Azitrox, 500 mg capsules 2 pcs

Pharmacotherapeutic group: antibiotic azalid

ATX code: [J01FA10]

Pharmacological properties

Pharmacodynamics

Mechanism of action

Azithromycin binds to the 23S rRNA 50S-subunit ribosomes of susceptible microorganisms. It blocks protein synthesis by inhibiting the transpeptidation/translocation stage and inhibiting assembly of the 50S-subunit of the ribosome.

In vitro, azithromycin is concentrated in phagocytes and fibroblasts. The ratio of intracellular to extracellular concentration >30 after 1 h of incubation. In vivo studies show that concentration in phagocytes can promote spread to inflamed tissues.

The mechanism of resistance

The most common mechanism of resistance to azithromycin is modification of 23S rRNA at positions corresponding to A2058 and A2059 (in the Escherichia coli numbering system). In addition to cross-resistance with other macrolides (erythromycin and clarithromycin), ribosomal modification can determine resistance to other classes of antibiotics (lincosamides and streptogramines B), which bind to overlapping ribosomal sites.

Asithromycin shows activity against most strains of the following bacteria, both in vitro and in clinical infections: Gram-positive bacteria – Staphylococcus aureus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes; Gram-negative bacteria – Haemophilus ducreyi, Haemophilus influenzae, Moraxella catarrhalis, Neisseria gonorrhoeae; other bacteria – Chlamydia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae.

Asithromycin demonstrates in vitro minimum inhibitory concentrations (MIC) ≤4 µg/mL against most (≥90%) strains of the following bacteria; however, the safety and efficacy of azithromycin in the treatment of clinical infections caused by these bacteria have not been established in adequate and well-controlled studies.

The Gram-positive bacteria are beta-haemolytic Streptococci (Groups C, F, G), Viridans group streptococci; Gram-negative bacteria are Bordetella pertussis; anaerobic bacteria are Peptostreptococcus species, Prevotella bivia; other bacteria are Ureaplasma urealyticum, Legionella pneumophila.

Preclinical toxicology

Carcinogenicity, mutagenicity, effects on fertility. No long-term animal studies have been conducted to evaluate the carcinogenic effects of azithromycin.

Asithromycin showed no mutagenicity in standard laboratory tests: a test on mouse lymphoma cells, micronucleus tests on human lymphocytes and mouse bone marrow.

There is no evidence of impaired fertility associated with azithromycin.

Toxicology in animals

Phospholipidosis (intracellular accumulation of phospholipids) has been observed in some tissues of mice, rats and dogs receiving multiple doses of azithromycin. This has been demonstrated in many organ systems (e.g., eyes, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats receiving azithromycin at doses that, in terms of body surface area, were approximately equal (in dogs) or approximately 1/6 (in rats) of the recommended adult dose. This effect has been shown to be reversible after discontinuation of azithromycin. Similarly, phospholipidosis was observed in the tissues of newborn rats and dogs receiving daily doses of azithromycin for 10 to 30 days. Based on pharmacokinetic data, phospholipidosis was observed in rats (30 mg/kg dose) with an observed plasma Cmax of 1.3 µg/ml (6 times the observed Cmax of 0.216 µg/ml in pediatric patients at the 10 mg/kg dose). Similar data were obtained in dogs (10 mg/kg dose) with an observed serum Cmax of 1.5 mcg/mL (7 times the observed Cmax at the dose used in the pediatric population). When converted to mg/m2 body surface area, the 30 mg/kg dose for newborn rats (135 mg/m2) and the 10 mg/kg dose for newborn dogs (79 mg/m2) are approximately 0.5 and 0.3, respectively, of the recommended dose in pediatric patients with an average body weight of 25 kg. Phospholipidosis, similar to that seen in adult animals, is reversible after discontinuation of azithromycin treatment. The significance of these results in animals and humans is unknown.

Heart electrophysiology

QTc interval prolongation was studied in a randomized, placebo-controlled, parallel-group study involving 116 healthy volunteers who received chloroquine (1000 mg) alone or in combination with oral azithromycin (500, 1000 and 1500 mg once daily). Combined use with azithromycin increased the QTc interval in a dose- and concentration-dependent manner. Compared with chloroquine alone, the maximum mean (95% upper CI) increases in QTcF were 5 (10), 7 (12), and 9 (14) ms when azithromycin 500, 1000, and 1500 mg were used concomitantly, respectively.

Clinical Studies

PEDIATRIC PATIENTS

The results in pediatric clinical trials were evaluated on days 11-14 because of the increased T1/2 of azithromycin. Data from days 11 to 14 are presented for clinical guidance. An assessment on days 24-32 was considered the primary endpoint of cure.

Acute otitis media

Safety and efficacy of azithromycin at a dose of 30 mg/kg for 5 days

Protocol 1. In a double-blind, controlled clinical trial of acute otitis media conducted in the United States, patients received azithromycin (10 mg/kg on day 1, then 5 mg/kg on days 2-5) or another antibacterial drug. For patients who underwent clinical efficacy assessment (n=553), the clinical success rate (i.e., cure + improvement) on day 11 of the visit was 88% for azithromycin. For patients evaluated at the 30th day visit (n=521), the clinical success rate for patients receiving azithromycin was 73%.

