Ziomycin®

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

Composition:

Active substance: azithromycin;

One tablet contains azithromycin dihydrate equivalent to 250 mg or 500 mg of azithromycin;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, povidone K 90, talc, magnesium stearate, coating Opadry 04B52069 yellow: hypromellose, titanium dioxide (E 171), quinoline yellow (E 104), polyethylene glycols.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: capsule-shaped, film-coated yellow tablets, marked "A 250" on one side and smooth on the other;

500 mg tablets: capsule-shaped, film-coated yellow tablets, marked "A 500" on one side and smooth on the other.

Pharmacotherapeutic group.

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

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the 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 among Streptococcus pneumoniae, beta-hemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant *Staphylococcus aure游戏副本

Commonly susceptible organisms

Aerobic gram-positive bacteria

Staphylococcus aureus methicillin-susceptible Streptococcus pneumoniae penicillin-susceptible Streptococcus pyogenes

Aerobic gram-negative bacteria

Haemophilus influenzae Haemophilus parainfluenzae Legionella pneumophila Moraxella catarrhalis Pasteurella multocida

Anaerobic bacteria

Clostridium perfringens Fusobacterium spp. Prevotella spp. Porphyriomonas spp.

Other microorganisms

Chlamydia trachomatis Chlamydia pneumoniae Mycoplasma pneumoniae

Organisms that may exhibit resistance

Aerobic gram-positive bacteria

Streptococcus pneumoniae with intermediate susceptibility to penicillin and penicillin-resistant

Naturally resistant organisms

Aerobic gram-positive bacteria

Enterococcus faecalis MRSA, MRSE* Staphylococci

Anaerobic bacteria

Bacteroides fragilis group

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

Pharmacokinetics.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after administration. Following oral intake, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that tissue concentrations of azithromycin are significantly higher (up to 50-fold) 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 (V_ss) is 31.1 L/kg.

The terminal plasma elimination 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 found in human bile. Ten metabolites have also been identified in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of liquid chromatography results 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 (ENT) 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), impetigo, secondary pyoderma, moderate acne vulgaris (common acne);
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Antacids. When studying the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine. In healthy volunteers, concomitant administration of azithromycin for 5 days and cetirizine 20 mg at steady state did not reveal any pharmacokinetic interaction or significant changes in QT interval.

Didanosine. In six HIV-positive volunteers, concomitant administration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day did not show any effect on the steady-state pharmacokinetics of didanosine 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 P-glycoprotein substrates. Therefore, when azithromycin is used concomitantly with P-glycoprotein substrates such as digoxin, the possibility of increased digoxin serum concentrations 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, administration of azithromycin increased concentrations of phosphorylated zidovudine, a clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not fully understood, but they may be beneficial in patient treatment.

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

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

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

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, cases of rhabdomyolysis have been reported in patients receiving azithromycin with statins during the post-marketing period.

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

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

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 administered to healthy volunteers. However, there are reports of potentiation of the anticoagulant effect after concomitant use of azithromycin and oral anticoagulants of the coumarin type. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. In a pharmacokinetic study involving 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. The overall exposure and elimination half-life of azithromycin were not altered by concomitant administration of fluconazole; however, a clinically insignificant decrease 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) leads to 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 intake has not been established.

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

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. However, such an interaction cannot be completely excluded; nevertheless, there are no specific data confirming such an interaction.

Theophylline. No clinically significant pharmacokinetic interaction was observed when azithromycin and theophylline were administered concomitantly to healthy volunteers.

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 did not show any significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum concentrations of azithromycin 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.

Hypersensitivity.

As with erythromycin and other macrolide antibiotics, serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases with fatal outcome), 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 observation and treatment.

Hepatotoxicity.

Since the liver is the main 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. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

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

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

Ergot derivatives.

In patients taking ergot derivatives, concomitant administration of some macrolide antibiotics may lead to rapid development of ergotism. There are no data on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

QT interval prolongation.

Prolongation of cardiac repolarization and QT interval, which may increase the risk of developing cardiac arrhythmias 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 pre-existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired QT prolongation;
• receiving treatment with other agents known to 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;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Superinfections.

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

Clostridium difficile-associated diarrhea (CDAD).

Cases of Clostridium difficile-associated diarrhea (CDAD) have been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal flora of the colon, 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 higher morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is necessary, as CDAD has been reported to occur up to two months after administration of antibacterial agents. If CDAD develops, azithromycin therapy should be discontinued and specific treatment for C. difficile initiated.

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 streptococcal infection in the oropharynx, there are no data demonstrating the efficacy of azithromycin in preventing 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.

