Date of approval.
Date of revision.
Instructions for Azithromycin for Injection
Please read the instructions carefully and use under the guidance of a physician.
Drug Name]
Generic name: Azithromycin for Injection
English name: Azithromycin for Injection
Hanyu Pinyin：Zhusheyong Aqimeisu
Ingredients
The main ingredient of this product is Azithromycin.
Chemical name: (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-nuclear-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4, 6-trideoxy-3-(dimethylamino)-β-D-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one.
Chemical structure formula.
Molecular formula: C38H72N2O12-2H2O
Molecular weight: 785.0
The excipients contained in this product are: citric acid, sodium hydroxide
Properties]: This product is white loose mass or powder.
Indications
This product is suitable for the following infections caused by sensitive pathogenic bacteria.
Community-acquired pneumonia
Patients caused by pathogenic bacteria such as Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Catamorax, Mycoplasma pneumoniae, Staphylococcus aureus or Streptococcus pneumoniae, and whose starting treatment requires intravenous administration.
Pelvic inflammatory disease
Patients due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis, and for whom intravenous administration is required for initiation of therapy. If anaerobic infections are suspected, an anti-anaerobic agent should be added in combination with this product.
If needed, oral azithromycin may be administered sequentially after the discontinuation of injectable azithromycin.
Bacterial cultures and drug sensitivity tests should be performed before administration to identify the causative organism and its susceptibility to azithromycin. Azithromycin therapy can be started after specimen collection and adjusted accordingly when the drug sensitivity results are known.
To reduce the development of resistant organisms and to maintain the effectiveness of Azithromycin and other antibacterial drugs, Azithromycin should be used only for the treatment or prevention of infections caused by confirmed or highly suspected susceptible organisms. If culture and drug sensitivity data are available, they should be considered when selecting or adjusting antimicrobial therapy. If these data are not available, local epidemiology and drug sensitivity patterns may assist in the selection of empirical therapy.
【Specifications】.
0.5g according to C38H72N2O12.
Dosage and Administration
(See [Indications] and [Pharmacokinetics])
The recommended dose for the treatment of community-acquired pneumonia caused by specific pathogens is 500 mg per day administered intravenously as a single dose for at least 2 days. Intravenous administration needs to be followed by oral sequential therapy with azithromycin at 500 mg once daily for a total of 7-10 days of intravenous and oral therapy. The timing of the switch from intravenous to oral administration should be determined by the physician based on clinical efficacy.
The recommended dose for the treatment of pelvic inflammatory disease caused by specific pathogens is 500 mg once a day intravenously, followed by oral sequential therapy with azithromycin at 250 mg once a day for a total of 7 days intravenously and orally. When to switch to oral administration is determined by the physician based on clinical efficacy. If anaerobic bacterial infection is suspected, additional antianaerobic drugs are required.
Renal insufficiency.
No dose adjustment is recommended for patients with renal impairment (GFR ≤ 80 mL/min.) Mean AUC0-120 in patients with GFR 10-80 mL/min is similar to that in patients with normal renal function, whereas GFR <10 mL/min is 35% elevated compared to patients with normal renal function. Azithromycin should be used with caution in patients with severe renal impairment (see [Pharmacokinetics],, Special Populations – Renal Insufficiency).
Hepatic insufficiency.
The pharmacokinetics of azithromycin in patients with hepatic impairment have not been determined. No dose adjustment is recommended for patients with hepatic impairment (see [Pharmacokinetics], Special Populations-Hepatic Insufficiency).
No dose adjustment based on age or gender is required (see [Pharmacokinetics],, Special Populations).
The dose should be administered at a rate of 3 hours at a concentration of 1 mg/mL and 1 hour at a concentration of 2 mg/mL.
According to the results of domestic clinical trials, the intravenous drip of this product should not be too fast, and the drip time of 4 hours per 500 mg/500 mL is appropriate.
Method of preparing the solution for intravenous administration.
Dissolve
Preparation of the drug stock solution: Add 4.8 mL of sterilized injection water to the 500 mg Azithromycin for Injection bottle and shake until the drug is completely dissolved. It is recommended that a standard 5 mL syringe (non-automatic) be used to ensure accurate withdrawal of 4.8 mL of sterile injection water. Make each mL of solution contain 100 mg of azithromycin. The solution can be stored below 30°C (or 86°F) for 24 hours.
Parenteral administration must be observed visually for particulate matter prior to use; if particulate matter is evident in the solution, the drug solution should be discarded.
Further dilute the drug solution prior to use as follows
Dilution
Prepare a 1.0-2.0 mg/mL azithromycin solution by adding 5 mL of 100 mg/mL azithromycin solution to any of the following solutions in the appropriate amount
Physiological saline (0.9% NaCl)
1/2 saline (0.45% NaCl)
5% dextrose solution
Sodium lactate Ringer’s solution
5% glucose + 1/2 saline (0.45% NaCl) containing 20 mmol/L potassium chloride
5% glucose sodium lactate Ringer’s solution
5% dextrose + 1/3 saline (0.3% NaCl)
5% dextrose + 1/2 saline (0.45% NaCl)
Normosol-M 5% dextrose solution
Normosol-R 5% dextrose solution
Final infusion concentration (mg/mL) Amount of diluent (mL) 1.0 mg/mL 500 mL 2.0 mg/mL 250 mL 500 mg is recommended The drip time for this product diluted as above is not less than 60 minutes.