The safety analysis in this study found that the incidence of treatment-related adverse events, primarily gastrointestinal events, in patients receiving azithromycin was 9%. The most frequent side effects were diarrhea/liquid stool (4%), vomiting (2%), and abdominal pain (2%).

Protocol 2. In a noncomparative clinical and microbiological study conducted in the United States, significant levels of beta-lactamase-producing organisms (35%) were found and clinical efficacy was evaluated in 131 patients. The combined clinical success rate (i.e., cure and improvement) at day 11 of the visit was 84% for patients receiving azithromycin. For the 122 patients who were evaluated at the 30th day visit, the clinical success rate for patients receiving azithromycin was 70%.

Microbiologic evaluation was performed at the visit before the start of treatment. No repeat microbiologic evaluation was performed at follow-up visits.

The estimated bacterial/clinical cure results (i.e., clinical success) obtained in the evaluable group at days 11 and 30 were as follows: S. pneumoniae 61/74 (82%) and 40/56 (71%), H. influenzae 43/54 (80%) and 30/47 (64%), M. catarrhalis 28/35 (80%) and 19/26 (73%), S. pyogenes 11/11 (100%) and 7/7, all 177/217 (82%) and 97/137 (73%).

The safety analysis in this study showed that the incidence of treatment-related side effects, primarily from the GI tract, was 9% in all treated patients. The most frequent side effect was diarrhea (4%).

Protocol 3. In another controlled comparative clinical and microbiological study conducted in the United States, azithromycin was used to treat otitis media. There were 2 investigators in this study that participated in the other trial (Protocol 2), and these 2 investigators included 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered an independent study. Significant numbers of beta-lactamase-producing organisms were found (20%). Ninety-two (92) patients were evaluated for clinical and microbiological success. The combined clinical success rate (i.e., cure and improvement) in patients with the initial pathogen on day 11 of the visit for patients receiving azithromycin was 88% and 82% on day 30.

Microbiologic evaluation was performed at the visit before the start of treatment. No repeat microbiological evaluation was performed at subsequent visits.

The estimated bacterial/clinical cure results (i.e., clinical success) obtained in the evaluated group at days 11 and 30 were as follows: S. pneumoniae 25/29 (86%) and 22/28 (79%), H. influenzae 9/11 (82%) and 8/10 (80%), M. catarrhalis 7/7 and 5/5, S. pyogenes 2/2 and 2/2, all 43/49 (88%) and 37/45 (82%). In the safety analysis in the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients receiving azithromycin was 4%. The most frequent side effect was diarrhea/iodine stools (2%).

The safety and efficacy of azithromycin at a dose of 30 mg/kg for 3 days

Protocol 4. In a double-blind, randomized controlled, comparative clinical trial (n=366) of acute otitis media in pediatric patients aged 6 months to 12 years, patients received azithromycin (10 mg/kg/day for 3 days), a comparison drug, and placebo.

For the 366 patients in whom clinical efficacy was evaluated at day 12 of the visit, the clinical success rate (i.e., cure plus improvement) for azithromycin was 83%. For the 362 patients who were evaluated on visit day 24-28, the clinical success rate for azithromycin was 74%.

In the safety analysis of the aforementioned study, the incidence of treatment-related adverse events, predominantly gastrointestinal, in all patients receiving azithromycin was 10.6%. The most frequent side effects while taking azithromycin were diarrhea/iodine stools (5.9%) and vomiting (2.1%).

The safety and efficacy of a single dose of 30 mg/kg azithromycin

Protocol 5. A double-blind, randomized controlled trial was conducted at 9 clinical sites. Pediatric patients aged 6 months to 12 years were randomized in a 1:1 ratio to treatment with either azithromycin (at a single dose of 30 mg/kg on day 1) or a comparison drug. Children received the active ingredient and a placebo corresponding to the comparison drug.

The clinical response (cure, improvement, no effect) was assessed at the end of therapy (days 12-16) and in a cure test (days 28-32). Safety was assessed throughout the trial for all patients on treatment. For the 321 patients evaluated at the end of treatment, the clinical success rate (cure plus improvement) was 87% for patients receiving azithromycin. For the 305 patients evaluated in the cure test, the clinical success rate was 75% for patients receiving azithromycin.

In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16.8% when azithromycin was taken. The most common adverse effects when taking azithromycin were diarrhea (6.4%), vomiting (4%), rash (1.7%), and nausea (1.7%).

Protocol 6. In a noncomparative clinical and microbiological study, 248 patients aged 6 months to 12 years with confirmed acute otitis media received a single oral dose of azithromycin (30 mg/kg on day 1).

The clinical success rate (i.e., cure plus improvement) at day 10 was 89% for 240 patients evaluated with the modified Intent-to-Treat (MITT) clinical analysis, and the clinical success rate (cure) was 85% for 242 patients evaluated at days 24-28.

