Azibiot®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZIBIOT® (AZIBIOT®)

Composition:

Active substance: azithromycin;

1 tablet contains 500 mg of azithromycin as azithromycin dihydrate;

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

Pharmaceutical form. Film-coated tablets.

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

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a member of the macrolide antibiotic group – azalides – with a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide translocation, without affecting polynucleotide synthesis.

Mechanism of resistance

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

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

Breakpoint values

Intermediate susceptibility breakpoints for azithromycin against typical bacterial pathogens as published by EUCAST:

Susceptibility

The prevalence of acquired resistance may vary depending on geographical location and time, so local information on resistance is necessary, especially when treating severe infections. Expert advice should be sought if local resistance patterns raise doubts about the efficacy of the drug in treating at least some types of infections.

Antimicrobial spectrum of azithromycin

*Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and is listed here due to 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 chloroquine-containing or artemisinin-containing drugs, since the efficacy of treatment for uncomplicated malaria has not been established.

Pharmacokinetics.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after administration.

After oral intake, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that tissue concentrations of azithromycin are significantly higher (up to 50 times) than plasma concentrations, indicating extensive tissue binding of the drug.

Protein binding in serum varies depending on plasma concentrations, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum. The apparent volume of distribution at steady state (Vss) is 31.1 L/kg.

The terminal plasma elimination half-life from tissues ranges from 2 to 4 days.

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

In animal studies, high concentrations of azithromycin were detected in phagocytes. It has been established that during active phagocytosis, higher concentrations of azithromycin are released from inactive phagocytes, leading to high concentrations of azithromycin at the site of infection.

Clinical characteristics.

Indications.

Treatment of infections caused by one or more susceptible microorganisms:

• bronchitis;
• community-acquired pneumonia;
• sinusitis;
• pharyngitis/tonsillitis (see section "Special precautions" regarding streptococcal infections);
• otitis media;
• skin and soft tissue infections: erythema migrans (early stage of Lyme disease), impetigo, secondary pyoderma;
• uncomplicated genital infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae.

Official guidelines on appropriate use of antibacterial agents should also be considered.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Antacids. Studies on the effect of concomitant antacid administration on azithromycin pharmacokinetics showed no overall changes in bioavailability, although plasma peak concentrations of azithromycin decreased by approximately 24%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid intake.

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

Didanosine (dideoxyinosine). No effect on didanosine pharmacokinetics was observed when daily doses of 1200 mg azithromycin and 400 mg didanosine were administered concomitantly compared to placebo.

Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine may increase serum levels of P-glycoprotein. Therefore, when azithromycin and P-glycoprotein substrates such as digoxin are co-administered, increased serum concentrations of digoxin should be considered. Clinical monitoring and possibly serum digoxin level measurements are required during and after azithromycin therapy.

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 mononuclear cells of peripheral circulation. The clinical significance of these findings is not fully understood, but this effect may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that azithromycin does not exhibit the pharmacokinetic drug interactions observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. In patients receiving ergot derivatives, concomitant use of certain macrolide antibiotics may lead to rapid development of ergotism. Due to the theoretical possibility of ergotism, azithromycin should not be used concomitantly with ergot derivatives (see section "Special precautions").

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin with the following agents, whose metabolism is largely mediated by cytochrome P450.

Atorvastatin. Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG CoA reductase inhibition analysis).

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin showed no significant effect on plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, a single dose of cimetidine taken 2 hours before azithromycin did not affect azithromycin pharmacokinetics.

Oral anticoagulants of the coumarin type. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin in healthy volunteers. However, during the post-marketing period, reports of potentiation of the anticoagulant effect have been received following concomitant use of azithromycin and oral anticoagulants of the coumarin type. Although a causal relationship has not been established, monitoring of prothrombin time is recommended when azithromycin is prescribed to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. According to pharmacokinetic study results, concomitant oral administration of azithromycin 500 mg for 3 days followed by a single 10 mg/kg dose of cyclosporine led to a significant increase in Cmax and AUC0-5 of cyclosporine (by 24% and 21%, respectively), although AUC0-∞ was not significantly altered. If concomitant use is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are required.