This product should not be pushed intravenously or injected intramuscularly
Other intravenous infusions, additives, and drugs should not be added to this product, nor should they be dosed simultaneously in the same intravenous route.
Adverse reactions
(I) Clinical trial experience
Because clinical trials are done under different conditions, the rate of adverse reactions observed in clinical trials for one drug 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 majority of adverse reactions reported in clinical trials of intravenous formulations of azithromycin for the treatment of community-acquired pneumonia, administered intravenously at 2-5 doses, were mild to moderate and recovered upon discontinuation of the drug. Most patients in these clinical trials had more than one comorbidity and required other medications. Approximately 1.2% of patients treated with injectable azithromycin discontinued the drug, and 2.4% of patients treated with intravenous or oral azithromycin discontinued the drug due to symptoms of adverse reactions or abnormal laboratory tests.
In clinical trials conducted in patients with pelvic inflammatory disease, 2% of female patients receiving azithromycin monotherapy after 1 to 2 doses administered intravenously discontinued the drug due to clinical adverse effects, and 4% of patients treated with azithromycin in combination with metronidazole discontinued treatment due to adverse effects.
The most common adverse reactions leading to discontinuation in the above studies were gastrointestinal reactions (abdominal pain, nausea, vomiting, diarrhea, etc.) and rash, and abnormal laboratory tests leading to discontinuation were mainly elevated amino transaminases and/or alkaline phosphatase.
In studies of community-acquired pneumonia, the most common adverse reactions in adult patients treated with intravenous/oral formulations of azithromycin were gastrointestinal reactions, including diarrhea or loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%). Adverse reactions related to intravenous injection occurred in approximately 12% of patients, the most common being injection site pain (6.5%) and local inflammatory reactions (3.1%).
In clinical trials in patients with pelvic inflammatory disease, the most common treatment-related adverse reactions in adult female patients treated with intravenous/oral formulations of azithromycin were also gastrointestinal reactions, with diarrhea (8.5%) and nausea (6.6%) being common, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), and rash and pruritus (1.9%). A higher proportion of female patients in these studies experienced nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), administration site reactions, stomatitis, dizziness, and dyspnea (1.9% total) when azithromycin was combined with metronidazole.
None of the other adverse reactions caused by the intravenous/oral multi-dose administration regimen of azithromycin exceeded 1%.
Adverse reactions that occurred at an incidence of no more than 1% were
Gastrointestinal reactions: dyspepsia, flatulence, mucositis, oral candidiasis, and gastritis.
Neurological: headache, drowsiness.
Allergic reactions: bronchospasm.
Special sensations: taste inversions.
(ii) Experience with post-marketing applications.
The following adverse events have been reported in post-marketing applications of oral azithromycin preparations in adult and/or pediatric patients, but it is not certain whether they were caused by azithromycin.
Metabolic reactions: arthralgia, edema, urticaria, angioneurotic edema.
Cardiovascular: Arrhythmias including ventricular tachycardia, hypotension. Prolonged QT interval and tip-twist ventricular tachycardia have been reported.
Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous enteritis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration have been reported.
Systemic reactions: malaise, abnormal sensation, fatigue, malaise, and anaphylactic shock reactions (including fatal cases).
Genitourinary system: interstitial nephritis, acute renal failure, vaginitis.
Hematopoietic system: thrombocytopenia.
Hepatic/biliary: abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and liver failure. (See WARNING, Hepatotoxicity).
Neurologic: convulsions, dizziness/vertigo, headache, drowsiness, hyperactivity, neuroticism, agitation, and syncope.
Ear and vagus abnormalities: deafness, tinnitus, auditory impairment, vertigo.
Psychiatric: aggressive reactions and anxiety.
Skin and adnexa: pruritus, severe skin reactions including erythema multiforme, Stevens Johnson syndrome, toxic epidermolysis bullosa necrotizing and eosinophilic infiltration and drug reactions with systemic symptoms (DRESS).
Special senses: Hearing impairment including hearing loss, deafness and/or tinnitus, abnormalities and/or loss of taste/smell have also been reported.
Laboratory test abnormalities.
Laboratory tests seen to be significantly abnormal in clinical trials (whether drug-related or not) were
Incidence 4-6%: elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine.
Incidence 1 to 3%: elevated lactate dehydrogenase (LDH), bilirubin.
Incidence less than 1%: leukopenia, neutropenia, reduced platelet count, elevated serum alkaline phosphatase.
Follow-up revealed that the above abnormalities in laboratory tests were reversible.
In a clinical trial of multiple doses of azithromycin (intravenous/oral) administered to more than 750 patients, no more than 2% of patients discontinued azithromycin due to treatment-related liver enzyme abnormalities.
[Contraindication
Contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or other macrolides. Contraindicated in patients with a history of cholestatic jaundice/hepatic insufficiency following previous azithromycin use.