The presumptive bacteriological eradication rates, when evaluated at days 10 and 24-28, were as follows: S. pneumoniae 70/76 (92%) and 67/76 (88%), H. influenzae 30/42 (71%) and 28/44 (64%), M. catarrhalis 10/10 (100%) and 10/10 (100%), all 110/128 (86%) and 105/130 (81%).

In the safety analysis in this study, the incidence of treatment-related adverse events, primarily gastrointestinal events, in all treated patients was 12.1%. The most frequent side effects were vomiting (5.6%), diarrhea (3.2%), and abdominal pain (1.6%).

Pharyngitis/tonsillitis

In 3 double-blind controlled trials conducted in the United States, patients received azithromycin (12 mg/kg once daily for 5 days) or a comparison drug for treatment of pharyngitis caused by documented group A hemolytic streptococci (GABHS or S. pyogenes).

The bacteriological eradication for azithromycin (for patients with documented GABHS) at days 14 and 30 was 323/340 (95%) and 255/330 (77%), respectively; clinical success (cure plus improvement) was 336/343 (98%) and 310/330 (94%), respectively.

Approximately 1% of S. pyogenes strains sensitive to azithromycin were resistant to azithromycin after therapy.

The incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated with azithromycin was 18%; the most frequent side effects were diarrhea/ liquid stool (6%), vomiting (6%), and abdominal pain (3%).

Adults

Acute bacterial exacerbations of chronic obstructive pulmonary disease

. In a randomized, double-blind, controlled clinical trial of acute exacerbations of chronic bronchitis (n=304), patients were treated with azithromycin (500 mg once daily for 3 days) or a comparison drug.

The primary endpoint of this study was clinical cure at day 21-24. For patients assessed using the clinical modified intention-to-treat analysis at day 21-24, the clinical cure rate after 3 days of azithromycin was 85% (125/147).

The bacteriologic rates of clinical cure in patients (with 3-day azithromycin therapy) at visits on days 21-24 for pathogens were: S. pneumoniae 29/32 (91%), H. influenzae 12/14 (86%), M. catarrhalis 11/12 (92%).

In the safety analysis in this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in patients receiving azithromycin was 25%. The most frequent side effects were diarrhea, nausea and abdominal pain with a frequency for each symptom of 5-9%.

Acute bacterial sinusitis

In a randomized, double-blind, placebo-controlled clinical trial of acute bacterial sinusitis, patients (n=594) received azithromycin (500 mg once daily for 3 days) or another antibacterial drug. Clinical response was assessed on days 10 and 28.

The primary endpoint of this study was prospectively defined as clinical cure on day 28. For patients who were evaluated using the clinical modified intention-to-treat analysis, the clinical cure rate with 3-day treatment with azithromycin was 88% (268/303) at a visit on day 10. For patients assessed with the clinical modified intention-to-treat analysis at day 28, the clinical cure rate for patients receiving azithromycin on 3-day therapy was 71.5% (213/298).

In the safety analysis in this study, the overall incidence of treatment-related adverse events, primarily gastrointestinal, in patients receiving azithromycin was 31%; the most frequent side effects were diarrhea (17%) and nausea (7%).

In an open, noncomparative study in patients who required an initial transantral sinus puncture and who received 500 mg of azithromycin once daily for 3 days, the following results were obtained for clinical success rates on days 7 and 28 of the visit for pathogens when assessed by clinical modified intention-to-treat analysis: S. pneumonia 23/26 (88%) and 21/25 (84%), H. influenzae 28/32 (87%) and 24/32 (75%), M. catarrhalis 14/15 (93%) and 13/15 (87%).

The overall incidence of treatment-related adverse events in the noncomparative study when assessed by the clinical modified intention-to-treat analysis was 21% in patients receiving azithromycin at a dose of 500 mg once daily for 3 days, with diarrhea (9%), abdominal pain (4%) and nausea (3%) being the most frequent side effects.

Pharmacokinetics

After oral administration of azithromycin on an empty stomach at a single dose of 500 mg (2 tablets of 250 mg) in 36 healthy male volunteers, the values (±S.D.) of pharmacokinetic parameters were as follows: AUC0-72 = 4.3 (1.2) μg-h/mL; Cmax = 0.5 (0.2) μg/mL; Tmax = 2.2 (0.9) h.

The pharmacokinetic parameters of azithromycin in plasma in healthy young adults (18-40 years of age) with a regimen of 500 mg (2 capsules of 250 mg*) on day 1 followed by daily administration of 250 mg (1 capsule of 250 mg) from days 2 to 5 on days 1 and 5 were as follows: Cmax, 0.41 and 0.24 µg/mL, Tmax, 2.5 and 3.2 h, AUC0-24, 2.6 and 2.1 µg-h/mL, Cmin, 0.05 and 0.05 µg/mL, and urinary excretion (% of dose), 4.5 and 6.5.

The Cmin and Cmax were virtually unchanged from day 2 to day 5 of therapy.

* Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules when taken on an empty stomach.

