Azithromycin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMYCIN (AZITHROMYCIN)

Composition:

Active substance: azithromycin dihydrate;

1 tablet contains 500.0 mg of azithromycin (in the form of azithromycin dihydrate);

Excipients: calcium hydrogen phosphate anhydrous, pregelatinized starch, sodium croscarmellose, sodium lauryl sulfate, magnesium stearate;

Coating: hypromellose, titanium dioxide (E 171), polyethylene glycol 400.

Pharmaceutical form. Film-coated tablets, 500 mg.

Main physicochemical properties: white, elongated, biconvex film-coated tablets with "500" marked on one side.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Macrolides. Azithromycin. ATC code J01FA10.

Pharmacological properties

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance.

Complete cross-resistance exists in Streptococcus pneumoniae, beta-hemolytic group A streptococcus, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance among these organisms may vary depending on geographical location and time; therefore, local information on resistance patterns is needed, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the efficacy of the drug for treatment of at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

*Methicillin-resistant Staphylococcus aureus exhibits a very high prevalence of acquired resistance to macrolides and is listed here due to rare sensitivity to azithromycin.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that azithromycin concentrations in tissues are significantly higher (up to 50-fold) than in blood plasma, indicating strong tissue binding of the drug.

Binding to serum proteins 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 (VVss) is 31.1 L/kg.

The terminal plasma half-life fully reflects the tissue elimination half-life over 2–4 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 detected in human bile. Ten metabolites were also identified in bile, formed as a result of N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of results from liquid chromatography and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Ear, nose, and throat infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• Respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• Skin and soft tissue infections: erythema migrans (early stage of Lyme disease), erysipelas, impetigo, secondary pyoderma, moderate severity acne vulgaris (common acne);
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

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. Studies on the effect of concomitant antacid administration on the pharmacokinetics of azithromycin have generally shown no changes in bioavailability, although the peak plasma concentration of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine. In healthy volunteers, no pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days with cetirizine 20 mg at steady state.

Didanosine. When daily doses of 1200 mg azithromycin were administered concomitantly with 400 mg didanosine daily in six HIV-positive volunteers, no effect on the steady-state pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with a P-glycoprotein substrate such as digoxin, the possibility of increased serum concentration of the substrate should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg azithromycin had minimal effect on 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 data is not fully understood, but it may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that the drug does not have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical possibility of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended.

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

Atorvastatin. Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter atorvastatin plasma concentrations (based on HMG CoA reductase inhibition analysis). However, post-marketing reports have documented cases of rhabdomyolysis in patients taking azithromycin with statins.

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, no changes in azithromycin pharmacokinetics were observed with a single dose of cimetidine administered 2 hours before azithromycin.

Oral coumarin-type anticoagulants. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. However, post-marketing reports have described potentiation of the anticoagulant effect following concomitant use of azithromycin and oral coumarin-type anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin-type anticoagulants.

Cyclosporine. In a pharmacokinetic study in healthy volunteers who received oral azithromycin 500 mg/day for 3 days followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in Cmax and AUC0-5 of cyclosporine was demonstrated. Therefore, caution should be exercised when administering these drugs concomitantly. If concomitant use is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

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. Concomitant administration of 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, although 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 did not significantly affect the pharmacokinetics of methylprednisolone.

Midazolam. In healthy volunteers, concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics or pharmacodynamics of midazolam administered as a single 15 mg dose.

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

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect serum concentrations of either drug. Neutropenia was observed in subjects receiving both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

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

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be entirely excluded; however, there are no specific data confirming such an interaction.

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

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with triazolam (0.125 mg) to healthy volunteers did not significantly affect 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 azithromycin 1200 mg on day 7 showed no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Hydroxychloroquine. Azithromycin should be used with caution in patients receiving medicinal products that prolong the QT interval and may cause cardiac arrhythmias, such as hydroxychloroquine.

Special precautions for use.

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), as well as dermatological reactions, such as acute generalized exanthematous pustulosis. Some of these azithromycin-induced reactions have been associated with recurrent symptoms and required prolonged monitoring and treatment.