Warnings
Allergic reactions
Serious allergic reactions, including angioneurotic edema, anaphylaxis reactions, skin reactions including Stevens-Johnson syndrome, toxic epidermolysis bullosa and drug reactions with eosinophil infiltration and systemic symptoms (DRESS), have been reported with azithromycin treatment (see [Contraindications]). Deaths have also been reported. In some patients with allergic symptoms, symptomatic treatment is initially effective, but if treatment is discontinued prematurely, allergic symptoms can recur rapidly even without reapplication of azithromycin. Such patients need to be treated symptomatically and observed for an extended period of time. It is not known whether these events are related to the long half-life of azithromycin in the tissues and thus the longer exposure of the body to the antigen.
If a metabolic reaction occurs, the drug should be discontinued immediately and appropriate treatment given. Physicians should be aware that allergic symptoms may reappear after discontinuation of symptomatic treatment.
Hepatotoxicity
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and liver failure have been reported, and in some cases may be fatal. If signs and symptoms of hepatitis develop, the product should be discontinued immediately.
Infantile hypertrophic pyloric stenosis (IHPS)
Infantile hypertrophic pyloric stenosis (IHPS) has been reported following the use of azithromycin in neonates (treatment within 42 days of birth). Parents and caregivers should be informed of the need to contact their physician if the infant has vomiting and stress reactions occurring with breastfeeding.
Clostridium difficile-associated diarrhea
Clostridium difficile-associated diarrhea (CDAD) has been reported with almost all antimicrobial applications, including this one, and can range in severity from mild diarrhea to fatal colitis. Antibacterial drug therapy can cause alterations in the normal flora of the colon, leading to an overgrowth of C. difficile.
Toxin A and toxin B produced by C. difficile are associated with the development of CDAD. Highly virulent C. difficile production leads to increased morbidity and mortality, and these infections may be difficult to treat with antimicrobials and may require colectomy. The possibility of CDAD must be considered in all patients who develop diarrhea after antibiotic use. A careful history is needed as CDAD has been reported after administration of antimicrobial therapy for more than 2 months.
If CDAD is suspected or confirmed, it may be necessary to discontinue ongoing antibiotics that are not directed against Clostridium difficile. Appropriate hydration, electrolytes, and protein must be given as clinically indicated, and antibiotics effective against C. difficile must be given and surgical evaluation performed if necessary.
【Caution】.
General: Azithromycin should be used with caution in patients with hepatic impairment because azithromycin is primarily cleared by the liver. data in subjects with GFR <10mL/min are limited, and azithromycin should also be used with caution in such patients. (See [Pharmacokinetics], Special Populations – Renal Insufficiency for more information.) Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and liver failure have been reported, and some of these cases may be fatal. If signs and symptoms of hepatitis develop, azithromycin should be discontinued immediately.
This product should be dissolved and diluted as directed and should not be given intravenously for less than 60 minutes (see [Dosage] for details).
There are reports of adverse reactions that can occur locally when azithromycin is injected during intravenous application. Administer azithromycin 500 mg, prepared to a concentration of 2 mg/mL, 250 mL solution to be dripped within 1 hour or to a 1 mg/mL, 500 mL solution to be dripped within 3 hours. The incidence and severity of adverse reactions were similar for topical injections (see [Adverse Reactions] for details). All volunteers who received azithromycin at concentrations greater than 2.0 mg/mL experienced local reactions to the injection, so the concentration of the drug should not be too high for the IV drip.
Prolonged QT interval
The application of other macrolide antibiotics, including azithromycin, has been reported to cause cardiac repolarization and prolongation of the QT interval, thereby risking the development of arrhythmias and tip-twisting ventricular tachycardia. Spontaneous reports of cases of tip-twisting ventricular tachycardia have been reported in post-marketing surveillance of patients on azithromycin. When weighing the risks and benefits of azithromycin use in high-risk groups, healthcare professionals should consider the risk of potentially fatal QT interval prolongation in high-risk groups including
Patients with a known history of prolonged QT interval, tip-twist ventricular tachycardia, congenital prolonged QT interval syndrome, bradyarrhythmias, or decompensated heart failure.
Patients taking medications known to prolong the QT interval, such as antipsychotics; antidepressants; and fluoroquinolone therapy.
Patients in an arrhythmogenic state, such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving type IA (quinidine, procainamide) and type III (dofetilide, amiodarone, sotalol) antiarrhythmic drugs.
Elderly patients: Elderly patients may be more sensitive to drug-related effects on the QT interval.
Exacerbation of myasthenia gravis symptoms or new onset of myasthenia gravis syndrome has been reported in patients treated with azithromycin.
The use of this product in the absence of a confirmed or not highly suspected bacterial infection, or in the absence of indications for prophylaxis, may not be beneficial to the patient and may increase the risk of development of drug-resistant organisms.
Patient Needs to Know.
Discontinue azithromycin immediately at the onset of any signs of metaplasia and contact your physician.
Patients should be informed that antibacterial drugs, including this product (azithromycin), should only be used to treat bacterial infections and not viral infections (e.g., the common cold). When using this product (azithromycin) for the treatment of bacterial infections, patients must be informed that although they usually feel better at the beginning of treatment, they should take the medication exactly as directed by their physician. Missing a dose or not completing the entire course of treatment may (1) reduce the efficacy of the current treatment and (2) increase the likelihood of bacterial resistance, which will result in the inability of azithromycin or other antibacterial drugs to treat these resistant organisms in the future.