In a two-way cross-over study, 12 adult healthy volunteers (6 men, 6 women) received 1,500 mg of azithromycin in a single dose daily for 5 days (2 250 mg tablets on day 1, then 1 250 mg tablet on days 2-5) or 3 days (500 mg daily for days 1-3). Because of the limited number of serum samples on day 2 (3-day regimen) and day 2-4 (5-day regimen), the serum concentration-time profile for each subject followed a three-component model and the AUC0-∞ for the matched concentration profile was comparable between the 5-day and 3-day regimens.

The pharmacokinetic parameters (±SD) of azithromycin in serum on the 3-day dosing regimen at days 1 and 3 were as follows: Cmax was (0.44±0.22) and (0.54±0.25) μg/ml, and Cmax was (0.43±0.2) and (0.24±0.06) μg/ml in the 5-day dosing regimen on days 1 and 5. For the 3-day and 5-day regimens, serum AUC0-∞ were (17.4±6.2)* and (14.9±3.1)* µg-h/ml, respectively, and T1/2 from serum was 71.8 and 68.9 h.

* Total AUC for the entire 3-day and 5-day regimens.

The median exposure of azithromycin (AUC0-288) in mononuclear and polymorphonuclear leukocytes after the 5-day or 3-day regimen was more than 1000 and 800 times greater than in serum, respectively. One would expect that administration of the same total dose on the 5-day or 3-day regimen would provide comparable concentrations of azithromycin in mononuclear and polymorphonuclear leukocytes.

Two 250-mg tablets of azithromycin are bioequivalent to 1 500-mg tablet.

The absolute bioavailability of azithromycin in 250 mg capsules is 38%.

In a two-way cross-over study in which 12 healthy volunteers received a single dose of 500 mg azithromycin (2 tablets of 250 mg) with or without a high-fat diet, food was shown to increase Cmax by 23% but had no effect on AUC.

When azithromycin suspension was taken with food in 28 healthy male adults, food intake increased Cmax by 56%; AUC was unchanged.

The co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules had no effect on the AUC of azithromycin, but the Cmax was reduced by 24%. Administration of cimetidine (800 mg) 2 h before azithromycin administration did not affect the absorption of azithromycin.

Distribution

The binding of azithromycin to serum proteins varies over a range of concentrations approaching human exposure and decreases from 51% at 0.02 µg/mL to 7% at 2 µg/mL.

After oral administration, azithromycin is widely distributed throughout the body with an apparent Vss of 31.1 L/kg. Tissue concentrations of azithromycin are higher than those in plasma or serum. The high tissue concentrations should not be interpreted as quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH-related and appears to decrease with decreasing pH. However, widespread distribution in tissues may be relevant to clinical activity.

The concentrations of azithromycin after a dose of 500 mg (2 caps. 250 mg) in adults reach 0.4 µg/ml in the skin (72-96 h after administration), a tissue (fluid)/plasma (serum) ratio of 35, 4 µg/ml in the lungs (72-96 h), a ratio of >100, in sputum (after 2-4 h) – 1 µg/ml, ratio 2, in sputum (after 10-12 h) – 2.9 µg/ml, ratio 30, in almond gland (after 9-18 h) – 4.5 µg/ml, ratio >100, in the amygdala gland (after 180 h) – 0.9 µg/ml, ratio >100, in the cervix (after 19 h) – 2.8 µg/ml, ratio 70.

The extensive distribution in tissues was confirmed by examination of additional tissues and fluids (bone, ejaculate, prostate, ovary, uterus, fallopian tube, stomach, liver, and gallbladder). Because data from adequate and well-controlled studies of azithromycin treatment of infections in these additional tissues and fluids are lacking, the clinical significance of these tissue concentration data is unknown.

After administration of 500 mg on day 1 and 250 mg daily for 4 days, only very low concentrations (less than 0.01 mcg/mL) in cerebrospinal fluid have been noted in noninflamed cerebrospinal fluid.

Metabolism

In vitro and in vivo studies have not been performed to assess the metabolism of azithromycin.

The decrease in plasma concentrations of azithromycin after single oral and intravenous administration at a dose of 500 mg is multiphasic with a mean apparent clearance from plasma of 630 ml/min and a final T1/2 of 68 h. The prolonged final T1/2 is thought to be due to extensive absorption and subsequent release from the tissues.

The excretion of azithromycin with bile, mostly unchanged, is the main route of elimination. Within 1 week, approximately 6% of the administered dose is excreted unchanged in the urine.

Dependence of pharmacokinetic parameters on some factors

Renal insufficiency. The pharmacokinetics of azithromycin have been studied in 42 adults (21 to 85 years) with varying degrees of renal impairment. After oral administration of a single dose of azithromycin 1000 mg mean Cmax and AUC0-120 were increased by 5.1 and 4.2% respectively in patients with mild and moderate renal impairment (FFR from 10 to 80 ml/min) compared with these values in subjects with normal renal function (FFR >80 ml/min). Mean Cmax and AUC values increased by 61% and 35%, respectively, in subjects with severe renal impairment (GFR <10 ml/min) compared to those with normal renal function (GFR >80 ml/min).

Hepatic failure. The pharmacokinetics of azithromycin in patients with hepatic impairment have not been established.

