Approved on.
Revision Date.
Azithromycin Tablets Instructions
Please read the instruction manual carefully and use under the guidance of your physician
[Medication Name].
Generic Name: Azithromycin Tablets
English Name: Azithromycin Tablets
Hanyu Pinyin: Aqimeisu Pian
[Ingredients].
The main ingredient of this product is Azithromycin dihydrate.
Chemical name:(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methylMethyl-a-L-nuclear-hexopyranosyl)oxygen]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-b-D-wood-Hexopyranosyl]oxo]-1-oxa-6-azacyclopentadecane-15-one
Chemical structure formula.
Molecular formula of dihydrate:C38H72N2O12-2H2O
Molecular weight of dihydrates:785.00
molecular formula of anhydrous substance:C38H72N2O12
molecular weight of anhydrous substance:749.00
[Properties].
This product is a film-coated tablet. The 0.25g tablet is engraved with “OE” on one side and “250” on the other side, while the 0.5g tablet is engraved with “OE” on one side and “500” on the other side. After removing the coating, it appears white or off-white.
[Indications].
This product is indicated for the following infections caused by sensitive bacteria.
lower respiratory tract infections such as bronchitis and pneumonia; skin and soft tissue infections; acute otitis media; and upper respiratory tract infections such as sinusitis, pharyngitis, and tonsillitis (penicillin is commonly used in the treatment of septic streptococcal pharyngitis and in the prevention of rheumatic fever. Azithromycin is effective in clearing streptococci from the oropharynx, but there is no information on the efficacy of azithromycin in treating and preventing rheumatic fever).
Azithromycin can be used for simple genital infections caused by Chlamydia trachomatis in men and women with sexually transmitted diseases. Azithromycin can also be used for simple genital infections caused by non-multiple drug-resistant gonococci and for soft chancre caused by Haemophilus ducreyi (co-infection with syphilis spirochetes must be excluded).
[Specifications]
In terms of Azithromycin (C38H72N2O12): (1) 0.25g ; (2) 0.5g.
[Dosage and Administration].
Azithromycin should be administered orally once daily, swallowed whole, and may be taken with food. The regimen and use of Azithromycin tablets for the treatment of various infectious diseases is as follows.
For sexually transmitted diseases caused by Chlamydia trachomatis, Haemophilus ducreyi, or sensitive gonococci, only a single oral dose of 1000 mg of this product is required.
For the treatment of other infections: 1500 mg total dose, 500 mg of this product once daily for three days. Or the same total dose, 500 mg on the first day and 250 mg of this product orally once daily on the second through fifth days.
Renal insufficiency Patients
Mild to moderate renal insufficiency (glomerular filtration rate of 10-80 ml/min) does not require dose adjustment. Use with caution in severe renal insufficiency (glomerular filtration rate <10ml/min) (see [Precautions] and [Pharmacokinetics]).
Patients with hepatic insufficiency
In patients with mild to moderate hepatic insufficiency, the dosage and administration of this product is the same as in normal hepatic function (see [Precautions] and [Pharmacokinetics]).
[Adverse Reactions].
(1) Adverse reactions in clinical trials
Clinical trials are conducted under a variety of different conditions; therefore, the incidence of adverse reactions observed in clinical trials of different drugs cannot be directly compared and may not reflect the incidence of adverse reactions observed during actual drug administration.
The majority of adverse reactions reported in clinical trials were mild to moderate in severity and were reversible after discontinuation of the drug. Cases of potentially severe angioedema and cholestatic jaundice have been reported. approximately 0.7% of patients (both adult and pediatric patients) in 5-day multi-dose clinical trials discontinued azithromycin therapy due to treatment-related adverse reactions. In adult patients taking a dose of 500 mg/day for 3 days, approximately 0.6% of patients discontinued due to treatment-related adverse reactions. In clinical trials in pediatric patients taking a single dose of 30 mg/kg or a total dose of 30 mg/kg for 3 days, approximately 1% of patients discontinued due to treatment-related adverse reactions. The majority of adverse reactions leading to discontinuation were gastrointestinal related, such as nausea, vomiting, diarrhea, or abdominal pain.