Myasthenia gravis.

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

Other.

Safety and efficacy for prevention or treatment of Mycoplasma avium complex in children have not been established.

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, doses corresponding to moderately toxic levels for the maternal organism were used. No evidence of fetal toxicity of azithromycin was observed in these studies. However, adequate and well-controlled studies in pregnant women are lacking. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding period

It has been reported that azithromycin penetrates into human breast milk, but adequate and well-controlled clinical studies characterizing the pharmacokinetics of excretion of azithromycin into human breast milk have not been conducted.

Fertility

Fertility studies were conducted in rats; the pregnancy rate decreased after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

The medicinal product should be administered as a single daily dose, regardless of food intake. Tablets should be swallowed whole without chewing. If a dose is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Adults and children with body weight > 45 kg.

Indications	Total dose	Treatment regimen
		Period	Dose	Frequency
Infections of the ear, nose and throat, respiratory tract, skin and soft tissues (except chronic migrating erythema)	1500 mg	Days 1 to 3	500 mg	Once daily
Vulgaris acne	6000 mg	1st week (days 1 to 3)	500 mg	Once daily
		Weeks 2 to 10	500 mg	Once weekly*
Migratory erythema	3000 mg	Day 1	1000 mg	Once daily
		Days 2 to 5	500 mg	Once daily
Sexually transmitted infections	1000 mg	Day 1	1000 mg	Once daily

* The dose for the 2nd week should be taken 7 days after the first day of drug administration. Doses from the 3rd to the 10th week should be taken at 7-day intervals.

Geriatric patients.

In elderly patients, there is no need to adjust the dosage.

Since elderly patients may be at risk for cardiac conduction disorders, caution is recommended when administering azithromycin due to the risk of developing cardiac arrhythmias, including torsades de pointes.

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 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 used in patients with severe hepatic impairment. Studies on treatment with azithromycin in such patients have not been conducted.

Children.

The drug should be administered to children with body weight above 45 kg. For children with body weight below 45 kg, azithromycin formulations in appropriate dosage forms are recommended.

Overdose.

Symptoms: adverse effects occurring after intake of doses higher than recommended are similar to those observed with usual therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss.

Treatment: if necessary, administration of activated charcoal and implementation of general symptomatic and supportive measures are recommended.

Adverse reactions

The adverse reactions listed in the table below are categorized by system organ class and frequency of occurrence, as identified in clinical studies and during the post-marketing surveillance period, and observed during the use of all azithromycin dosage forms. Adverse reactions reported during the post-marketing period are indicated in italics. Frequency groups are 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 group, adverse events are listed in descending order of severity.

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

System Organ Class	Adverse Reaction	Frequency
Infections and infestations	Candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory tract disorder, rhinitis	Uncommon
	Pseudomembranous colitis	Not known
Blood and lymphatic system disorders	Leukopenia, neutropenia, eosinophilia	Uncommon
	Thrombocytopenia, hemolytic anemia	Not known
Immune system disorders	Angioedema, hypersensitivity reactions	Uncommon
	Anaphylactic reaction	Not known
Metabolism and nutrition disorders	Anorexia	Common
Psychiatric disorders	Nervousness, insomnia	Uncommon
	Agitation	Rare
	Aggression, anxiety, delirium, hallucinations	Not known
Nervous system disorders	Headache	Common
	Dizziness, somnolence, dysgeusia, paraesthesia	Uncommon
	Syncope, convulsions, hypoaesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis	Not known
Eye disorders	Visual disturbance	Uncommon
Ear and labyrinth disorders	Ear disorders, vertigo	Uncommon
	Hearing impairment, including deafness and/or tinnitus	Not known
Cardiac disorders	Palpitations	Uncommon
	Ventricular flutter and fibrillation (torsade de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG	Not known
Vascular disorders	Flushing	Uncommon
	Arterial hypotension	Not known
Respiratory system disorders	Dyspnea, epistaxis	Uncommon
Gastrointestinal disorders	Diarrhea	Very common
	Vomiting, abdominal pain, nausea	Common
	Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulcers, hypersalivation	Uncommon
	Pancreatitis, change in tongue color	Not known
Hepatobiliary disorders	Liver function abnormalities, cholestatic jaundice	Uncommon
	Liver failure (rarely resulting in fatal outcome), fulminant hepatitis, hepatic necrosis	Not known
Skin and subcutaneous tissue disorders	Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis	Uncommon
	Photosensitivity, acute generalized exanthematous pustulosis (AGEP)	Rare
	Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS)	Not known
Musculoskeletal and connective tissue disorders	Osteoarthritis, myalgia, back pain, neck pain	Uncommon
	Arthralgia	Not known
Renal and urinary disorders	Dysuria, renal pain	Uncommon
	Acute renal failure, interstitial nephritis	Not known
Reproductive system and breast disorders	Uterine bleeding, testicular disorders	Uncommon
General disorders and administration site conditions	Edema, asthenia, malaise, fatigue, facial swelling, chest pain, hyperthermia, pain, peripheral edema	Uncommon
Investigations	Decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count	Common
	Elevated aspartate aminotransferase, elevated alanine aminotransferase, elevated blood bilirubin, elevated blood urea, elevated blood creatinine, blood potassium fluctuations, elevated alkaline phosphatase, elevated chloride level, elevated glucose level, elevated platelet count, decreased hematocrit, elevated bicarbonate level, sodium level deviation	Uncommon
Injury, poisoning and procedural complications	Procedural complications	Uncommon