Gender. There are no significant differences in pharmacokinetics of azithromycin in men and women. Adjustment of the dose according to gender is not recommended.

Elderly age. In a study in healthy elderly volunteers aged 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in younger volunteers; however, in elderly women, although higher peak concentrations (30-50% increase) were observed, no significant cumulation was observed. Dose adjustments based on age are not recommended.

Pediatric patients. In two clinical trials, azithromycin as an oral suspension at a dose of 10 mg/kg on day 1 followed by a dose of 5 mg/kg on days 2 through 5 was given to 2 groups of pediatric patients (ages 1-5 years and 5-15 years, respectively). Pharmacokinetic values on day 5 were as follows: Cmax = 0.216 μg/mL, Tmax = 1.9 h, and AUC0-24 = 1.822 μg-h/mL in the 1 to 5-year-old group and were Cmax = 0.383 μg/mL, Tmax = 2.4 h, and AUC0-24 = 3.109 μg-h/mL in the 5-15-year-old patient group.

Two clinical studies were conducted with 68 pediatric patients aged 3 to 16 years to determine the pharmacokinetics and safety of azithromycin as an oral suspension. Azithromycin was taken after a low-fat breakfast.

In the first study, 35 pediatric patients received azithromycin at a dose of 20 mg/kg/day (maximum daily dose of 500 mg) for 3 days, and pharmacokinetic parameters were evaluated in 34 patients.

In a second study, 33 pediatric patients received azithromycin at doses of 12 mg/kg/day (maximum daily dose of 500 mg) for 5 days; pharmacokinetics were evaluated in 31 patients.

In both studies, azithromycin concentrations were determined within 24 hours of the last daily dose. Patients with a body weight greater than 25 kg in the 3-day study and 41.7 kg in the 5-day study received a maximum daily adult dose of 500 mg. Eleven patients (25 kg or less) in the first study and 17 patients (41.7 kg or less) in the second study received a total dose of 60 mg/kg. The values of pharmacokinetic parameters (±SD) in subgroups of pediatric patients who received a total dose of 60 mg/kg in the first (n=11) and second (n=17) study were as follows: Cmax, (1.1±0.4) and (0.5±0.4) μg/mL, Tmax, (2.7±1.9) and (2.2±0.8) h, AUC0-24, (7.9±2.9) and (3.9±1.9) μg-h/mL.

The similarity of total exposure (AUC0-∞) between the 3-day and 5-day regimens in pediatric patients is unknown.

The pharmacokinetics of single dose in pediatric patients at doses of 30 mg/kg have not been studied.

Indications

According to the FDA (2020), oral azithromycin is indicated for the treatment of patients with mild to moderate infections (pneumonia: see “Precautions”). “Precautions”) caused by susceptible strains of the indicated microorganisms under certain conditions listed below.

Adults

Acute bacterial exacerbations of chronic obstructive pulmonary disease caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Acute bacterial sinusitis caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Out-of-hospital pneumonia caused by Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who are prescribed oral therapy.

. Azithromycin should not be used in patients with pneumonia who are not indicated for oral therapy because of moderate to severe disease or when risk factors are present, such as patients with cystic fibrosis, patients with nosocomial infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or frail patients, patients with serious underlying health problems that may impede their ability to respond to disease (including immunodeficiency or functional

Pharyngitis/tonsillitis caused by Streptococcus pyogenes is an alternative to first-line therapy in patients in whom first-line therapy cannot be used.

Note. Penicillin administered by injection/m is usually the drug of choice in the treatment of infections caused by Streptococcus pyogenes and the prevention of rheumatic fever. Azithromycin is often effective in eradicating sensitive strains of Streptococcus pyogenes from the nasopharynx. Since some strains are resistant to azithromycin, tests for azithromycin sensitivity should be performed during treatment of patients. There are no data confirming the effectiveness of azithromycin in the subsequent prevention of rheumatic fever.

Uncomplicated infections of the skin and skin structures caused by Staphylococcus aureus, Streptococcus pyogenes or Streptococcus agalactiae. Abscesses usually require surgical intervention.

Urethritis and cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoeae.

Infectious genital disease in men caused by Haemophilus ducreyi (Chancroid). Because of the small number of women included in clinical trials, the effectiveness of azithromycin in the treatment of chancroid in women has not been established.

Azithromycin should not be relied on at the recommended dose to treat syphilis. Antimicrobials used in high doses for short periods of time to treat nongonococcal urethritis may mask or delay the presentation of symptoms during the incubation period of syphilis. All patients with urethritis or cervicitis as a result of a sexually transmitted infection should have a serologic test for syphilis and appropriate cultures for gonorrhea at the time of diagnosis. If the infection is confirmed, appropriate antimicrobial therapy should be started and follow-up tests for these diseases should be performed.

At the beginning of treatment, appropriate tests should be performed to determine the pathogen and its sensitivity to azithromycin. Azithromycin therapy may be initiated before the results of these tests are available; once the results are available, antimicrobial therapy should be adjusted.