Adult patients
Multiple-dose dosing regimens: Overall, the most common treatment-related adverse reactions in adult patients on multiple-dose dosing regimens were related to the gastrointestinal system, with the most commonly reported adverse reactions being diarrhea/dilute stool (4%-5%), nausea (3%), and abdominal pain (2%-3%).
No other adverse reactions with an incidence >1% were seen in adult patients on a multiple-dose dosing regimen. Adverse reactions with an incidence of ≤1% included.
Cardiovascular: palpitations, chest pain.
Gastrointestinal system: dyspepsia, flatulence, vomiting, black stools, cholestatic jaundice.
Genitourinary system: Candida infection, vaginitis, nephritis.
Nervous system: Dizziness, headache, vertigo, drowsiness.
Systemic: Fatigue
Allergic: rash, pruritus, photosensitivity dermatitis and angioedema.
1g single-dose dosing regimen.
Overall, the most common adverse reactions in patients on the 1g single-dose dosing regimen were related to the gastrointestinal system and were reported more frequently than in patients on the multiple-dose dosing regimen.
Adverse reactions with an incidence of ≥1% in patients on the 1g single-dose dosing regimen included diarrhea/dilute stool (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).
2g single-dose dosing regimen.
Overall, the most common adverse reactions in patients on the 2g single-dose dosing regimen were related to the gastrointestinal system. In this study, adverse reactions with an incidence of ≥1% included nausea (18%), diarrhea/dilute stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%), with the majority of adverse reactions being mild in severity.
Pediatric patients:
Single- and multiple-dose dosing regimens: The types of adverse reactions observed in pediatric patients were similar to those observed in adult patients, but the incidence of adverse reactions varied among the recommended dosing regimens in pediatric patients.
Acute otitis media: For patients treated with the recommended total dose dosing regimen (30 mg/kg), the most common (incidence ≥1%) treatment-related adverse reactions were diarrhea, abdominal pain, vomiting, nausea, and rash [see [Dosage]].
The following table shows the incidence of adverse reactions by dosing regimen.
Dosing day protocolDiarrhea%Abdominal Pain%Vomiting%Nauseous%Rash%1st4.3%1.4%4.9%1.0%1.0%3rd2.6% 1.7%2.3%0.4%0.6%5th1.8%1.2%1.1%0.5%0.4%Community-acquired pneumonia: The most common adverse reactions due to treatment when using the recommended dosing regimen (10 mg/kg on day 1 and 5 mg/kg on days 2-5) are diarrhea/dilute stools, abdominal pain, vomiting, nausea, and rash.
The following table lists the incidence of each adverse reaction.
Dosing regimenDiarrhea/Dilute stool%Abdominal Pain%Vomiting%Nauseous%Rash%5th5.8%1.9%1.9%1.9%1.6%Pharyngitis/tonsillitis: for those on the recommended dosing regimen (12 mg/kg on days 1-5), the most common adverse reactions due to treatment are diarrhea, vomiting, abdominal pain, nausea, and headache.
The following table shows the incidence of each adverse reaction.
Dosing regimenDiarrhea%Abdominal Pain%vomiting%Nauseous%Rash%Headache5th5.4%3.4%5.6%1.8% 0.7%1.1%1.1%Regardless of the treatment regimen, no other adverse reactions with an incidence >1% occurred in pediatric patients receiving treatment. Adverse reactions with an incidence of ≤1% included.
Cardiovascular: Chest pain.
Gastrointestinal system: indigestion, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, oral candidiasis.
Blood and lymphatic system: anemia, leukopenia.
Nervous system: Headache (otitis media dose), hypermobility, dizziness, agitation, nervousness and insomnia.
Systemic: fever, facial edema, fatigue, fungal infections, discomfort and pain.
Allergic: rash, allergic reactions.