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

Fluconazole. A single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not have a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Methylprednisolone. In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.

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

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) increases azithromycin concentrations. No clinically significant adverse events were observed; therefore, dose adjustment is not necessary.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect plasma concentrations of either agent. Neutropenia was observed in subjects receiving both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin intake has not been established (see section "Adverse reactions").

Sildenafil. No evidence was found of the effect of azithromycin (500 mg daily for 3 days) on AUC or Cmax of sildenafil or its main circulating metabolite in healthy male volunteers.

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. However, such an interaction cannot be completely excluded, although data on its occurrence are lacking.

Theophylline. There are no data on clinically significant pharmacokinetic interactions when azithromycin and theophylline are administered concomitantly in healthy volunteers.

Triazolam. Concomitant administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg triazolam had no significant effect on any pharmacokinetic parameters of triazolam compared to triazolam with placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with 1200 mg azithromycin 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.

Medicinal products that prolong the QT interval. Azithromycin should not be administered concomitantly with other medicinal products that may prolong the QT interval.

Special precautions for use.

Hypersensitivity reactions

As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioedema and anaphylaxis (in isolated cases with fatal outcome), dermatological reactions, including acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Some of these reactions induced by azithromycin have led to recurrent symptoms and required prolonged monitoring and treatment.

In the event of hypersensitivity reactions, administration of azithromycin should be discontinued immediately and appropriate treatment initiated. Hypersensitivity reactions may recur after discontinuation of azithromycin therapy.

Hepatic function impairment

Since the liver is the primary route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported during azithromycin therapy (see section "Adverse reactions"). Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products.

Cases of hepatic dysfunction, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which resulted in fatal outcomes. Azithromycin therapy should be discontinued immediately upon onset of signs or symptoms of hepatitis.

Liver function tests should be performed if signs or symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Congenital hypertrophic pyloric stenosis (IHPS)

Cases of hypertrophic pyloric stenosis (IHPS) in infants following azithromycin treatment have been reported, particularly within the first 42 days of life. Parents and caregivers should be informed to seek medical advice if vomiting or irritability during feeding occurs.

Ergot derivatives

In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics may lead to rapid development of ergotism. There are no data available on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

QT interval prolongation

Prolongation of cardiac repolarization and QT interval, which increases the risk of developing cardiac arrhythmias 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) may lead to cardiac arrest, azithromycin should be administered with caution in patients with existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired QT prolongation;
• currently receiving treatment with other agents that prolong the QT interval, e.g.: class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin, chloroquine or hydroxychloroquine;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure;
• elderly patients who may be more susceptible to QT interval prolongation.

Development of superinfection

Like other antibiotics, azithromycin may lead to the development of superinfection. During treatment, patients should be monitored for signs of superinfection caused by non-susceptible organisms, including fungi.

Clostridium difficile-associated diarrhea (CDAD)

Diarrhea associated with Clostridium difficile (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. Hyperproducing toxin strains of Clostridium difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. Therefore, CDAD should be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is essential, as CDAD may occur up to two months after antibiotic administration. If pseudomembranous colitis is suspected, azithromycin should be discontinued immediately and specific therapy initiated.

Streptococcal infections

Penicillin is the drug of choice for the treatment of Streptococcus pyogenes-induced pharyngitis/tonsillitis and for the prevention of rheumatic fever. While azithromycin is generally effective in treating streptococcal oropharyngeal infection, there are no data demonstrating its efficacy in the prevention of rheumatic fever.

Renal dysfunction

In patients with severe renal impairment (glomerular filtration rate <10 ml/min), a 33% increase in systemic exposure to azithromycin has been observed (see section "Pharmacokinetics").

Myasthenia gravis

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported during azithromycin therapy (see section "Adverse reactions").