In order to prevent the development of drug-resistant bacteria and to maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should only be used to treat or prevent infections for which sensitive bacteria are proven or reasonably suspected to cause them. When culture and sensitivity information is available, it should be considered when selecting or modifying antibiotic therapy. In the absence of such data, the local epidemiologic situation and sensitivity patterns may contribute to the empirical choice of therapy.

Pediatric patients

Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Out-of-hospital pneumonia caused by Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who are indicated for oral therapy.

. Azithromycin should not be used in pediatric patients with pneumonia who are not indicated for oral therapy because of moderate to severe disease or when risk factors are present, such as patients with cystic fibrosis, patients with hospital-acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, patients with serious underlying health problems that may impede the ability to respond to disease (including immune deficiency or functional asperity).

Pharyngitis/tonsillitis caused by Streptococcus pyogenes is an alternative to first-line therapy in patients in whom first-line therapy cannot be used.

Note. Penicillin administered by injection/m is usually the drug of choice in the treatment of infections caused by Streptococcus pyogenes and the prevention of rheumatic fever. Azithromycin is often effective in eradicating sensitive strains of Streptococcus pyogenes from the nasopharynx. Since some strains are resistant to azithromycin, tests for azithromycin sensitivity should be performed during treatment of patients. There are no data confirming the efficacy of azithromycin in the subsequent prevention of rheumatic fever.

At the beginning of treatment, appropriate tests should be performed to determine the causative agent and its sensitivity to azithromycin. Azithromycin therapy may be initiated before the results of these tests are available; once the results are available, antimicrobial therapy should be adjusted.

Active ingredient

Composition

Active ingredient:

Excipients:

mannitol (mannitol),

corn starch,

How to take, the dosage

Ingestion, once daily, at least 1 hour before or 2 hours after meals.

Adults (including elderly) and children over 12 years of age with body weight over 45 kg

Infections of upper and lower respiratory tract, ENT organs, skin and soft tissue

500 mg (1 capsule) 1 time daily for 3 days (course dose 1.5 g).

In case of initial stage of Lyme disease (borreliosis) – erythema migrans

Once daily for 5 days: 1 day – 1.0 g (2 capsules), then from day 2 to day 5 – 500 mg (1 capsule) (course dose – 3.0 g).

In case of moderate acne on the 1st, 2nd and 3rd day of treatment 500 mg once a day, then a break on the 4th to 7th day, from the 8th day of treatment 500 mg once a week for 9 weeks (cumulative dose – 6 g).

Infections of the urogenital tract caused by Chlamydiatrachomatis (urethritis, cervicitis)

Uncomplicated urethritis/cervicitis – 1 g (2 capsules) once.

In patients with impaired renal function: in patients with a GFR of 10-80 ml/min, no dose adjustment is required.

In patients with hepatic impairment: No dose adjustment is required in patients with mild to moderate hepatic impairment.

Elderly patients: No dose adjustment is required. Since elderly people may already have current proarrhythmogenic conditions, caution should be exercised when using Azitrox® due to the high risk of cardiac arrhythmias, including “pirouette” arrhythmias.

Interaction

Antacids (aluminum and magnesium-containing) do not affect bioavailability of azithromycin, but reduce its maximum concentration in blood by 30%, therefore the interval between their use should be at least 1 hour before or 2 hours after taking these drugs.

The concomitant use of ergotamine and dihydroergotamine derivatives may increase their toxic effects (vasospasm, dysesthesia).

When concomitant use with coumarin-type indirect anticoagulants (warfarin) and azithromycin (in usual doses), patients require close monitoring of prothrombin time.

Caution should be exercised when prescribing terfenadine and azithromycin concomitantly, because it has been found that concomitant administration of terfenadine and macrolides may cause arrhythmias and prolongation of the QT interval. Therefore, these complications cannot be excluded when terfenadine and azithromycin are taken together.

In concomitant use of azithromycin and cyclosporine, the dose of cyclosporine should be adjusted. When concomitant use of digoxin and azithromycin it is necessary to monitor the concentration of digoxin in blood, since many macrolides increase digoxin absorption in the intestine.

The concomitant use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times daily) causes increase of equilibrium plasma concentration of azithromycin, no clinically significant adverse effects were observed and no dose adjustment of azithromycin is required in concomitant use with nelfinavir.

When azithromycin and zidovudine are coadministered, azithromycin has little effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite; azithromycin interacts weakly with cytochrome P450 isoenzymes, azithromycin has not been found to be involved in pharmacological interactions similar to those with erythromycin and other macrolides, azithromycin is not an inducer or inhibitor of cytochrome P450 isoenzymes.

In concomitant use of azithromycin and rifabutin in rare cases development of neutropenia is possible; the mechanism of its development, as well as the presence of a causal relationship with taking the drug have not been determined.

Asithromycin does not affect blood concentrations of carbamazepine, cimetidine, didanosine, efavirenz, fluconazole, indinavir, midazolam, theophylline, triazolam, trimethoprim/sulfamethoxazole, cetirizine, sildenafil, atorvastatin, rifabutin and methylprednisolone when administered simultaneously.

Special Instructions

If one dose of the drug is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken 24 hours apart.