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

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

System Organ Class		Adverse Reaction	Frequency
Metabolism and nutrition disorders		Anorexia	Common
Nervous system disorders		Dizziness, headache, paraesthesia, dysgeusia	Common
		Hypoesthesia	Uncommon
Eye disorders		Visual disturbance	Common
Ear and labyrinth disorders		Deafness	Common
		Hearing impairment, tinnitus	Uncommon
	Cardiac disorders	Palpitations	Uncommon
	Gastrointestinal disorders	Diarrhoea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools	Very common
	Hepatobiliary disorders	Hepatitis	Uncommon
	Skin and subcutaneous tissue disorders	Rash, pruritus	Common
		Stevens-Johnson syndrome, photosensitivity	Uncommon
	Musculoskeletal and connective tissue disorders	Arthralgia	Common
	General disorders and administration site conditions	Increased fatigue	Common
		Asthenia, malaise	Uncommon

Reporting of suspected adverse reactions.

Reporting of adverse reactions after registration of the medicinal product is of great importance. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of effectiveness of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

250 mg tablets: 6 or 21 tablets in a blister, 1 blister per cardboard pack.

500 mg tablets: 3 tablets in a blister, 1 blister per cardboard pack.

Prescription category.

By prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's address and location of its business activities.

40020, Ukraine, Sumy region, Sumy city, Skryabina St., 54.

INSTRUCTION

for medical use of the medicinal product

ZIOMYCIN®

(ZIOMYCIN®)

Composition:

Active substance: azithromycin (azithromycin);

1 tablet contains azithromycin dihydrate equivalent to azithromycin 250 mg or 500 mg;

Excipients: microcrystalline cellulose, sodium croscarmellose, sodium lauryl sulfate, povidone K 90, talc, magnesium stearate, Opadry 04B52069 yellow coating: hypromellose, titanium dioxide (E 171), quinoline yellow (E 104), polyethylene glycols.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

250 mg tablets: capsule-shaped, film-coated yellow tablets with the imprint "A 250" on one side and smooth on the other;

500 mg tablets: capsule-shaped, film-coated yellow tablets with the imprint "A 500" on one side and smooth on the other.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. 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 through binding to the 50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance.

Complete cross-resistance exists among 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.

The prevalence of acquired resistance may vary depending on geographic location and time for isolated species; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin.

Usually sensitive species

Aerobic gram-positive bacteria

Staphylococcus aureus methicillin-sensitive Streptococcus pneumoniae penicillin-sensitive Streptococcus pyogenes

Aerobic gram-negative bacteria

Haemophilus influenzae Haemophilus parainfluenzae Legionella pneumophila Moraxella catarrhalis Pasteurella multocida

Anaerobic bacteria

Clostridium perfringens Fusobacterium spp. Prevotella spp. Porphyromonas spp.

Other microorganisms

Chlamydia trachomatis Chlamydia pneumoniae Mycoplasma pneumoniae

Species that may develop resistance

Aerobic gram-positive bacteria

Streptococcus pneumoniae with intermediate sensitivity to penicillin and penicillin-resistant

Naturally resistant organisms

Aerobic gram-positive bacteria

Enterococcus faecalis MRSA, MRSE* Staphylococci

Anaerobic bacteria

Bacteroides fragilis group

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

Pharmacokinetics.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after drug intake. After oral administration, 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 strong 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 (VVss) is 31.1 L/kg.

The terminal plasma elimination 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 were found in human bile. Ten metabolites were also detected in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of liquid chromatography results and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Otorhinolaryngological 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), pertussis, impetigo, secondary pyoderma, moderate severity acne vulgaris (common acne);
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

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

Interaction with other medicinal products and other forms of interaction.

