Azibiot film-coated tablets 500 mg blister No. 3

Instructions for use Azibiot film-coated tablets 500 mg blister No. 3

Composition

active ingredient: azithromycin;

1 tablet contains 500 mg of azithromycin in the form of azithromycin dihydrate;

Excipients: pregelatinized starch, crospovidone, calcium hydrogen phosphate, sodium lauryl sulfate, magnesium stearate, hypromellose, titanium dioxide (E 171), lactose monohydrate, triacetin.

Dosage form

Film-coated tablets.

Main physicochemical properties: oval white tablets, film-coated, with a score.

Pharmacotherapeutic group

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01F A10.

Pharmacological properties

Pharmacodynamics.

Azithromycin is a member of the macrolide group of antibiotics - azalides, which have a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin is to inhibit bacterial protein synthesis by binding to the 50 S subunit of ribosomes and preventing peptide translocation without affecting polynucleotide synthesis.

Mechanism of resistance

Resistance to azithromycin can be congenital or acquired. There are three main mechanisms of bacterial resistance: alteration of the target site, alteration of antibiotic transport, and modification of the antibiotic. Complete cross-resistance exists in Streptococcus pneumoniae, group A beta-hemolytic streptococcus, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

Azithromycin exhibits cross-resistance to erythromycin-resistant Gram-positive isolates. Decreased susceptibility to macrolides over time has been observed, in particular, in Streptococcus pneumoniae and Staphylococcus aureus. Similarly, decreased susceptibility has been observed among Streptococcus viridans and Streptococcus agalactiae (group B) streptococci to other macrolides and lincosamides.

Limit values

Azithromycin intermediate susceptibility breakpoints for typical bacterial pathogens published by EUCAST:

Susceptibility

The prevalence of acquired resistance may vary with location and time, therefore local information on resistance is necessary, especially when treating severe infections. Qualified advice may be sought if the local prevalence of resistance is such that the efficacy of the drug in the treatment of at least some types of infections is questionable.

Spectrum of antimicrobial activity of azithromycin

*Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and is listed here because of its rare susceptibility to azithromycin.

Children.

According to data from studies conducted in children, the use of azithromycin is not recommended for the treatment of malaria, either as monotherapy or in combination with drugs containing chloroquine or artemisinin, since the effectiveness of the treatment of uncomplicated malaria has not been established.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentrations are reached 2–3 hours after administration.

When administered orally, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that azithromycin concentrations in tissues are significantly higher (50 times) than in plasma, indicating strong tissue binding of the drug.

Serum protein binding varies with plasma concentrations and ranges from 12% at 0.5 μg/mL to 52% at 0.05 μg/mL in serum. The apparent volume of distribution at steady state (VVss) was 31.1 L/kg.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in the urine over the next 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also found in bile are 10 metabolites formed by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses showed that the metabolites of azithromycin are not microbiologically active.

In animal tests, high concentrations of azithromycin have been found in phagocytes. It has been established that during active phagocytosis, higher concentrations of azithromycin are released from inactive phagocytes, resulting in high concentrations of azithromycin at the site of infection.

Indication

Treatment of the following infections caused by one or more susceptible microorganisms:

bronchitis;

community-acquired pneumonia;

sinusitis;

pharyngitis/tonsillitis (see section "Special warnings and precautions for use" for streptococcal infections);

otitis media;

Skin and soft tissue infections: erythema migrans (initial stage of Lyme disease), erysipelas, impetigo, secondary pyodermatoses;

uncomplicated genital infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae.

Official requirements for the appropriate use of antibacterial drugs should also be considered.

Contraindication

Hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any other component of the drug.

Interaction with other medicinal products and other types of interactions

Antacids: In a study of the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin, there was generally no change in bioavailability, although peak plasma concentrations of azithromycin were decreased by approximately 24%. Azithromycin should be taken at least 1 hour before or 2 hours after taking an antacid.

Cetirizine: No pharmacokinetic interaction or significant changes in the QT interval were observed when azithromycin was coadministered with cetirizine 20 mg for 5 days at steady state.