Azitrox® should be taken at least one hour before or two hours after taking antacids.

Azitrox® should be used with caution in patients with mild to moderate hepatic impairment because of the possibility of fulminant hepatitis and severe hepatic failure. In case of symptoms of liver dysfunction such as rapidly increasing asthenia, jaundice, darkened urine, bleeding tendency, hepatic encephalopathy, treatment with azithromycin should be stopped and liver function tests should be performed.

In patients with kidney dysfunction: in patients with GFR 10-80 ml/min a dose adjustment is not required, treatment with Azitrox® should be performed with caution under renal function monitoring. As with other antibacterials, during therapy with Azitrox® patients should be regularly examined for the presence of non-susceptible microorganisms and signs of superinfections, including fungal.

Asitrox® should not be used for longer courses than directed, because the pharmacokinetic properties of azithromycin recommend a short and simple dosing regimen.

There are no data on possible interaction between azithromycin and ergotamine and dihydroergotamine derivatives, but because of the development of ergotism when using macrolides with ergotamine and dihydroergotamine derivatives simultaneously, this combination is not recommended.

Long-term use of Azitrox® may cause pseudomembranous colitis caused by Clostridium difficile, both as mild diarrhea and severe colitis. If antibiotic-associated diarrhea develops against the background of the drug, as well as 2 months after the end of therapy, clostridial pseudomembranous colitis should be excluded.

Do not use drugs that inhibit intestinal peristalsis.

In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and QT interval have been observed, increasing the risk of cardiac arrhythmias, including pirouette arrhythmias.

Azitrox® should be used with caution in patients with the presence of proarrhythmogenic factors (especially in elderly patients): with congenital or acquired prolongation of the QT interval; in patients receiving therapy with antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with disorders of fluid and electrolyte balance, especially in case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia or severe heart failure.

The use of Azitrox® may provoke myasthenic syndrome or worsen myasthenia gravis.

In case of adverse CNS reactions, patients are advised to refrain from driving and engaging in other potentially dangerous activities requiring increased concentration, rapid psychomotor and motor reactions.

Contraindications

Side effects

In clinical trials, most side effects reported were mild to moderate in severity and reversible after azithromycin withdrawal. Potentially serious side effects, such as angioneurotic edema and cholestatic jaundice, were rarely reported. Approximately 0.7% of patients (adults and children) in 5-day multiple-dose clinical trials discontinued azithromycin therapy because of the development of treatment-related side effects. In adults who received azithromycin at a dose of 500 mg/day, the rate of discontinuation due to treatment-related side effects after 3 days of treatment was 0.6%. In clinical trials involving pediatric patients, when 30 mg/kg was administered either as a single dose of azithromycin or for 3 days, discontinuation of azithromycin associated with the development of treatment-associated side effects was about 1%. Most side effects leading to discontinuation were GI-related, including nausea, vomiting, diarrhea, or abdominal pain.

The results of clinical trials

Because clinical trials are conducted with a different set of conditions, the incidence of adverse reactions observed in these clinical trials may not match that obtained in other clinical trials and observed in clinical practice.

Adults

Multidose regimens. Overall, the most common treatment-associated adverse reactions in adult patients receiving multiple doses of azithromycin were gastrointestinal effects. The most commonly reported adverse reactions were diarrhea/ fluid stools (4-5%), nausea (3%), and abdominal pain (2-3%).

There were no other treatment-related adverse effects with an incidence greater than 1% in patients receiving multiple doses of azithromycin.

The undesirable reactions that occurred with a frequency of ≤1% included the following.

Cardiovascular side: palpitations, chest pain.

Gastrointestinal disorders: dyspepsia, flatulence, vomiting, melena, cholestatic jaundice.

Urinary system: candidiasis, vaginitis, nephritis.

Nervous system disorders: dizziness, headache, vertigo, drowsiness.

General: fatigue.

Allergic reactions: rash, skin itching, photosensitivity, angioedema.

The single dose regimen is 1 g. In general, the most frequent adverse effects in patients who received azithromycin single dose 1 g were gastrointestinal related and were reported more frequently than in patients who received the multiple-dose regimen.

The side effects reported in patients receiving single-dose azithromycin with a frequency of 1% or more included diarrhea/iodine stool (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), vaginitis (1%).

The single dose regimen is 2 g. Overall, the most frequent side effects in patients who received azithromycin in a single dose of 2 g were gastrointestinal related.

The side effects reported in patients on a single dose of azithromycin in this study with a frequency of 1% or more included nausea (18%), diarrhea/ fluid stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). Most complaints were moderate in nature.

Pediatric patients

Single- and multiple-dose regimens. The types of side effects in pediatric patients were comparable to those in adults, with different frequencies for the dosing regimens recommended in pediatric practice.

Acute otitis media: at the recommended total dosage of 30 mg/kg, the most frequent treatment-related side effects (≥1%) were diarrhea, abdominal pain, vomiting, nausea, and rash.

