Abraxane, lyophilizate 100 mg

Pharmacological group

An antibiotic of the macrolide group.

Asithromycin dihydrate is a white crystalline powder. The molecular weight is 785.

Pharmacology

Pharmacodynamics

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.

Azithromycin 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) at 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.

Microbiological 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 frequency 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 GI-related, in all patients who received 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 regimens 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 a 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

How to take, the dosage

Interaction

Nelfinavir. Co-administration of nelfinavir at equilibrium with a single oral dose of azithromycin resulted in a significant increase in serum concentrations (Cmax and AUC) of azithromycin. Although no azithromycin dose adjustment is recommended when taken in combination with nelfinavir, close monitoring is required for azithromycin side effects such as liver enzyme abnormalities and hearing impairment.

Warfarin. Although in a study involving 22 healthy men, a 5-day course of azithromycin had no effect on PV with a subsequent dose of warfarin, spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Careful monitoring of PV should be undertaken if patients receive azithromycin and oral anticoagulants concomitantly.

Interaction studies have been conducted with azithromycin and other drugs that may be used simultaneously. When used in therapeutic doses azithromycin had moderate effect on pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (IV and oral), triazolam, trimethoprim/sulfamethoxazole and zidovudine. Combined use with efavirenz or fluconazole had a moderate effect on the pharmacokinetics of azithromycin. Dose adjustment of the above drugs is not recommended when combined with azithromycin.

In clinical trials of azithromycin no interactions with the drugs listed below have been reported. However, no specific studies have been conducted to evaluate potential interactions. Interactions have been observed with other drugs from the group of macrolides. It is recommended to carefully monitor patients until additional data on interaction of the following drugs with azithromycin are obtained: digoxin (increased concentration of digoxin); ergotamine or dihydroergotamine (acute ergotamine toxicity characterized by severe peripheral vasospasm and dysesthesia); terfenadine, cyclosporine, hexobarbital and phenytoin (concentration changes).

Interaction studies have been conducted with azithromycin and other drugs that can be used simultaneously. The effect of azithromycin co-administration on the pharmacokinetics of other drugs is shown in Table 1, and the effect of other drugs on the pharmacokinetics of azithromycin is shown in Table 2.

The concomitant use of azithromycin at therapeutic doses had a moderate effect on the pharmacokinetics of the drugs listed in Table 1. When concomitant use with azithromycin, no dose adjustments of the drugs listed in Table 1 are recommended.

The co-administration of azithromycin with efavirenz or fluconazole had a moderate effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased C and AUC of azithromycin. Dose adjustment of azithromycin is not recommended when taken with the drugs listed in Table 2.

Table 1

Interaction with other drugs: Pharmacokinetic parameters of co-administered drugs in the presence of azithromycin

Ratio (with/without azithromycin) of pharmacokinetic parameters of simultaneously used drugs (90% CI);

no effect = 1

NA No data

* 90% CI not specified.

The values of rifabutin concentrations half a day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo.

Table 2

Interaction with other drugs: Pharmacokinetic parameters of azithromycin in the presence of co-administered drugs

Ratio (with/without co-administered drug) of azithromycin pharmacokinetic parameters (90% CI);

no effect = 1

NA No data

* 90% CI not specified.

The values of azithromycin concentrations one day after the last dose were 53 ng/mL when taken concomitantly daily with 300 mg rifabutin and 49 ng/mL when taken concomitantly with placebo.

Special Instructions

Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis and dermatological reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have rarely been observed in patients receiving azithromycin. Fatal cases, although rare, have been reported. Despite initially successful symptomatic treatment of allergic symptoms, after discontinuation of symptomatic therapy, some patients reappeared shortly thereafter with a recurrence of allergic symptoms without further exposure to azithromycin. Long-term follow-up and symptomatic treatment was required in these patients. The relationship of these episodes to the prolonged half-life of azithromycin in the tissues and subsequent prolonged exposure to the antigen is currently unknown.

In the event of an allergic reaction, azithromycin should be discontinued and appropriate therapy administered. Physicians should be aware that allergic symptoms may reappear after discontinuing symptomatic therapy.

Hepatotoxicity

Hepatic dysfunction, hepatitis, cholestatic jaundice, hepatic necrosis and hepatic failure, some of which have resulted in death, have been reported. The use of azithromycin should be discontinued immediately if signs and symptoms of hepatitis appear.

The treatment of pneumonia

The safety and efficacy of azithromycin has been shown only in the treatment of community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients who are indicated for 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 hospital-acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or frail patients, patients with serious underlying health problems that may impede responsiveness to the disease (including immunodeficiency or functional

Diarrhea associated with Clostridium difficile

The development of diarrhea associated with Clostridium difficile has been reported with virtually all antibacterials, including azithromycin for injection, and can range in severity from mild diarrhea to fatal colitis. Treatment with antibacterials leads to a modification of the normal flora of the large intestine and an overgrowth of C. difficile.