Antibiotic therapy can often cause diarrhea, which usually recovers when antibiotics are discontinued. Sometimes after antibiotic therapy is given, patients develop watery or bloody stools (with or without stomach cramps and fever) even 2 months or more after the last dose of antibiotics. If this occurs, patients should contact their doctor as soon as possible.
Pregnant women and nursing mothers
Pregnancy
Teratogenic effects. This product is in category B of the pregnancy drug classification: in fertility studies in rats and mice, doses reached maternal moderately toxic levels (i.e., 200 mg/kg/day orally). These doses are based on body surface area mg/m2 and are approximately two and four times the human oral dose of 500 mg/day, respectively. No damaging effects of azithromycin on embryos have been found in animal studies. However, there are no controlled studies in pregnant women with adequate sample size. Since animal fertility studies are not fully predictive of human response, a definitive indication for azithromycin in pregnancy is needed.
Lactating women: It is not known whether azithromycin is secreted through breast milk. Since many drugs are secreted through breast milk, care should be taken when administering azithromycin to nursing women.
Pediatric Dosage]
The efficacy and safety of azithromycin for injection in children and adolescents under 16 years of age have not been confirmed by rigorous controlled clinical studies.
Geriatric Use]
Pharmacokinetic studies of intravenous administration of azithromycin have not been conducted in elderly volunteers. The pharmacokinetic characteristics of a 5-day regimen of oral azithromycin in elderly volunteers (65-85 years of age) are similar to those in younger volunteers (18-40 years of age).
In clinical trials of multiple intravenous doses of azithromycin for the treatment of community-acquired pneumonia, 45% of patients (188/414) were 65 years of age or older and 22% of patients (91/414) were 75 years of age or older. Safety did not differ overall between these patients and younger patients in terms of adverse events, abnormal laboratory tests, and withdrawal from the trial. The decrease in clinical efficacy with increasing patient age was found to be similar between the azithromycin-treated and control drug-treated groups.
This product (azithromycin for injection) contains approximately 114 mg (4.96 mEq) of sodium per vial. At the regular recommended dose, patients would consume 114 mg (4.96 mEq) of sodium. For sodium loading, urinary sodium excretion is reduced in the elderly population. Total sodium intake from dietary and non-dietary sources is clinically important for specific diseases (e.g., congestive heart failure).
[Drug Interactions].
Drug Interactions: The combination of a single oral dose of azithromycin at steady state with nafinavir may result in increased serum concentrations of azithromycin. Although no dose adjustment of azithromycin is required when combined with nafinavir, known side effects of azithromycin such as liver enzyme abnormalities and hearing impairment (see Adverse Reactions) must be monitored closely.
Although a 5-day course of azithromycin had no effect on prothrombin time after subsequent warfarin administration in a study of 22 healthy men, spontaneous postmarketing reports suggest that the combined use of azithromycin may potentiate the effects of oral anticoagulants. Patients should be closely monitored for prothrombin time when combining azithromycin and oral anticoagulants.
Drug interactions between azithromycin and other drugs that may be combined have been studied (see [Pharmacokinetics] – Drug Interactions). When used at therapeutic doses, azithromycin has little effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, desoxymethylparaben, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral administration), triazolam, meperidine/sulfamethoxazole, or zidovudine. The pharmacokinetics of azithromycin are not significantly affected by efavirenz or fluconazole when used in combination. No dose adjustment of either drug is required when azithromycin is combined with any of these drugs.
No interactions between azithromycin and the following drugs have been reported in clinical trials. However, no specific studies have been conducted to date to evaluate potential interactions between azithromycin and these drugs. However, these have occurred with the application of other macrolides. Therefore, in the absence of new study data, close patient observation is advisable when azithromycin is combined with the following drugs.
Digoxin-Elevated digoxin concentrations.
Ergotamine or dihydroergotamine – Acute ergotism, manifested by severe peripheral vasospasm and sensory dullness.
Elevated concentrations of terfenadine, cyclosporine, hysobitol and phenytoin.
Effects on laboratory tests: No effects on laboratory test results have been reported.
[Drug Overdose].
No relevant research data are available.
Pharmacology and Toxicology
Pharmacological effects.
Azithromycin is an azide compound, a macrolide antibiotic, derived by chemically inserting a nitrogen atom into the erythromycin A lactone ring.
Microbiology: The antibacterial mechanism of action of azithromycin is to bind to the 50S ribosomal subunit of sensitive bacteria and impede their protein synthesis. Its nucleic acid synthesis is not affected.
In vitro cultures showed that azithromycin was concentrated in phagocytes and fibroblasts. Using in vitro cultures, the ratio of intracellular and extracellular drug concentrations was determined to be greater than 30 after 1 h. In vivo studies suggest that high concentrations of drug within phagocytes may contribute to drug distribution to inflamed tissues.
Azithromycin has antibacterial activity (including in vitro effects and clinical efficacy, see the [Indications] section of the package insert for this product) against most strains of the following bacteria.