Respiratory: cough, pharyngitis, pleural effusion and rhinitis.
Skin and adnexa: eczema, fungal dermatitis, pruritus, sweating, urticaria, blistering rash.
Special sensory system: Conjunctivitis.
(2) Experience with post-marketing applications
The following adverse reactions have been identified after the approval of azithromycin for marketing. Because these reactions are derived from spontaneous reports from populations of indeterminate size, it may often not be possible to reliably estimate their incidence or to determine their relationship to drug exposure.
Adverse reactions reported in adult and/or pediatric patients while taking azithromycin after its launch that may not have a causal relationship to the drug include.
Allergy: arthralgia, edema, urticaria, and angioedema.
Cardiovascular: Arrhythmias, including ventricular tachycardia and hypotension. Cases of prolonged QT interval and tip-twist ventricular tachycardia have been reported.
Gastrointestinal system: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous enteritis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration.
Systemic: malaise, abnormal sensation, fatigue, malaise, anaphylaxis.
Genitourinary: Interstitial nephritis, acute renal failure, vaginitis.
Hematopoietic system: thrombocytopenia.
Liver/biliary: abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, liver failure [see Cautions].
Neurologic: Convulsions, dizziness/vertigo, headache, drowsiness, hyperfunction, nervousness, agitation, syncope.
Psychiatric: aggressive reactions, anxiety.
Skin and adnexa: pruritus, severe skin reactions (including erythema multiforme, acute generalized eruptive impetigo, Stevens-Johnson syndrome, toxic epidermolysis bullosa and eosinophilia granulocytosis, and systemic symptoms of drug reactions).
Specialized sensory systems: Hearing impairment (including hearing loss, deafness, and/or tinnitus) and a history of reported taste/olfactory abnormalities and/or loss.
(3) Abnormal laboratory tests.
Adult patients.
Clinically significant abnormalities reported in clinical trials (regardless of their correlation with drugs) include.
Occurrence >1%: decreased hemoglobin, decreased red blood cell pressure, decreased lymphocytes, decreased neutrophils, decreased blood glucose, increased serum creatine phosphokinase, increased potassium ions, increased ALT, GGT, AST, BUN, increased creatinine, increased blood glucose, increased increased platelet count, lymphocytosis, neutrophilia, and eosinophilia.
Occurrence <1%: leukopenia, neutropenia, decreased sodium, decreased potassium, decreased platelet count, increased monocytes, increased basophils, increased bicarbonate, increased serum alkaline phosphatase, increased bilirubin, increased LDH, and increased phosphate. elevated.
The majority of patients with elevated serum creatinine also have abnormal baseline values. Changes in laboratory values are reversible when follow-up is performed.
In a multi-dose clinical trial involving more than 5,000 patients, four patients discontinued treatment due to treatment-related liver enzyme abnormalities and one patient discontinued treatment due to abnormal renal function.
Patients with children.
1-day, 3-day, and 5-day dosing regimens
After using two 3day regimens (30 mg/kg
or
60 mg/kg administered over 3 days) or two 5 day regimens (30 mg/kg or 60 mg/kg administered over 5 days) controlled Laboratory test data were collected in a clinical trial. The data for the azithromycin regimen were found to be similar to those for all controls combined, with an incidence of most clinically meaningful laboratory test abnormalities of 1to 5%. Data were collected in a single-center trial in patients with a single dose of 30 mg/kg azithromycin. In this trial, 64 patients were given a single administered dose of 30 mg/kg azithromycin, 62 patients were given a total of 30 mg/kg azithromycin over 3 days, and 63 control patients. In these three groups of patients, 10, 9, and 8 patients developed absolute neutrophil values of 500-1500 neutrophils/mm3, respectively. No patient had absolute neutrophil values less than 500 neutrophils/mm3.
In the multi-dose clinical trial involving approximately 4700 pediatric patients, no patient discontinued treatment due to treatment-related laboratory abnormalities.