Since the liver is the primary route of azithromycin elimination, caution is advised when administering azithromycin to patients with severe hepatic impairment. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin use. Some of these patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products.

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 confirmed, azithromycin should be discontinued.

In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with rapid onset of ergotism. Data on a potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

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. Antibacterial therapy alters the normal gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile that hyperproduce toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after administration of antibacterial agents.

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

Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachycardia/torsade de pointes, has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used 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 medicinal products known to prolong the QT interval, such as 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;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Streptococcal infections. For treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is the drug of choice and is also used for prevention of acute rheumatic fever. While azithromycin is generally effective in treating oropharyngeal streptococcal infection, there are no data demonstrating its efficacy in preventing rheumatic fever. The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

The safety and efficacy of azithromycin for prevention or treatment of Mycobacterium avium complex in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on azithromycin use in pregnant women. In animal reproductive toxicity studies, azithromycin was not teratogenic, but it did cross the placenta. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding.

Azithromycin has been reported to be excreted into human breast milk; however, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted.

Fertility.

Fertility studies conducted in rats showed a decreased pregnancy rate following azithromycin administration. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

There is no direct evidence that azithromycin impairs the ability to drive or operate machinery. However, the possibility of adverse reactions such as delirium, hallucinations, dizziness, somnolence, syncope, and seizures, which may affect the ability to drive or operate machinery, should be considered.

Dosage and Administration

Azithromycin 500 mg tablets should be taken as a single daily dose, independent of food intake. Tablets should be swallowed whole, without chewing. If a dose is missed, it should be taken as soon as possible, and subsequent doses should be administered at 24-hour intervals.

Adults and children with body weight ≥45 kg.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema), the total dose of azithromycin is 1500 mg (500 mg once daily). The treatment duration is 3 days.

For acne vulgaris, the recommended total dose of azithromycin is 6 g, administered as follows: 1 tablet of 500 mg once daily for 3 days, followed by 1 tablet of 500 mg once weekly for 9 weeks. The dose for the second week should be taken 7 days after the first tablet, and the following 8 doses should be taken at 7-day intervals.

For migratory erythema, the total dose of azithromycin is 3 g, administered as follows: 1 g (2 tablets of 500 mg as a single dose) on day 1, followed by 500 mg once daily from day 2 to day 5.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (2 tablets of 500 mg as a single dose).

Elderly patients.

Dosage adjustment is not required in elderly patients.

However, since elderly patients may be at increased risk of cardiac conduction disorders, caution is recommended when using azithromycin due to the potential risk of cardiac arrhythmias, including torsade de pointes.

Patients with renal impairment.

For patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as in patients with normal renal function may be used. Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate <10 mL/min).

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. Clinical studies on azithromycin use in such patients have not been conducted.

Children.

Azithromycin 500 mg tablets are indicated for children with body weight ≥45 kg. For this pediatric group, the adult dose is recommended.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with normal 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 if necessary.

Adverse reactions.

The adverse reactions identified from clinical trials and post-marketing surveillance observed during the use of all azithromycin dosage forms are listed in the table below by system organ class and frequency of occurrence. Adverse reactions identified during post-marketing surveillance are italicized. Frequency groups were defined according to the following scale: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin based on data obtained from clinical trials and post-marketing surveillance

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical trials and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release drug formulations.

Adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex

Suspected Adverse Reactions Reporting

Reporting of suspected adverse reactions after marketing authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of the reach and sight of children.

Packaging.

3 tablets per blister pack and cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Bluepharma – Industria Farmaceutica, S.A. / Bluepharma – Industria Farmaceutica, S.A.

Manufacturer’s address and place of business / Marketing Authorization Holder’s and/or its representative’s address.

S. Martinho do Bispo, Coimbra, 3045-016, Portugal / S. Martinho do Bispo, Coimbra, 3045-016, Portugal.

Contact details of the Marketing Authorization Holder’s representative in Ukraine – LLC "CALLIPHARM" / CALLIPHARM LLC. Ukraine, 08205, Kyiv region, Irpin, 2 Poesii street, office 35 / Ukraine, 08205, Kyiv region, Irpin, 2 Poesii street, 35 office.