Aerobic and parthenogenic gram-positive bacteria
Staphylococcus aureus
Streptococcus pneumoniae
Note: Azithromycin is cross-resistant to erythromycin-resistant gram-positive bacteria. Most Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.
Aerobic and parthenogenic gram-negative bacteria
Haemophilus influenzae
Cataplasma
Neisseria gonorrhoeae
Other microorganisms
Chlamydia pneumoniae
Chlamydia trachomatis
Legionella pneumophila
Human mycoplasma
Mycoplasma pneumoniae
Bacterially produced β-lactamases have no effect on azithromycin activity.
Azithromycin has antibacterial activity against most of the following strains.
Aerobic and parthenogenic Gram-positive bacteria
Staphylococcus aureus
Streptococcus lactis
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic and part-time gram-negative bacteria
Haemophilus ducreyi
Haemophilus influenzae
Cataplasma
Neisseria gonorrhoeae
Other microorganisms
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
Bacterially produced β-lactamases have no effect on azithromycin activity.
The following in vitro test data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms have in vitro minimum inhibitory concentrations (MIC) less than or equal to the threshold value for azithromycin susceptibility. However, there is no well-documented clinical controlled trial data to confirm the safety and efficacy of azithromycin in the treatment of infections caused by these pathogens.
Aerobic and parthenogenic Gram-positive bacteria
Streptococcus (Groups C, F and G)
Streptococcus gramineus group
Aerobic and parthenogenic gram-negative bacteria
Bordetella pertussis
Anaerobic bacteria
Streptococcus digestiveis
Two-way Prevotella
Other microorganisms
Ureaplasma urealyticum
β-lactamases produced by bacteria have no effect on azithromycin activity.
Method of drug sensitivity testing
Results of in vitro drug sensitivity tests for antimicrobial drugs used in hospital wards should be made available to physicians, if possible, as a periodic report describing the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient clinics, but help physicians select the most effective antimicrobial drug.
Dilution technique.
The minimum inhibitory concentration (MIC) of an antimicrobial drug is determined by a quantitative method. MIC allows estimation of bacterial susceptibility to an antimicrobial drug, and determination of MIC must be done by a standardized method, which is based on a dilution method (broth dilution or agar dilution) or an equivalent method that requires a standard bacterial solution concentration and a standard azithromycin concentration. The significance of MIC values is determined by the criteria in Table 1.
Diffusion method
Measurement of the diameter of the inhibition circle also allows estimation of bacterial susceptibility to antimicrobial agents, and the test results are reproducible. The standardized test method requires standardization of the amount of bacteria inoculated. The method uses paper tablets containing 15 g of azithromycin to test bacterial susceptibility to azithromycin, and the laboratory report of the paper sensitivity test should be interpreted according to the criteria in Table 1.
Table 1. criteria for interpretation of susceptibility results to azithromycin Criteria for interpretation of susceptibility test results Minimum inhibitory concentration (mg/ml) Paper diffusion method
(diameter of inhibition circle, mm) Pathogenic bacteria
S
I
Ra
S
I
Ra Haemophilus spp. £ 4 – – ³ 12 – – Staphylococcus aureus £ 24 ³ 8³ 1814-17 £ 13 Streptococcus including
Streptococcus pneumoniae b
£ 0.5
1
³ 2
³ 18
14-17
£ 13a Due to the lack of information on resistant strains, there are currently no criteria for assigning a category other than “sensitive”. If the MIC value is outside the “sensitive” range, the strain should be sent to a reference laboratory for further testing.
The susceptibility of Streptococcus b, including Streptococcus pneumoniae, to azithromycin and other macrolides can be predicted by testing for erythromycin.
There are no established drug sensitivity criteria for Neisseria gonorrhoeae, and drug sensitivity testing for Neisseria gonorrhoeae is not routine.
A report of “sensitive” means that the pathogen may be inhibited if the antimicrobial drug is administered at a concentration that is normally achievable. A report of “intermediate sensitivity” means that the outcome of treatment is uncertain, and if the bacteria are not fully sensitive to other available drugs, the drug sensitivity test needs to be repeated. The clinical significance of the results in this category is that azithromycin may be used in both cases where the concentration of the drug at the site of infection is high or where a higher dose can be administered. The results provide a buffer against small uncontrolled technical factors that may cause significant differences in interpretation of the results. Reporting “resistant” indicates that the pathogen is unlikely to be suppressed at the normally achievable concentration of the antimicrobial drug and that another therapeutic agent should be selected.
Quality control
Standardized methods of drug sensitivity testing require the use of quality control strains to control technical aspects of the testing process. The range of drug sensitivity results for each quality control strain using azithromycin standard powder is shown in Table 2. quality control strains are specific strains with intrinsic biological properties. QC strains are very stable and give standard and reproducible drug sensitivity results. Specific strains used for microbiological quality control have no clinical significance.