[Contraindication
Allergic reactions
It is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, other macrolides or ketolactones.
Hepatic dysfunction
Contraindicated in patients with a history of cholestatic jaundice/hepatic insufficiency following azithromycin use.
[Precautions].
General Patient Information
Azithromycin tablets can be taken before or after meals.
Patients should be aware that azithromycin and antacids containing aluminum and magnesium should not be taken together.
At the first sign of any allergic reaction after taking azithromycin, patients should stop taking the medication immediately with guidance and contact their physician.
Physicians should inform patients that antibacterial drugs, including azithromycin, should only be used to treat bacterial infections and should not be used for viral infections (e.g., the common cold). When prescribing azithromycin to patients for bacterial infections, physicians should inform patients that they should take the medication as prescribed, although most patients will feel relief from symptoms in the early stages of treatment. Not taking the medication on time or stopping it during treatment may (1) reduce the effectiveness of timely treatment and (2) increase the likelihood that bacteria will develop resistance, which in turn may lead to the development of bacteria that cannot be destroyed later with azithromycin or other antibacterial drugs.
Diarrhea is a common adverse effect of antibacterial drugs, and this symptom usually resolves when the drug is discontinued. Patients may sometimes develop watery stools and bloody stools (with/without stomach cramps and high fever) after starting antimicrobial therapy, and these symptoms may occur up to 2 months or more after the patient’s last dose of antimicrobial medication. If these symptoms occur, patients should contact their physician as soon as possible.
Allergic reactions
Severe drug allergic reactions have been reported in patients taking azithromycin for treatment, including angioedema, anaphylaxis, and skin reactions (including acute pancytopenia, Stevens-Johnson syndrome, and toxic epidermolysis bullosa). Johnson syndrome, and toxic epidermolysis bullosa). [See [Contraindications]]
Fatal cases of azithromycin hypersensitivity have been reported. Cases of drug reactions with eosinophilia and systemic symptoms (DRESS) have also been reported. Although symptomatic treatment of allergic symptoms is initially successful, allergic symptoms reappear soon after treatment is discontinued in some patients even if they are no longer taking azithromycin. These patients require an extended period of observation and treatment of allergic symptoms. The relationship between the longer semi-retention period of azithromycin in human tissues and the prolonged presence of the antigen thereafter has not been established.
In the event of an allergic reaction, the drug should be stopped immediately and treated appropriately. Physicians should be aware that allergic reactions may reappear after allopathic treatment has been stopped.
Liver toxicity
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and liver failure have been reported, some of which are lethal. Azithromycin should be discontinued as soon as signs and symptoms of hepatitis appear.
Infantile hypertrophic pyloric stenosis
Infantile hypertrophic pyloric stenosis has been reported in newborns after azithromycin administration (treatment within 42 days of birth). If vomiting and irritation occurs during feeding, parents and their caregivers should contact their physician directly.
Prolonged QT interval
Prolonged cardiac repolarization process and prolonged QT interval have been reported during treatment with macrolides such as azithromycin, which may lead to arrhythmias and tip-twisting ventricular tachycardia. Cases of tip-twisting ventricular tachycardia have been spontaneously reported in patients taking azithromycin during postmarketing surveillance. In weighing the possible risks and benefits of azithromycin, health care providers should consider that the following high-risk groups may be at risk for developing lethal QT interval prolongation.
Patients with known prolonged QT interval, a history of tip-twist ventricular tachycardia, congenital long QT interval syndrome, bradyarrhythmias, or non-compensated heart failure Patients with diseases.
Patients who are taking medications known to cause prolonged QT interval.
Patients with conditions that cause sustained arrhythmias (e.g., uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and being treated with class IA antiarrhythmic drugs (quinidine, procainamide) or class III antiarrhythmic drugs (dofetilide, amiodarone, sotalol)).
Patients who are older are more likely to be affected by drug effects on the QT interval.