Didanosine (Dideoxysine): Coadministration of daily doses of 1200 mg azithromycin and 400 mg didanosine had no effect on the pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine has been shown to increase serum P-glycoprotein levels. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered concomitantly, the possibility of increased serum digoxin concentrations should be considered. Clinical monitoring and possibly serum digoxin levels should be considered during and after azithromycin treatment.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is unknown, but they may be useful for patients.

Azithromycin does not have a significant interaction with the hepatic cytochrome P450 system. Azithromycin is not expected to have the pharmacokinetic drug interactions seen with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives: In patients taking ergot derivatives, the simultaneous use of some macrolide antibiotics contributes to the rapid development of ergotism. Due to the theoretical possibility of ergotism, azithromycin should not be used concomitantly with ergot derivatives (see section "Special instructions").

Pharmacokinetic studies have been conducted on the use of azithromycin and the following drugs, the metabolism of which occurs to a large extent with the participation of cytochrome P450.

Atorvastatin: Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on an HMG CoA reductase inhibition assay).

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not show a significant effect on the plasma levels of carbamazepine or its active metabolites.

Cimetidine: In a pharmacokinetic study of the effect of a single dose of cimetidine taken 2 hours before azithromycin on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were observed.

Cyclosporine: In a pharmacokinetic study, co-administration of 500 mg azithromycin orally for 3 days followed by a single oral dose of 10 mg/kg cyclosporine resulted in a significant increase in Cmax and AUC0-5 of cyclosporine (24% and 21%, respectively), but no significant change in AUC0-∞. If co-administration is considered warranted, cyclosporine levels should be closely monitored and the dosage adjusted accordingly.

Efavirenz: Co-administration of a single dose of azithromycin 600 mg and efavirenz 400 mg daily for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole: Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. The total exposure and half-life of azithromycin were not altered by coadministration of fluconazole, but a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir: Coadministration of a single dose of azithromycin 1200 mg had no statistically significant effect on the pharmacokinetics of indinavir administered at a dose of 800 mg 3 times daily for 5 days.

Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.

Midazolam: Concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam 15 mg.

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg 3 times a day) resulted in increased azithromycin concentrations. No clinically significant adverse events were observed, so no dosage adjustment is required.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect the plasma concentrations of these agents. Neutropenia has been observed in subjects receiving azithromycin and rifabutin concomitantly. Although neutropenia has been associated with rifabutin, a causal relationship to concomitant azithromycin administration has not been established (see Adverse Reactions).

Sildenafil: There was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite in healthy male volunteers.

Terfenadine: No pharmacokinetic interaction has been reported between azithromycin and terfenadine. The possibility of such an interaction cannot be completely excluded, but there is no evidence of such an interaction.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction with the simultaneous use of azithromycin and theophylline in healthy volunteers.

Triazolam: Coadministration of azithromycin 500 mg on the first day and 250 mg on the second day with 0.125 mg of triazolam did not significantly affect all pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole: Coadministration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 had no significant effect on Cmax, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Azithromycin plasma concentrations were consistent with those observed in other studies.

Drugs that prolong the QT interval: Azithromycin should not be administered to patients concomitantly with other drugs that may prolong the QT interval.

Application features

Hypersensitivity reactions

As with erythromycin and other macrolide antibiotics, rare serious allergic reactions, including angioedema and anaphylaxis (in isolated cases fatal), dermatological reactions, including acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported. Some of these reactions caused by azithromycin have resulted in recurrent symptoms and have required longer observation and treatment.

If hypersensitivity reactions occur, azithromycin should be discontinued and appropriate treatment initiated. Recurrence of hypersensitivity reactions may occur upon discontinuation of azithromycin therapy.

Liver dysfunction

Since the liver is the primary route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe liver disease. Cases of fulminant hepatitis, resulting in life-threatening liver dysfunction, have been reported with azithromycin (see Adverse Reactions). Some patients may have a history of liver disease or may be taking other hepatotoxic drugs.

Cases of liver dysfunction, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have been fatal. Azithromycin should be discontinued immediately if signs or symptoms of hepatitis appear.