Table 2. Acceptable quality control ranges for azithromycin Quality control
Strain minimum inhibition concentration (mg/ml) Paper diffusion method
(diameter of inhibition circle, mm) Haemophilus influenzae
ATCC 49247
1.0-4.0
13-21 Staphylococcus aureus
ATCC 29213
0.5-2.0 Staphylococcus aureus
ATCC 25923
21-26 Streptococcus pneumoniae
ATCC 49619
0.06-0.25
19-25
Toxicological studies
Repeated dosing toxicity
Phospholipidosis (intracellular phospholipid aggregation) can occur in some tissues after repeated administration of azithromycin to mice, rats and dogs. Such alterations have been shown to occur in many organs such as the eye, dorsal ganglion root, liver, gallbladder, kidney, spleen, and pancreas after administration of approximately the adult dose of azithromycin to dogs and 1/6 of the adult dose to rats, based on body surface area mg/m2. These changes can be restored after discontinuation of azithromycin. Phospholipidosis also occurs in tissues of neonatal rats and dogs given azithromycin once daily for 10 to 30 days and to the same extent. According to pharmacokinetic data, a Cmax value of 1.3 mg/ml was observed for the development of phospholipidosis in rats given 30 mg/kg azithromycin (this value is 6 times higher than the Cmax value of 0.216 mg/ml for children given 10 mg/kg). Similarly, dogs given 10 mg/kg azithromycin had a Cmax value of 1.5 mg/ml when phospholipidosis occurred (this value is 7 times the Cmax value and dose administered in the pediatric population studied). Based on body surface area mg/m2, a dose of 30 mg/kg in neonatal rats (135 mg/m2) and 10 mg/kg in dogs (79 mg/m2) is approximately 0.45 and 0.3 times, respectively, the recommended dose in pediatric patients with a mean body weight of 25 kg. This effect was reversible after discontinuation of azithromycin and was similar to that observed in adult animals. What these findings mean for animals and humans is unclear.
Genotoxicity
Azithromycin was not found to be potentially mutagenic in standard laboratory tests such as the mouse lymphoma test, the human lymphocyte test and the mouse bone marrow micronucleus test.
Reproductive toxicity
Reproductive toxicity tests in both rats and mice showed no teratogenic effects when azithromycin was administered at dose levels that produced moderate maternal toxicity (i.e., 200 mg/kg/day, approximately 2-4 times the human dose of 500 mg/kg/day based on body surface area). No damage to fertility or fetuses was found.
Carcinogenicity
Long-term animal tests have not been conducted to evaluate whether azithromycin is potentially carcinogenic.
[Pharmacokinetics] According to the literature.
In hospitalized patients with community-acquired pneumonia who received 500 mg of azithromycin intravenously at a concentration of 2 mg/mL once daily for 1 hour, the mean Cmax±S.D. of azithromycin was 3.63±1.60 μg/mL after 2-5 days of dosing, with a 24-hour trough concentration level of 0.20±0.15 μg/mL and an AUC24 of 9.60±4.80 μ g-h/mL.
In normal volunteers given 500 mg azithromycin intravenously for 3 hours at a dose of 1 mg/mL, the mean Cmax, 24-hour trough concentration and AUC24
values were 1.14 ± 0.14 g/ml, 0.18 ± 0.02 g/ml and 8.03 ± 0.86 g-h/ml, respectively.The pharmacokinetic parameters of patients hospitalized with community-acquired pneumonia using the same drip dosing regimen for 3 hours, after 2-5 days of dosing, were were similar to those described above for normal subjects.
Plasma concentrations (μg/mL±S.D.) on the last 1 day of intravenous drip administration of 500 mg azithromycin
Plasma concentration (μg/mL±S.D.) of the drug solution, time after the start of the drip (hr) 0.512346812242 mg/mL, 1hra2.983.360.600.400.330.260.270.200.20±1.12±1.73±0.31±0.23±0.16±0.14± 0.15±0.12±0.15 1mg/mL, 3hrb0.911.021.141.130.320.280.270.220.18±0.13±0.11±0.13±0.16±0.05±0.04±0.03±0.02±0.02a=Patients with community-acquired pneumonia received azithromycin 500 mg (2 mg/mL) intravenously for 2-5 days.
b=Healthy subjects received azithromycin 500 mg (1 mg/mL) intravenously for 5 days.
The mean CLt and Vd values in the 18 normal volunteers were 10.18 mL/min/kg and 33.3 L/kg, respectively, after an IV drip of 1000-4000 mg (1 mg/mL) azithromycin over 2 hours.
Comparison of plasma pharmacokinetic parameters after once-daily intravenous azithromycin 500 mg dosing on days 1 and 5 revealed that Cmax was only 8% higher after day 5 dosing, but AUC24 increased by 61%, indicating a 3-fold increase in C24 trough concentration.
After a single oral dose of 500 mg azithromycin in 12 healthy volunteers, Cmax, trough concentration and AUC24 were 0.41 μg/mL, 0.05 μg/mL and 2.6 μg-h/mL, respectively. the parameters after oral administration were 38%, 83% and 52% of those after a single intravenous dose of 500 mg (drip time 3 h) (post-intravenous Cmax: 1.08 μg/ mL; trough concentration: 0.06 μg/mL; AUC24: 5.0 μg-h/mL). Therefore, the blood concentration per 24-hour intravenous dosing is high. Pharmacokinetic parameters for a 500 mg loading dose of azithromycin capsules administered orally to healthy adults (18-40 years) followed by 250 mg orally daily on day 5 were as follows: Cmax=0.24 μg/mL and AUC24=2.1 μg-h/mL.