Clostridium difficile-associated diarrhea
Almost all antimicrobial agents, including azithromycin, have been reported to cause C. difficile-associated diarrhea during administration, which can range in severity from mild diarrhea to fatal colitis. Treatment with antimicrobial agents can cause alterations in the normal colonic flora, leading to C. difficile overgrowth.
Clostridium difficile produces both A and B toxins, causing patients to develop C. difficile-associated diarrhea. Highly toxin-producing C. difficile leads to increased morbidity and mortality in patients, and these infections are ineffective with antimicrobial therapy and may require colon resection. The possibility of C. difficile-associated diarrhea must be considered in all patients who develop diarrhea after taking antibiotics. Cases of C. difficile-associated diarrhea have been reported after more than two months of antimicrobial agents, so a careful history needs to be taken.
If C. difficile-associated diarrhea is suspected or confirmed, patients may need to discontinue antibiotics that do not act directly on C. difficile. Appropriate hydration, electrolytes, and protein must be given as clinically indicated, as well as antibiotics effective against C. difficile, and surgical evaluation if necessary.
Worsening myasthenia gravis
Patients treated with azithromycin have reported cases of worsening myasthenia gravis and new onset myasthenia gravis syndrome.
For sexually transmitted infections
Recommended doses of azithromycin do not treat syphilis. Antimicrobial agents used to treat non-gonococcal urethritis may mask the symptoms of latent syphilis or delay the onset of these symptoms. At the time of diagnosis, a syphilis serologic test and an appropriate gonorrhea test should be performed on all patients with sexually transmitted urethritis or cervicitis. If infection is confirmed, appropriate antimicrobial therapy and follow-up should be instituted.
Production of drug-resistant bacteria
Use of this product in the absence of a confirmed or not highly suspected bacterial infection, or in the absence of an indication for prophylaxis, may not be beneficial to the patient, but may increase the risk of drug-resistant bacteria development.
Restrictions for use
Azithromycin should not be used in patients with pneumonia who are not candidates for oral therapy because of the presence of moderate to severe disease or risk factors such as.
Patients with cystic fibrosis disease.
The patient has a hospital-acquired infection.
The patient is diagnosed with or suspected of having bacteremia.
The patient requires hospitalization.
The patient is older or more frail.
Patients with underlying health problems (including immunodeficiency or absence of spleen syndrome) that may impair their ability to respond to disease.
[For Pregnant and Lactating Women
Pregnant women
Teratogenic effects: Class B gestational drugs: Reproductive toxicity tests in both rats and mice have shown that when dosing reaches dose levels that produce moderate maternal toxicity ( i.e., 200 mg/kg/day, which is approximately 22 of the human dose of 500 mg/kg/day based on body surface area. font-family:isoline”>to 4fold), no teratogenic effect was found. However, rigorous and adequate studies have not been performed on pregnant women. Because it is not always possible to predict the appropriate response in humans from animal reproduction studies, azithromycin should be given to pregnant women only when clearly needed. .
Females who are breastfeeding
Small amounts of azithromycin have been reported to be secreted in breast milk; therefore, azithromycin should be used with caution in breastfeeding women.
[Pediatric use
Azithromycin is recommended at a maximum total dose of 1500 mg in children, regardless of infection.
Azithromycin tablets should be used only in children weighing >45 kg, with the same dosage and administration as in adults.
Pharmacokinetic data in children suggest that 20 mg/kg in children is comparable to the adult dose of 1200 mg, but with a higher Cmax value.
[Geriatric Use
In multi-dose clinical trials of oral azithromycin, 9% of patients were 65 years of age or older (458/4949) and 3% were 75 years of age or older (144/4949). There was no overall difference in the efficacy or safety of azithromycin between these subjects and younger subjects, and other reported clinical experience has not identified differences in drug response between older and younger patients, but it cannot be ruled out that some older patients may be more sensitive to the drug.