If liver function impairment is detected, azithromycin should be discontinued.

Congenital hypertrophic pyloric stenosis (IHPS)

Infantile hypertrophic pyloric stenosis (IHPS) has been reported in infants following treatment with azithromycin, especially in the first 42 days of life. Parents and caregivers should be informed that if vomiting or irritability occurs during breastfeeding, a doctor should be consulted.

Horns

In patients taking ergot derivatives, the simultaneous use of some macrolide antibiotics contributes to the rapid development of ergotism. There is no data on the possibility of interaction between ergot and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be prescribed simultaneously with ergot derivatives.

QT prolongation

Prolongation of cardiac repolarization and the QT interval, which increases the risk of cardiac arrhythmia and ventricular tachycardia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin (see section "Adverse reactions"). Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) can lead to cardiac arrest, azithromycin should be prescribed with caution in patients with existing proarrhythmic conditions (especially women and elderly patients), in particular patients with:

with congenital or registered prolonged QT interval;

who are currently being treated with other agents that prolong the QT interval, such as: antiarrhythmics of classes IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin, chloroquine or hydroxychloroquine;

with electrolyte disturbances, especially in the case of hypokalemia and hypomagnesemia;

with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure;

Elderly patients may be more prone to QT prolongation.

Development of superinfection

Azithromycin, like other antibiotics, may cause superinfection. When using the drug, observation for signs of superinfection caused by non-susceptible organisms, including fungi, should be carried out.

Clostridium difficile-associated diarrhea

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, and has ranged in severity from mild diarrhea to fatal colitis. Clostridium difficile produces toxins A and B that contribute to CDAD. Toxin-overproducing strains of Clostridium difficile cause increased morbidity and mortality because these infections may be resistant to antimicrobial therapy and require colectomy. Therefore, the possibility of CDAD should be considered in all patients presenting with antibiotic-associated diarrhea. A careful medical history should be taken, as CDAD may occur within 2 months of antibiotic therapy. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and specific therapy should be initiated.

Streptococcal infections

The drug of choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes and for the prevention of rheumatic fever is penicillin. Azithromycin is generally effective in the treatment of streptococcal infection of the oropharynx; there are no data demonstrating the efficacy of azithromycin for the prevention of rheumatic fever.

Kidney dysfunction

In patients with severe renal dysfunction (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin was observed (see Pharmacokinetics).

Myasthenia gravis

Exacerbation of myasthenia gravis symptoms or new onset of myasthenic syndrome has been reported with azithromycin (see section 4.8).

Special warnings regarding inactive ingredients

The drug contains lactose, so it should not be used in patients with rare hereditary disorders of galactose deficiency, Lapp lactase deficiency or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding

Pregnancy

Animal reproduction studies have been performed at doses that are moderately toxic to the mother. These studies have not produced any evidence of fetal toxicity. However, there are no adequate and well-controlled studies in pregnant women. Since animal reproduction studies are not always representative of human effects, azithromycin should be used during pregnancy only if clearly needed.

Breastfeeding period

Limited data indicate that azithromycin is excreted in human milk at an estimated highest average daily dose of 0.1-0.7 mg/kg/day. No serious adverse reactions in breast-fed infants have been observed. A decision should be made whether to discontinue breast-feeding or to discontinue/abstain from azithromycin therapy, taking into account the benefit of breast-feeding for the child and the benefit of the drug for the woman.

Ability to influence reaction speed when driving vehicles or other mechanisms

Azithromycin does not affect the ability to drive vehicles and other mechanisms.

Method of administration and doses

The drug is intended for oral use. The drug should be taken once a day. Like many other antibiotics, the drug can be taken with or without food, washed down with sufficient liquid. The tablets should be swallowed without chewing.

Adults, including elderly patients and children weighing more than 45 kg

The total dose of azithromycin is 1500 mg (500 mg once daily) for 3 days.

Erythema migrans: The dose of azithromycin is 1000 mg on the first day, followed by 500 mg once daily for 4 days.