Median azithromycin exposure (AUC0-288) in monocytes (MN) and polymorphonuclear (PMN) leukocytes was 1000 and 800 times higher than in serum, respectively, after 12 healthy volunteers received azithromycin orally once daily for 5 days (2 250 mg tablets on day 1, followed by 1 250 mg tablet on days 2-5) or a total dose of 1500 mg for 3 days (500 mg per day on days 1-3). 1000-fold and 800-fold.
Distribution.
The serum protein binding of azithromycin varied with blood concentration, with a protein binding rate of 51% at a blood concentration of 0.02 g/ml in humans, decreasing to 7% at elevated blood concentrations of 2 µg/ml.
The tissue concentrations following intravenous azithromycin drips are not available, and some of the tissue (or body fluid) concentrations and the ratio of tissue (body fluid) to plasma/serum concentrations following oral azithromycin administration are shown in the following table.
Concentrations after oral administration of 500 mg (250 mg x 2) azithromycin in adults
Tissue or body fluid concentrations (h) after dosing
(µg/g or µg/mL)1 Corresponding plasma or serum concentration (µg/mL) Tissue (body fluid) plasma (serum) concentration ratio1 Skin 72-960.40.01235 Lungs 72-964.00.012>100 Sputum*2-41.00.642 Sputum**10-122.90.130 Tonsils***9-184.50. 03>100 tonsil***1800.90.006>100 cervical ****192.80.04701 There was no clear correlation between high tissue concentration and clinical efficacy. The antibacterial activity of azithromycin was pH dependent. It decreases with
decreasing pH. However, the wide distribution of the drug in the tissues may be related to its clinical efficacy.
* Specimens taken 2-4 hours after the 1st dose.
** Specimens taken 10-12 hours after the first dose.
*** Dosing regimen of 250 mg orally every 12 hours, 2 doses.
**** Specimens taken 19 hours after a single dose of 500 mg dose.
Tissue concentrations were determined in 7 obstetric and gynecological patients after a single oral dose of 500 mg of azithromycin. Approximately 17 hours after dosing, concentrations were 2.7 μg/g in ovarian tissue, 3.5 μg/g in uterine tissue, and 3.3 μg/g in oviductal tissue. In the absence of inflammation of the meninges, concentrations in cerebrospinal fluid were less than 0.01 µg/mL after administration of 500 mg on day 1, followed by 250 mg once daily starting on day 2, using a 4-day regimen.
Metabolism
In vitro and in vivo studies evaluating the metabolism of azithromycin have not been conducted.
Clearance
Following single doses of 500 mg orally and intravenously, plasma concentrations of azithromycin decrease in a multiphasic pattern with a mean apparent plasma clearance of 630 ml/min and a terminal clearance half-life of 68 hours. The prolonged terminal half-life is generally believed to be due to extensive tissue uptake followed by release of the drug.
In a multi-dose dosing study in 12 normal volunteers administered azithromycin 500 mg (1 mg/mL) intravenously for 1 hour over 5 days, the amount excreted in the urine 24 hours after the first dose was 11% of the administered dose, and the amount excreted in the urine 24 hours after the fifth dose was approximately 14% of the administered dose. After oral administration of azithromycin 6% of the administered dose was excreted in the urine in its original form, and excretion in the urine was higher after intravenous dosing than after oral administration. After oral administration, biliary secretion is the main route of excretion of the drug in its original form.
Special Populations
Renal insufficiency
The pharmacokinetics of azithromycin were studied in 42 adults (21-85 years of age) with varying degrees of renal impairment. After a single dose of azithromycin 1000 mg administered orally, mean Cmax and AUC0-120 were increased by 5.1% and 4.2%, respectively, in patients with mild to moderate renal impairment (GFR 10-80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). Mean Cmax and AUC0-120 were increased by 61% and 35%, respectively, in patients with severe renal impairment (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). (See [Dosage]).
Hepatic insufficiency
The pharmacokinetics of azithromycin in patients with hepatic impairment are not known.
Gender
There is no significant difference in the course of azithromycin in male and female subjects. No dose adjustment based on gender is recommended.
Geriatric Patients
Pharmacokinetic studies of the intravenous administration of azithromycin have not been performed in elderly volunteers.
The pharmacokinetics of a 5-day regimen of oral azithromycin in elderly volunteers (65 to 85 years of age) were similar to those in younger volunteers (18 to 40 years of age).
Pediatric Patients
Pharmacokinetic studies of intravenous administration of azithromycin have not been performed in children.
Drug Interactions
Drug interaction studies have been performed with oral azithromycin and other drugs that may be combined. The effects of combining azithromycin on the pharmacokinetics of other drugs are given in Table 3, and the effects of other drugs on the pharmacokinetics of azithromycin are given in Table 4.
The effect of combining azithromycin at therapeutic doses on the pharmacokinetics of the drugs in Table 3 was not significant. No dose adjustment of the drugs in Table 3 is recommended when co-administered with azithromycin.