Older patients may be more likely to develop tip-twist ventricular tachyarrhythmias compared with younger patients. [See [Caution]]
[Drug Interactions
Nelfinavir at steady state in combination with a single oral dose of azithromycin may increase azithromycin serum concentrations. Although no dose adjustment of azithromycin is required in combination with nelfinavir, known adverse effects of azithromycin such as liver enzyme abnormalities and hearing impairment must be monitored closely.
In a study of 22 healthy men, a 5-day treatment with azithromycin followed by warfarin did not affect prothrombin time, although spontaneous postmarketing reports suggest that the combination of azithromycin may potentiate the effects of oral anticoagulants. Patients should be closely monitored for prothrombin time when combining azithromycin and oral anticoagulants.
Studies have been conducted on the interactions between azithromycin and other drugs that may be combined with it. When used at therapeutic doses, azithromycin has little effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, desoximethylparaben, 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. When azithromycin is combined with any of these drugs, no dose adjustment of either drug is required.
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 research data, close patient monitoring is appropriate when azithromycin is combined with.
Digoxin: Blood concentrations of digoxin are elevated.
Ergotamine or dihydroergotamine: acute ergot toxicity, manifested by severe peripheral vasospasm and sensory dullness.
Tefenadine, cyclosporine, hydantoin, and phenytoin concentrations are elevated.
Effects on laboratory tests: No effects on laboratory findings have been reported.
[Drug overdose
Adverse events occurring in overdose are the same as those for the recommended dose. Once an overdose is detected, symptomatic and supportive treatment can be given according to the condition
[Pharmacology and Toxicology
Pharmacological effects
Azithromycin is the first drug in one of the subclasses of macrolide antibiotics, the azelaide antibiotics.
The mechanism of action of azithromycin is to inhibit bacterial protein synthesis by binding to subunits of the 50s ribosome and by blocking the bacterial transpeptide process.
In vitro tests have demonstrated that azithromycin is effective against a wide range of pathogenic bacteria. These include.
Gram-positive aerobic bacteria: Staphylococcus aureus, Streptococcus pyogenes (group A b-hemolytic streptococci), Streptococcus pneumoniae, a-hemolytic streptococci (Streptococcus griseus group), other streptococci, and Corynebacterium diphtheriae. Azithromycin is cross-resistant to erythromycin-resistant gram-positive bacteria including Streptococcus faecalis (enterococci) and most methicillin-resistant staphylococcal strains.
Gram-negative aerobic bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Catamorax, Bacteroides immobilis spp, Yersinia spp, Pneumophila Legionella pneumophila, Bacillus pertussis, Bacillus parapertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, Vibrio parahaemolyticus, Shigella-like Pyrococcus. The activity against Escherichia coli, Salmonella enterica, Salmonella typhi, Enterobacter spp, Aeromonas hydrophila and Klebsiella spp varies and susceptibility testing is required. It is usually resistant to Aspergillus spp, Serratia spp, Morganella spp, and Pseudomonas aeruginosa.
Anaerobic bacteria: Bacteroides fragilis, Bacteroidetes spp, P. aeruginosa, Streptococcus peptidis and Streptococcus peptidis, Clostridium necrophorum, and Propionibacterium acnes.
Sexually transmitted disease microorganisms: Chlamydia trachomatis, Syphilis dense spirochetes, gonococcus, Haemophilus ducreyi.
Other microorganisms: Spirochaete bovis (Lyme pathogen), Chlamydia pneumoniae, Mycoplasma pneumoniae, Mycoplasma histolytica, Ureaplasma urealyticum Protozoa, Campylobacter spp, Listeria monocytogenes.
Conditionally pathogenic bacteria associated with HIV infection: Mycobacterium avium intracellulare, Pneumocystis carinii, and Toxoplasma gondii.