The frequency of side effects, depending on dosing regimen, for 1-, 3-, and 5-day dosing regimens were: diarrhea, 4.3; 2.6 and 1.8%; abdominal pain, 1.4; 1.7 and 1.2%; vomiting, 4.9; 2.3 and 1.1%; nausea, 1, 0.4 and 0.5%; rash, 1, 0.6 and 0.4%.

Out-of-hospital pneumonia: for the recommended dosing regimen of 10 mg/kg on day 1 followed by 5 mg/kg on days 2-5, the most common treatment-related side effects were diarrhea/ladder stool (5.8%), abdominal pain (1.9%), vomiting (1.9%), nausea (1.9%), and rash (1.6%).

Pharyngitis/tonsillitis: with a recommended dosing regimen of 12 mg/kg on days 1-5, the most common treatment-related side effects were diarrhea (5.4%), abdominal pain (3.4%), vomiting (5.6%), nausea (1.8%), rash (0.7%), and headache (1.1%).

There were no other treatment-related side effects occurring at a frequency of >1% in pediatric practice with any treatment regimen.

The side effects observed with a frequency of ≤1% included the following.

Cardiovascular side: chest pain.

Gastrointestinal disorders: dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, oral candidiasis.

With the blood and lymphatic system: anemia, leukopenia.

Nervous system disorders: headache (in otitis media), hyperkinesia, dizziness, agitation, nervousness, insomnia.

General: fever, facial swelling, fatigue, fungal infection, malaise, pain.

Allergic: rash and allergic reaction.

Respiratory system: increased cough, pharyngitis, pleural effusion, rhinitis.

Skin and its appendages: eczema, fungal dermatitis, itching, sweating, urticaria, vesiculobulic rash.

Sensory organs: conjunctivitis.

Postmarketing experience

Unwanted reactions reported when taking azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship has not been established include the following.

Allergic reactions: arthralgia, edema, urticaria and angioedema.

Systemic reactions: arrhythmias, including ventricular tachycardia and hypotension. There have been reports of cases of prolonged QT interval and torsade de pointes.

Gastrointestinal disorders: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, rarely leading to dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, gateway stenosis; there have been rare reports of discolored tongue.

General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).

Urogenital system disorders: interstitial nephritis, acute renal failure and vaginitis.

Hematopoietic disorders: thrombocytopenia.

Liver/biliary tract disorders: adverse reactions associated with liver dysfunction.

Nervous system disorders: seizures, dizziness/vertigo, headache, drowsiness, hyperactivity, nervousness, agitation and fainting.

Mental disorders: aggressive reactions and anxiety.

Skin and skin appendages: itching, severe skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS syndrome.

Sensory organs: hearing disorders, including hearing loss, deafness and/or tinnitus, as well as reports of perversion and/or loss of taste/sensation.

Laboratory abnormalities

Adults

Clinically significant abnormalities (without regard to drug association) reported during clinical trials with an incidence greater than 1% have been reported: Decreased Hb, hematocrit, lymphocytes, neutrophils and blood glucose, increased serum CPK, potassium, ALT, GGT, AST, bilirubin, creatinine, blood glucose, platelet count, lymphocytes, neutrophils and eosinophils; with a frequency less than 1%: Leukopenia, neutropenia, decreased sodium, potassium, platelet count, increased monocyte count, basophils, bicarbonate, serum ALP, bilirubin, LDH, and phosphate. Most patients with elevated serum creatinine also had abnormal baseline values.

The changes in laboratory tests were reversible.

In multiple-dose clinical trials involving more than 5,000 patients, 4 patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities and 1 because of impaired renal function.

Pediatric patients

One-, three-, and five-day regimens. Laboratory data collected in comparative clinical trials using two 3-day regimens (30 or 60 mg/kg in divided doses for 3 days) or two 5-day regimens (30 or 60 mg/kg) in divided doses for 5 days) were similar in all azithromycin regimens, with the most clinically significant laboratory abnormalities occurring at a rate of 1-5%. Laboratory data for patients receiving 30 mg/kg as a single dose were collected in a single-center study. In this trial, absolute neutrophil counts between 500-1500 cells/mm3 were observed in 10 of 64 patients receiving 30 mg/kg once, in 9 of 62 patients receiving 30 mg/kg for 3 days, and in 8 of 63 patients in the comparison group. No patient had an absolute neutrophil count < 500 cells/mm3.

In multiple-dose clinical trials involving approximately 4,700 pediatric patients, not one patient had therapy discontinued because of treatment-related laboratory abnormalities.

Overdose

Symptoms: adverse reactions observed at doses higher than recommended were similar to those observed at normal doses, particularly nausea, diarrhea, and vomiting.

Treatment: if necessary, symptomatic and supportive therapy.

Pregnancy use

The use of the drug during pregnancy is possible only when the expected benefit to the mother exceeds the potential risk to the fetus.

Descriptions of individual cases and observational studies have shown that the use of azithromycin during pregnancy does not increase the incidence of adverse pregnancy outcomes and is not associated with any specific malformations in the child.

The WHO recommends azithromycin as the drug of choice for the treatment of chlamydial infection in pregnant women.

Breastfeeding should be stopped if it is necessary to prescribe the drug during lactation.

Similarities