The pharmacokinetics of azithromycin are not significantly affected when azithromycin is combined with efavirenz or fluconazole. No dose adjustment of azithromycin is recommended in combination with the drugs in Table 4. (See [Drug Interactions]).
Table 3. Drug Interactions: Pharmacokinetic Parameters of Drugs Combined with Azithromycin
Combined drug Dose of combined drug Dose of azithromycin Number of cases Combined drug Pharmacokinetic parameters Ratio (combined/not with azithromycin) (90% CI); no effect = 1.00 Mean Cmax Mean AUC Atorvastatin 10 mg/day 8 days Days 6 to 8 500 mg/day
Day PO120.83 (0.63 to 1.08)1.01
(0.81 to 1.25) Carbamazepine 200 mg/day 2
Day 2, followed by 200 mg BID for 18 days Day 16-18 500 mg/day
mg/day PO70.97
(0.88 to 1.06)0.96 (0.88 to 1.06)Cetirizine 20 mg/day 11 days Day 7 500 mg PO, followed by Day 8 to 11 250 mg/day 141.03 (0.93 to 1.14)1.02 (0.92 to 1.13)Dehydroxylinosine 200 mg mg PO BID21 days 8 to 21 1200
mg/day PO61.44
(0.85～2.43)1.14 (0.83～1.57)Efavirenz 400 mg/day 7 days Day 7 600 mg PO141.04*0.95* Fluconazole single dose 200 mg PO single dose 1200 mg PO181.04 (0.98～1.11)1.01 (0.97 to 1.05) Indinavir 800 mg TID 5 days Day 5 1200 mg PO180.96 (0.86 to 1.08)0.90 (0.81 to 1.00) Midazolam Day 3 15 mg PO500 mg/day PO 3
Day 121.27 (0.89 to 1.81)1.26
(1.01 to 1.56) Nafinavir 750 mg TID 11 days day 9 1200 mg PO 140.90 (0.81 to 1.01) 0.85
(0.78~0.93) Rifabutin 300 mg/day Day 1 of 10 500 mg PO, followed by 250 mg PO on Days 2-10
Followed by 250 mg/day on days 2 to 10 6 See footnote below NA Sildenafil days 1 and 4 100 mg500 mg/day PO 3
Days 121.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline Days 1, 11, 25 4 mg/kg IV Day 7 500 mg PO,
Days 8 to 11 250 mg/day 101.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg PO BID
15 days Day 6 500 mg PO,
followed by 250 mg/day on days 7 to 10 81.09 (0.92-1.29)1.08
(0.89 to 1.31) Triazolam Day 2 0.125 mg Day 1 500 mg PO, followed by Day 2
250 mg/day 121.06*1.02*methoprene/sulfamethoxazole 160 mg/800 mg/day
PO 7 days Day 7 1200 mg PO120.85
(0.75 to 0.97)/
0.90
(0.78 ~ 1.03)0.87 (0.80 ~ 0.95/
0.96
(0.88～ 1.03)Zidovudine 500 mg/day PO 21 days 600 mg/day PO 14
Day 51.12
(0.42 ~ 3.02) 0.94
(0.52 ~ 1.70) Zidovudine 500 mg/day PO 21 days 1200 mg/day PO 14 days 41.31
(0.43 ~ 3.97)1.30
(0.69 to 2.43)NA – not available
* – not reported
90% confidence interval
When combined with azithromycin, rifabutin last
half a day after the 1st dose, its mean concentration was
60 ng/mL in combination with placebo and
71 ng/mL in combination with placebo.
Table 4 Drug Interactions: Pharmacokinetic parameters of azithromycin in combination with other drugs (see [Drug Interactions])
Dose of combined drugs Dose of combined drugs Dose of azithromycin Number of cases Ratio of pharmacokinetic parameters of combined drugs (with/without azithromycin) (90% CI); no effect = 1.00 Mean Cmax Mean AUC Efavirenz 400 mg/day 7 days Day 7 600 mg PO141.22
(1.04 to 1.42)0.92* Fluconazole single dose 200 mg PO single dose 1200 mg PO180.82 (0.66 to 1.02)1.07 (0.94 to 1.22)Nafinavir 750 mg TID 11 days day 9 1200 mg PO142.36
(1.77 ~ 3.15)2.12
(1.80 to 2.50) Rifabutin 300 mg/day 10 days day 1 500 mg PO,
Followed by 250 mg/day on days 2 to 10.6 See footnote below NANA – not obtained
* – not reported
90% confidence interval
In combination with rifabutin daily
300 mg when combined with rifabutin daily, the last
1 day after 1 dose
1 day, the mean azithromycin concentration was
53 ng/mL, compared to 49 ng/mL in combination with placebo.
49 ng/mL in combination with placebo.
Storage】Store in a dry place under airtight condition.
Package】Cillin bottle, 10pcs/box.
Expiration date】24 months.
Execution Standard
Approval number】
Manufacturer
Company name: Hainan Puri Pharmaceutical Co.
Production Address: Guilin Yang Economic Development Zone, Meilan District, Haikou City, Hainan Province
Postal code: 571127
Telephone number: 0898-65710369
Fax number: 0898-65710298
Web address: http://www.hnpoly.com