Mechanisms of resistance
There are two major clusters of resistance determinants in clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes: mef and erm. The mef-encoded efflux pump causes bacterial resistance to only the 14- and 15-membered rings of macrolide antibiotics. mef has been detected in a variety of other genera. the erm gene encodes a 23S-rRNA methyltransferase that adds a methyl group to adenine 2058 of 23S rRNA (the numbering system of E. coli rRNA). The methylated nucleotide, in the V region, interacts with macrolide antibiotics, but also with lincosamide antibiotics and streptomycin B to form the MLSB resistance phenotype. erm(B) and erm(A) genotypes have both been detected in clinical isolates of Streptococcus pneumoniae and Streptococcus pyogenes.
AcrAB-TolC pump in Haemophilus influenzae, resulting in an inherently elevated MIC to macrolide antibiotics.
23S rRNA variants, particularly of nucleotides at positions 2057-2059 or 2611 in the V region, or of ribosomal proteins L4 or L22, are rare in clinical isolates.
Sensitive folding points
The recommended sensitivity folds for MIC values (in µg/ml) for azithromycin are (NCCLS recommended criteria).
Haemophilus spp: S £ 4, no recommendation on resistance fold *
Streptococcus including Streptococcus pneumoniae and Streptococcus pyogenes: S £ 0.5, R ³ 2
* Given the lack of information on drug-resistant strains, it is not possible to define types other than sensitive. If the MIC value of the strain is not in the sensitive range, it should be sent to the reference laboratory for further testing.
Susceptibility of bacteria
The prevalence of acquired resistance to specific strains may be geographically and temporally variable, and information on local resistance is important, especially for the treatment of severe infections. If the local resistance profile would raise concerns about treatment with the drug in at least some infections, expert advice should be sought in due course.
Usually sensitive strains
Gram-positive aerobic bacteria.
Staphylococcus aureus, Streptococcus lactis, Streptococcus (groups C, F and G) and Streptococcus straw green groups.
Gram-negative aerobic bacteria.
Bacillus pertussis, Haemophilus ducreyi, Haemophilus influenzae*$, Haemophilus parainfluenzae, Legionella pneumophila, Catamorax *, and Neisseria gonorrhoeae.
Other
Chlamydia pneumoniae*, Chlamydia trachomatis, Mycoplasma pneumoniae* and Ureaplasma urealyticum.
Strains with acquired drug resistance have been reported for.
Gram-positive aerobic bacteria.
Streptococcus pneumoniae*
Streptococcus pyogenes*
Note: Azithromycin is cross-resistant to erythromycin-resistant gram-positive strains.
Inherently resistant strains.
Enterobacteriaceae
Pseudomonas spp.
*The efficacy of this strain has been confirmed in clinical trials
$Strain with natural mediator susceptibility
Toxicological studies
Genotoxicity: Human lymphocyte assay, mouse bone marrow micronucleus assay and mouse in vitro lymphoma cell assay The results of the human lymphocyte assay, mouse bone marrow micronucleus assay and mouse in vitro lymphoma cell assay all confirm that this product is not mutagenic.
Reproductive toxicity: Reproductive toxicity tests in rats and mice have shown that at doses of moderate maternal toxicity (i.e., 200 mg/kg/day) (i.e., 200 mg/kg/day, approximately 2-4 times the human dose of 500 mg/kg/day based on body surface area), no teratogenic effects were observed.
No damage to fertility or fetus has been found.
Carcinogenicity: No data are available on the carcinogenicity of this product for long-term use in animals.
High-dose tolerance tests in animals have found that azithromycin can cause reversible phospholipid deposition when administered at concentrations 40 times the clinically used dose, but usually without the observed toxicological response. There is no evidence that similar events occur in humans when normal doses of azithromycin are applied.
Preclinical Safety Data
After multiple doses of azithromycin, microscopic examination of various tissues (e.g., eye, spinal dorsal root ganglion, liver, gallbladder, kidney, spleen, and/or pancreas) in mice, rats, and dogs reveals phospholipid foci (intracellular phospholipid accumulation). Phospholipid foci may also be seen in similar tissues in young rats and dogs. The effect was reversible after stopping azithromycin treatment. The significance of this finding for animals and humans is unclear.
