Cmax), while adults need 500 mg, 1 every 24 hours Only after reaching steady state plasma exposure.

gender

If the differences in creatinine clearance of the subjects are considered, there is no significant difference in the pharmacokinetics of levofloxacin between male and female subjects. Levofloxacin was administered orally to healthy male subjects at a dose of 500 mg, with an average terminal plasma clearance half-life of about 7.5 hours, compared to about 6.1 hours for women. The reason for this difference is that the renal function status of male and female subjects is different and is not considered clinically significant. The subject's gender had no effect on drug absorption. There is no need to adjust the dosage of levofloxacin based on gender alone.

race

Covariance analysis was used to analyze the data of 72 subjects to explore the effect of racial factors on the pharmacokinetics of levofloxacin, including 48 whites and 24 non-whites. Subjects' race had no effect on apparent clearance and apparent volume of distribution.

Kidney damage

Patients with renal impairment (creatinine clearance <50mL / min) have significantly reduced levofloxacin clearance and a significantly longer plasma clearance half-life. Therefore, the dosage of these patients needs to be adjusted to avoid drug accumulation.

Neither hemodialysis nor continuous ambulatory peritoneal dialysis (CAPD) can effectively remove levofloxacin from the body, indicating that levofloxacin need not be taken after hemodialysis and CAPD.

Liver damage

The pharmacokinetics of patients with liver impairment has not been studied. Because the metabolism of levofloxacin is small, liver dysfunction may not affect the pharmacokinetics of levofloxacin.

Bacterial infections

The pharmacokinetic characteristics of levofloxacin in patients with severe community-acquired bacterial infections were similar to those of healthy subjects.

Pharmaceuticals interactions

The pharmacokinetics of levofloxacin and theophylline, warfarin, cyclosporine, digoxin, probenecid, cimetidine, sucralfate, and antacids were studied (see Pharmaceuticals interactions).

[Storage] Store in a shady, cool (not more than 20 ° C) dry place in a tightly closed place.

[Packing] glass ampoules; (1) 5mL: 0.5g (calculated as levofloxacin), 5 pieces / box.

(2) 5mL: 0.3g (based on levofloxacin), 5 sticks / box.

[Validity] 24 months

[Executive Standard] WS1- (X-018) -2005Z

Approval Number

(1) 5mL: 0.5g (calculated as levofloxacin) National Pharmaceuticals Standard H20084255

(2) 5mL: 0.3g (calculated as levofloxacin) National Pharmaceuticals Standard H20084256

manufacturer

Company Name: Shandong Viwit Baike Pharmaceutical Co., Ltd.

Production address: No. 369, Shengong Road, High-tech Industrial Development Zone, Zaozhuang City, Shandong Province

Zip Code: 277000

Phone: 0632-5765365 5765318

Fax: 0632-5765365

Website: http://www.viwit.com

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