The C. difficile strains produce toxins A and B, which cause the development of diarrhea. C. difficile strains producing hypertoxin lead to an increased risk of morbidity and mortality because these infections may be resistant to antimicrobial therapy and require colectomy. The possibility of C. difficile-associated diarrhea should be considered in all patients who present with complaints of diarrhea after antimicrobial use. A thorough history should be taken, as C. difficile-associated diarrhea may develop within 2 months after antimicrobial use.

If C. difficile-associated diarrhea is suspected or confirmed, azithromycin should be stopped and appropriate treatment (including fluids and electrolytes, protein supplements, antibiotics to which C. difficile strains are sensitive) and surgical evaluation should be initiated if clinically indicated.

QT interval prolongation

In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and the QT interval have been observed, leading to a risk of cardiac arrhythmias and torsade de pointes. Cases of torsade de pointes have been reported during post-marketing follow-up in patients receiving azithromycin. The risk of QT interval prolongation, which can be fatal, should be considered when evaluating the risks and benefits of azithromycin for at-risk groups, including:

Patients with known QT interval prolongation, a history of torsade de pointes, congenital prolonged QT interval syndrome, bradyarrhythmia, or uncompensated heart failure;

Patients taking medications that prolong the QT interval;

Patients taking current arrhythmias – patients with current proarrhythmic conditions such as unadjusted hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (quinidine, procainamide) or Class III antiarrhythmic agents (dofetilide, amiodarone, sotalol).

The elderly patients may be more sensitive to the effects of drugs that cause prolongation of the QT interval.

The exacerbation of myasthenia gravis symptoms and myasthenic syndrome have been reported in patients receiving azithromycin therapy.

The development of resistant bacteria

The administration of azithromycin in the absence of a confirmed/suspected bacterial infection or for prophylactic reasons is unlikely to benefit the patient and increases the risk of development of resistant bacteria.

Hepatic impairment in adults

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

As azithromycin is mainly excreted through the liver, caution should be exercised when prescribing azithromycin in patients with hepatic impairment.

Dose adjustment is not recommended for patients with renal impairment with a GFR ≥80 mL/min. The AUC0-120 was similar in subjects with a GFR of 10-80 ml/min and those with normal renal function, whereas in patients with a GFR of <10 ml/min it was increased by 35% compared to that in normal renal function. Caution should be exercised when azithromycin is administered in patients with severe renal impairment (GFR <10 ml/min) due to limited data.

Pediatric use

Acute otitis media. The safety and efficacy of oral azithromycin for the treatment of acute otitis media in children less than 6 months old has not been established.

Acute bacterial sinusitis. The safety and effectiveness of treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. The oral use of azithromycin for the treatment of acute bacterial sinusitis in pediatric patients (6 months of age and older) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and children, and studies of acute otitis media in pediatric patients.

Out-of-hospital pneumonia. The safety and effectiveness of treatment of pediatric patients with community-acquired pneumonia before 6 months of age have not been established.

Safety and effectiveness in pneumonia caused by Chlamydophila pneumoniae and Mycoplasma pneumoniae have been documented in pediatric clinical trials.

Safety and efficacy in pneumonia caused by Haemophilus influenzae and Streptococcus pneumoniae have not been confirmed bacteriologically in pediatric clinical trials because of difficulties in obtaining specimens. The use of azithromycin against these two microorganisms, however, is supported by data from adequate and well-controlled studies in adults.

Pharyngitis/tonsillitis. Safety and efficacy in the treatment of pediatric patients under 2 years of age with pharyngitis/tonsillitis have not been established.

There have been no studies evaluating the use of repeated courses of therapy.

Geriatric use

The pharmacokinetic parameters of azithromycin in elderly volunteers (65-85 years) were similar to those in younger volunteers (18-40 years) with a 5-day therapy regimen. Dose adjustment is not required in elderly patients with normal renal and hepatic function on this dosing regimen.

In clinical trials of multiple doses of oral azithromycin, 9% of patients were at least 65 years of age (458/494949) and 3% of patients (144/494949) were older than 75 years. No overall differences in safety or efficacy were observed between these and younger patients; other reported clinical experience showed no differences in response between older and younger patients, but the higher sensitivity of some older patients cannot be ruled out.

Elderly patients may be at greater risk of developing torsade de pointes arrhythmias than younger patients.

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

Pregnancy

The FDA fetal category is B.

Teratogenic effects. Reproduction studies have been performed on rats and mice when administered orally at doses to moderately toxic maternal concentrations (i.e., 200 mg/kg/day). These daily doses for rats and mice, depending on body surface area, are estimated to be 4 and 2 times the daily dose of 500 mg for adults, respectively. No evidence of fetal harm due to the effects of azithromycin has been found in animal studies. However, adequate and well-controlled studies in pregnant women have not been conducted. Because animal studies do not always predict effects in humans, azithromycin should only be used during pregnancy if absolutely necessary.

Breastfeeding

It has been reported that azithromycin is excreted in small amounts into human breast milk. Caution should be exercised when azithromycin is used in breastfeeding women.

Similarities