[Pharmacokinetics
Absorption
After oral administration, azithromycin is widely distributed throughout the body, with bioavailability of about 37% and peak plasma concentration in 2 to 3 hours.
Distribution
Animal tests have shown that high concentrations of azithromycin are present in phagocytes. The experimental model found that activated phagocytes released higher concentrations of azithromycin than non-activated phagocytes. The results of this animal model suggest that high concentrations of azithromycin can be released to the site of infection.
Human pharmacokinetic studies have shown that tissue concentrations of azithromycin are much higher than plasma concentrations (50 times higher than the maximum plasma concentration), and that concentrations in target tissues such as lung, tonsil, and prostate are higher than the MIC of most common pathogens for a single 500 mg dose 90.
Azithromycin 600 mg orally administered daily had peak blood concentrations of 0.33 μg/ml and 0.55 μg/ml on days 1 and 22, respectively.The disseminated Mycobacterium avium intracellulare complex predominantly infected leukocytes, and the mean peak concentration of azithromycin in leukocytes The mean peak concentration of azithromycin in leukocytes was 252 μg/ml (±49%), and its concentration was maintained above 146 μg/ml (±33%) at steady state for 24 hours.
Elimination
Plasma terminal elimination half-life is closely related to tissue elimination half-life at 2-4 days.
About 12% of the intravenously administered dose is excreted in the urine in its original form within 3 days, and most of it is excreted within the first 24 hours. Azithromycin is mainly excreted in its original form via the biliary tract after oral administration. High concentrations of azithromycin and 10 metabolites were seen in human bile. Comparison of the results of HPLC of tissues and microbial content assays showed that the metabolites did not have antibacterial activity.
Pharmacokinetics in Special Populations
Elderly
Older healthy volunteers (>65 years) were found to have a slightly higher AUC than younger healthy volunteers (<40 years) after 5 days of dosing, but it is not clear what the clinically significant significance of this difference is, and therefore no dose adjustment is recommended.
Impaired renal function
The pharmacokinetic properties of azithromycin did not change significantly after a single oral dose of 1 g of this product in patients with mild to moderate renal insufficiency (glomerular filtration rate of 10 to 80 ml/min). The pharmacokinetic parameters of patients with severe renal insufficiency (glomerular filtration rate <10 ml/min) were statistically significantly different compared to those with normal renal function, with an area under the drug-time curve (0 to 120 h) of 11.7 μg.h/ml and 8.8 μg.h/ml, peak concentrations of 1.6 μg/ml and 1.0 μg/ml, respectively, and renal clearance The peak concentrations were 1.6 μg/ml and 1.0 μg/ml, respectively, and the renal clearance was 0.2 ml/min/kg and 2.3 ml/min/kg, respectively.
Impaired liver function
Patients with mild (grade A) and moderate (grade B) hepatic insufficiency had plasma pharmacokinetics that were not significantly different from those with normal liver function, but these patients had significantly increased urinary azithromycin recovery, which may be related to compensation.
[Storage]at room temperature (not to exceed 25°C)
[Packaging
(1) 0.25g: HDPE bottle: 30 tablets/bottle; Pharmaceutical aluminum foil and polyamide/aluminium/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets:6 tablets/plate.
(2) 0.5g: HDPE bottle: 30 tablets/bottle; Pharmaceutical aluminum foil and polyamide/aluminium/polyvinyl chloride cold pressed solid pharmaceutical compound hard tablets: 4 tablets/plate .
[Expiration date]24 months.
months.
[Execution Standard]
[Approval Number
(1) 0.25g: State Drug Registration H10980218
(2) 0.5g: GMP H20031081
[Manufacturer
Enterprise Name: Shiyao Group Ouyi Pharmaceutical Co.
Manufacturing Address: No. 88 Yangzi Road, Shijiazhuang Economic and Technological Development Zone
Postal Code: 052165
Tel: 0311-87886158
Fax number: 0311-87039126
Website: http://www.ouyipharma.com