Antacids. When studying the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although plasma peak concentrations 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 together with cetirizine 20 mg at steady state.

Didanosine. In six HIV-positive volunteers, coadministration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day showed no effect on the steady-state pharmacokinetics of didanosine 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 P-glycoprotein substrates such as digoxin, the possibility of increased serum digoxin concentrations 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 they may be beneficial in patient treatment.

Azithromycin does not significantly interact with the hepatic cytochrome P450 system. The drug is considered not to have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not induce or inactivate 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, cases of rhabdomyolysis have been reported in the post-marketing period in patients taking azithromycin with statins.

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

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

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 administered to healthy volunteers. However, there are reports of potentiation of the anticoagulant effect following concomitant use of azithromycin and oral anticoagulants of the coumarin type. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. In a pharmacokinetic study involving 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. The overall exposure and elimination half-life of azithromycin were unchanged when fluconazole was administered concomitantly, 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 necessary.

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 that azithromycin (500 mg daily for 3 days) affects the AUC or Cmax of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. However, such an interaction cannot be completely ruled out, although there are no specific data confirming it.

Theophylline. No clinically significant pharmacokinetic interaction was observed when azithromycin and theophylline were administered concomitantly to healthy volunteers.

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam 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.

Hypersensitivity.

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

Hepatotoxicity.

Since the liver is the main route of elimination of azithromycin, azithromycin should be administered with caution in patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported during azithromycin therapy. Possibly, some patients had a history of liver disease or were taking other hepatotoxic medicinal products.

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

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

Ergot derivatives.

In patients taking ergot derivatives, concomitant use of some macrolide antibiotics may promote rapid development of ergotism. There are no data on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

QT interval prolongation.

Prolongation of cardiac repolarization and QT interval, which may increase the risk of cardiac arrhythmia and ventricular tachyarrhythmia (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 administered with caution in patients with pre-existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired QT prolongation;
• receiving treatment with other medicinal products 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;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Superinfections.

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

Clostridium difficile-associated diarrhea (CDAD).

Cases of Clostridium difficile-associated diarrhea (CDAD) have been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal flora of the colon, 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 necessary, as CDAD has been reported to occur up to 2 months after administration of antibacterial agents. If CDAD occurs, azithromycin therapy should be discontinued and specific treatment for C. difficile initiated.

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 the efficacy of azithromycin in preventing rheumatic fever.

Renal impairment.

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

Myasthenia gravis.

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

Other.

Safety and efficacy for the prevention or treatment of Mycobacterium avium complex (MAC) in children have not been established.

Excipients.

This medicinal product contains less than 1 mmol (23 mg) of sodium per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of azithromycin in pregnant women. In reproductive toxicity studies in animals, doses corresponding to moderately toxic levels for the maternal organism were used. These studies did not provide evidence of teratogenic effects of azithromycin. However, adequate and well-controlled studies in pregnant women are lacking. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding period

It has been reported that azithromycin penetrates into human breast milk, but adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted.

Fertility

Fertility studies were conducted in rats; the pregnancy rate decreased after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to influence the reaction rate when driving vehicles or operating machinery.

There is no evidence that azithromycin impairs the ability to drive vehicles or operate machinery. However, the possibility of adverse reactions such as delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be taken into account.

Method of administration and dosage.

The medicinal product should be administered as a single daily dose, regardless of food intake. Tablets should be swallowed whole without chewing. If one dose is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Adults and children with body weight > 45 kg.

Indications	Total dose	Treatment regimen
		Period	Dose	Frequency
Infections of the ears, nose, throat, respiratory tract, skin and soft tissues (except chronic migrating erythema)	1500 mg	Days 1 to 3	500 mg	Once daily
Vulgaris acne	6000 mg	1st week (days 1 to 3)	500 mg	Once daily
		Weeks 2 to 10	500 mg	Once weekly*
Migratory erythema	3000 mg	Day 1	1000 mg	Once daily
		Days 2 to 5	500 mg	Once daily
Sexually transmitted infections	1000 mg	Day 1	1000 mg	Once daily

* The dose for the 2nd week should be taken 7 days after the first day of drug administration. Doses from the 3rd to the 10th week should be taken at 7-day intervals.

Geriatric patients.

In elderly patients, there is no need to adjust the dosage.

Since elderly patients may belong to risk groups for disturbances in cardiac conduction, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmia and torsade de pointes arrhythmia.

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 prescribed with caution to 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. Studies on treatment with azithromycin in such patients have not been conducted.