Uncomplicated sexually transmitted infections caused by Neisseria gonorrhoeae:

The recommended dose of azithromycin is 1000–2000 mg in combination with ceftriaxone 250–500 mg according to local treatment guidelines.

Patients with renal impairment

For patients with mild renal impairment (glomerular filtration rate 10-80 ml/min), the same dosage can be used as for patients with normal renal function. Azithromycin should be administered with caution to patients with severe renal impairment (glomerular filtration rate <10 ml/min) (see sections 5.2 and 4.8).

Patients with liver dysfunction

Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be used in patients with severe hepatic impairment. Studies related to the use of azithromycin in such patients have not been conducted (see section "Special warnings and precautions for use").

Children.

The drug can be used in children weighing more than 45 kg.

Overdose

Clinical experience with azithromycin suggests that adverse reactions that develop when taking higher than recommended doses of the drug are similar to those observed with the use of usual therapeutic doses. They may include diarrhea, nausea, vomiting, reversible hearing loss. In case of overdose, if necessary, it is recommended to take activated charcoal and carry out general symptomatic and supportive treatment.

Side effects

Adverse reactions are listed below by body system and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000).

Within each frequency grouping, side effects are listed in order of decreasing severity.

Infections and infestations:

Uncommon: candidiasis, oral candidiasis, vaginal infections Not known: pseudomembranous colitis.

From the blood and lymphatic system:

infrequently - leukopenia, neutropenia; unknown - thrombocytopenia, hemolytic anemia.

On the part of the immune system:

uncommon - angioedema, hypersensitivity reactions; unknown - anaphylactic reactions.

Metabolism and nutrition:

often – anorexia.

From the psyche:

infrequently - nervousness; rarely - agitation; unknown - aggressiveness, restlessness.

From the nervous system:

often - dizziness, headache, paresthesia, dysgeusia; infrequently - hypoesthesia, drowsiness, insomnia; unknown - syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis.

On the part of the organs of vision:

often - visual disturbances.

On the part of the hearing organs:

often - deafness; infrequently - hearing impairment, tinnitus; rarely - vertigo.

From the heart:

uncommon – palpitations; unknown – ventricular tachycardia (torsade de pointes), arrhythmia, including ventricular tachycardia.

From the vascular side:

unknown - arterial hypotension.

From the digestive tract:

very often - diarrhea, abdominal pain, nausea, flatulence; often - vomiting, dyspepsia; infrequently - gastritis, constipation; unknown - pancreatitis, tongue discoloration.

From the hepatobiliary system:

uncommon – hepatitis; rare – liver function abnormalities; not known – hepatic failure (which has rarely resulted in death), fulminant hepatitis, necrotizing hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders:

common - rash, itching; uncommon - Stevens-Johnson syndrome, photosensitivity reactions, urticaria; rare - acute generalized exanthematous pustulosis (AGEP), DRESS syndrome; unknown - toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders:

often – arthralgia.

From the urinary system:

not known – acute renal failure, interstitial nephritis.

General violations:

often - fatigue, infrequently - chest pain, edema, malaise, asthenia.

Laboratory indicators:

common - decreased white blood cell count, increased eosinophil count, decreased plasma bicarbonate level; uncommon - increased aspartate aminotransferase (AST), increased alanine aminotransferase (ALT), increased plasma bilirubin level, increased plasma urea level, increased plasma creatinine level, change in plasma potassium levels; unknown - prolonged QT interval on ECG.

Reporting adverse reactions after registration of a medicinal product is of great importance. This allows monitoring of the benefit/risk ratio when using this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of a medicinal product to the State Expert Center of the Ministry of Health of Ukraine at the link: https://aisf.dec.gov.ua.

Expiration date

5 years.

Storage conditions

This medicinal product does not require any special storage conditions. Keep out of the reach of children.

Packaging

3 tablets in a blister; 1 blister in a cardboard box.

Vacation category

According to the recipe.

Producer

KRKA, dd, Novo mesto, Slovenia.

KRKA Polska Sp. z oo, Poland.

Location of the manufacturer and address of its place of business.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

ul. Rownolegla 5, 02-235 Warszawа, Poland.