Special warnings regarding inactive ingredients

The product contains lactose; therefore, it should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy

Reproductive toxicity studies in animals were conducted using doses corresponding to moderately toxic levels for the maternal organism. These studies did not demonstrate any evidence of azithromycin-induced fetal toxicity. However, adequate and well-controlled studies in pregnant women are lacking. Since animal reproductive studies do not always predict human response, azithromycin should be used during pregnancy only if clearly needed.

Period of breastfeeding

Limited data indicate that azithromycin is excreted into human breast milk, with an estimated maximum average daily infant dose of 0.1–0.7 mg/kg/day. No serious adverse reactions have been observed in breastfed infants. The decision to discontinue breastfeeding or to discontinue azithromycin should be based on the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Ability to affect reaction speed when driving or operating machinery.

Azithromycin does not affect the ability to drive or operate machinery.

Dosage and Administration

The drug is intended for oral administration. The drug should be taken once daily. As with many other antibiotics, the drug can be taken with or without food, with sufficient fluid. Tablets should be swallowed whole without chewing.

Adults, including elderly patients and children with body weight over 45 kg

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

Lyme disease (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 at a dose of 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 as for patients with normal renal function can be used. Azithromycin should be administered with caution to patients with severe renal impairment (glomerular filtration rate <10 mL/min) (see sections "Pharmacokinetics" and "Adverse Reactions").

Patients with hepatic impairment

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to patients with severe hepatic impairment. Studies on the use of azithromycin in such patients have not been conducted (see section "Special Warnings and Precautions for Use").

Children

The drug can be administered to children with body weight over 45 kg.

Overdose

Clinical experience with azithromycin indicates that adverse reactions occurring after ingestion of doses higher than recommended are similar to those observed with standard therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive treatment measures are recommended as necessary.

Adverse Reactions

The adverse reactions listed below are classified by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000).

Within each frequency group, adverse effects are listed in decreasing order of severity.

Infections and infestations:

Uncommon – candidiasis, oral candidiasis, vaginal infections; unknown frequency – pseudomembranous colitis.

Blood and lymphatic system disorders:

Uncommon – leukopenia, neutropenia; unknown frequency – thrombocytopenia, haemolytic anaemia.

Immune system disorders:

Uncommon – angioneurotic oedema, hypersensitivity reactions; unknown frequency – anaphylactic reactions.

Metabolism and nutrition disorders:

Common – anorexia.

Psychiatric disorders:

Uncommon – nervousness; rare – agitation; unknown frequency – aggression, restlessness.

Nervous system disorders:

Common – dizziness, headache, paraesthesia, dysgeusia; uncommon – hypoaesthesia, somnolence, insomnia; unknown frequency – syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis.

Eye disorders:

Common – visual disturbances.

Ear and labyrinth disorders:

Common – deafness; uncommon – hearing impairment, tinnitus; rare – vertigo.

Cardiac disorders:

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

Vascular disorders:

Unknown frequency – arterial hypotension.

Gastrointestinal disorders:

Very common – diarrhoea, abdominal pain, nausea, flatulence; common – vomiting, dyspepsia; uncommon – gastritis, constipation; unknown frequency – pancreatitis, change in tongue colour.

Hepatobiliary disorders:

Uncommon – hepatitis; rare – liver function abnormalities; unknown frequency – hepatic failure (rarely leading to fatal outcome), fulminant hepatitis, necrotic hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders:

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

Musculoskeletal and connective tissue disorders:

Common – arthralgia.

Renal and urinary disorders:

Unknown frequency – acute renal failure, interstitial nephritis.

General disorders and administration site conditions:

Common – fatigue; uncommon – chest pain, oedema, malaise, asthenia.

Investigations:

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, changes in plasma potassium levels; unknown frequency – QT interval prolongation on ECG.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy to the State Expert Centre of the Ministry of Health of Ukraine via the following link: https://aisf.dec.gov.ua.

Shelf life. 5 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

Packaging.

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

Prescription status.

Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia.

KRKA Poland Sp. z o.o., Poland.

Manufacturer's address and location of operations.

Smarjeska cesta 6, 8501 Novo mesto, Slovenia.

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