Children.

The drug should be administered to children with body weight over 45 kg. For children with body weight less than 45 kg, azithromycin formulations in appropriate dosage are recommended.

Overdose.

Symptoms: adverse effects occurring after ingestion of doses higher than recommended are similar to those observed with usual therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss.

Treatment: if necessary, administration of activated charcoal and implementation of general symptomatic and supportive treatment measures are recommended.

Adverse reactions

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

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

System Organ Class	Adverse Reaction	Frequency
Infections and infestations	Candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory tract disorder, rhinitis	Uncommon
	Pseudomembranous colitis	Unknown
Blood and lymphatic system disorders	Leukopenia, neutropenia, eosinophilia	Uncommon
	Thrombocytopenia, hemolytic anemia	Unknown
Immune system disorders	Angioedema, hypersensitivity reactions	Uncommon
	Anaphylactic reaction	Unknown
Metabolism and nutrition disorders	Anorexia	Common
Psychiatric disorders	Nervousness, insomnia	Uncommon
	Agitation	Rare
	Aggression, anxiety, delirium, hallucinations	Unknown
Nervous system disorders	Headache	Common
	Dizziness, somnolence, dysgeusia, paraesthesia	Uncommon
	Loss of consciousness, convulsions, hypoesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis	Unknown
Eye disorders	Visual disturbance	Uncommon
Ear and labyrinth disorders	Ear disorders, vertigo	Uncommon
	Hearing impairment, including deafness and/or tinnitus	Unknown
Cardiac disorders	Palpitations	Uncommon
	Ventricular fibrillation (torsade de pointes), arrhythmia, including ventricular tachycardia, QT interval prolongation on ECG	Unknown
Vascular disorders	Flushing	Uncommon
	Arterial hypotension	Unknown
Respiratory system disorders	Dyspnea, epistaxis	Uncommon
Gastrointestinal disorders	Diarrhea	Very common
	Vomiting, abdominal pain, nausea	Common
	Constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulcers, increased salivation	Uncommon
	Pancreatitis, change in tongue color	Unknown
Hepatobiliary disorders	Liver function abnormalities, cholestatic jaundice	Rare
	Liver failure (rarely fatal), fulminant hepatitis, hepatic necrosis	Unknown
Skin and subcutaneous tissue disorders	Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis	Uncommon
	Photosensitivity, acute generalized exanthematous pustulosis (AGEP)	Rare
	Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS)	Unknown
Musculoskeletal and connective tissue disorders	Osteoarthritis, myalgia, back pain, neck pain	Uncommon
	Arthralgia	Unknown
Renal and urinary disorders	Dysuria, renal pain	Uncommon
	Acute renal failure, interstitial nephritis	Unknown
Reproductive system and breast disorders	Uterine bleeding, testicular disorders	Uncommon
General disorders and administration site conditions	Edema, asthenia, malaise, fatigue, facial swelling, chest pain, hyperthermia, pain, peripheral edema	Uncommon
Investigations	Decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count	Common
	Increased blood aspartate aminotransferase level, increased blood alanine aminotransferase level, increased blood bilirubin level, increased blood urea level, increased blood creatinine level, blood potassium level abnormalities, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit level, increased bicarbonate level, sodium level abnormalities	Uncommon
Injury, poisoning and procedural complications	Procedural complications	Uncommon

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

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

System Organ Class		Adverse Reaction	Frequency
Metabolism and nutrition disorders		Anorexia	Common
Nervous system disorders		Dizziness, headache, paraesthesia, dysgeusia	Common
		Hypoaesthesia	Uncommon
Eye disorders		Visual disturbance	Common
Ear and labyrinth disorders		Deafness	Common
		Hearing impairment, tinnitus	Uncommon
	Cardiac disorders	Palpitations	Uncommon
	Gastrointestinal disorders	Diarrhoea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools	Very common
	Hepatobiliary disorders	Hepatitis	Uncommon
	Skin and subcutaneous tissue disorders	Rash, pruritus	Common
		Stevens-Johnson syndrome, photosensitivity	Uncommon
	Musculoskeletal and connective tissue disorders	Arthralgia	Common
	General disorders and administration site conditions	Increased fatigue	Common
		Asthenia, malaise	Uncommon

Reporting of suspected adverse reactions.

Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. This enables ongoing monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of effectiveness of the medicinal product through 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 25 °C.

Keep out of reach and sight of children.

Packaging.

Tablets 250 mg: 6 or 21 tablets in a blister pack, 1 blister pack in a cardboard box.

Tablets 500 mg: 3 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and site of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.