Azithromycin Ecomed® tablets 500 mg

Instructions for use of Azithromycin Ecomed® tablets 500 mg

Registration number: LP-000268

Trade name of the drug: Azithromycin Ecomed^®

International Nonproprietary Name: azithromycin

Dosage form: film-coated tablets

Composition

One tablet contains:

active substance: azithromycin dihydrate equivalent to azithromycin 250 mg/ 500 mg;

excipients: lactitol 300.0 mg / 600.0 mg, calcium phosphate dihydrate 59.8 mg / 119.6 mg, corn starch 24.0 mg /48.0 mg, croscarmellose sodium 20.0 mg / 40.0 mg, magnesium stearate 6.0 mg /12.0 mg, hypromellose 5.0 mg/ 10.0 mg, sodium lauryl sulfate 1.2 mg/ 2.4 mg, microcrystalline cellulose up to a core tablet weight of 700 mg/ 1400 mg;

coating excipients: hypromellose 9.49 mg/ 18.98 mg, titanium dioxide 5.2 mg/ 10.4 mg, macrogol-4000 3.744 mg/ 7.488 mg, talc 1.12 mg/ 2.24 mg, povidone-K17 0.416 mg/0.832 mg, tropaeolin O dye 0.030 mg/ 0.060 mg up to a coated tablet weight of 720 mg / 1440 mg.

Description

Capsule-shaped, biconvex, film-coated tablets, yellow in color. A cross-section shows two layers; the inner layer is white or almost white.

Pharmacotherapeutic group: Antibiotic - azalide

ATC Code: J01FA10.

Pharmacological Properties

Pharmacodynamics

Azithromycin is a broad-spectrum bacteriostatic antibiotic from the macrolide-azalide group. It has a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin is associated with the suppression of microbial cell protein synthesis. By binding to the 50S ribosomal subunit, it inhibits peptidyl transferase during translation and suppresses protein synthesis, slowing the growth and reproduction of bacteria. In high concentrations, it exerts a bactericidal effect.

It is active against a range of gram-positive, gram-negative, anaerobic, intracellular, and other microorganisms. Microorganisms may be initially resistant to the antibiotic or may acquire resistance.

Susceptibility scale of microorganisms to azithromycin (Minimum Inhibitory Concentration (MIC), mg/l)

Microorganisms	MIC, mg/l
	Susceptible	Resistant
Staphylococcus	≤ 1	˃ 2
Streptococcus A, B, C, G	≤ 0.25	˃ 0.5
Streptococcus pneumoniae	≤ 0.25	˃ 0.5
Haemophilus influenzae	≤ 0.12	˃ 4
Moraxella catarrhalis	≤ 0.5	˃ 0.5
Neisseria gonorrhoeae	≤ 0.25	˃ 0.5

 Usually Susceptible Microorganisms:

1.  Gram-positive aerobes:
   

• Staphylococcus aureus (methicillin-susceptible)
• Streptococcus pneumoniae (penicillin-susceptible)
• Streptococcus pyogenes

2. Gram-negative aerobes:

• Haemophilus influenzae
• Haemophilus parainfluenzae
• Legionella pneumophila
• Moraxella catarrhalis
• Pasteurella multocida
• Neisseria gonorrhoeae

3. Anaerobes:

• Clostridium perfringens
• Fusobacterium spp.
• Prevotella spp.
• Porphyromonas spp.

4. Other microorganisms:

• Chlamydia trachomatis
• Chlamydia pneumoniae
• Chlamydia psittaci
• Mycoplasma pneumoniae
• Mycoplasma hominis
• Borrelia burgdorferi

Microorganisms Capable of Developing Resistance to Azithromycin:

Gram-positive aerobes:

Streptococcus pneumoniae (penicillin-resistant)

Naturally Resistant Microorganisms:

Gram-positive aerobes:

Enterococcus faecalis

Staphylococci (methicillin-resistant staphylococci show a very high degree of resistance to macrolides). Gram-positive bacteria resistant to erythromycin.

Anaerobes

Bacteroides fragilis

Pharmacokinetics

After oral administration, azithromycin is well absorbed and rapidly distributed throughout the body. Bioavailability following a single 500 mg dose is 37% (due to the first-pass effect). Maximum plasma concentration (0.4 mg/L) is reached within 2–3 hours. The apparent volume of distribution is 31.1 L/kg. Plasma protein binding is inversely proportional to blood concentration and ranges from 7% to 50%. Azithromycin penetrates cell membranes (making it effective against intracellular pathogens).

It is transported by phagocytes to the site of infection, where it is released in the presence of bacteria. Azithromycin readily crosses histohematological barriers and accumulates in tissues. Tissue concentrations are 10–50 times higher than those in plasma, and concentrations at the site of infection are 24–34% higher than in healthy tissues.

Azithromycin has a very long elimination half-life—35–50 hours—and an even longer half-life in tissues. Therapeutic concentrations persist for 5–7 days after the last dose. Azithromycin is primarily excreted unchanged: approximately 50% via the intestines and 6% via the kidneys. It undergoes hepatic demethylation, resulting in inactive metabolites.

Indications for Use

Infectious and inflammatory diseases caused by microorganisms susceptible to azithromycin:

• Infections of the upper respiratory tract and ENT organs: pharyngitis, tonsillitis, sinusitis, otitis media;
• Infections of the lower respiratory tract: acute bronchitis, exacerbation of chronic bronchitis, pneumonia, including those caused by atypical pathogens;
• Skin and soft tissue infections: moderate acne vulgaris, erysipelas, impetigo, secondarily infected dermatoses;
• Early stage of Lyme disease (borreliosis)—erythema migrans;
• Genitourinary infections caused by Chlamydia trachomatis (urethritis, cervicitis).

Contraindications

• Hypersensitivity to macrolide antibiotics;
• Hypersensitivity to any other component of the formulation;
• Severe hepatic impairment;
• Severe renal impairment (creatinine clearance below 40 mL/min);
• Children under 12 years of age weighing less than 45 kg (for this dosage form);
• Breastfeeding;
• Concurrent administration with ergotamine or dihydroergotamine.

Use with Caution

• Myasthenia gravis;
• Mild to moderate hepatic impairment;
• Mild to moderate renal impairment (creatinine clearance above 40 mL/min);
• In patients with proarrhythmic risk factors (especially elderly patients): congenital or acquired QT interval prolongation; concurrent use of Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents, cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin, levofloxacin); electrolyte imbalances, particularly hypokalemia or hypomagnesemia; clinically significant bradycardia; cardiac arrhythmias; or severe heart failure;
• Concurrent use with terfenadine, warfarin, digoxin, or cyclosporine.

Use During Pregnancy and Lactation

Azithromycin should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding must be discontinued during treatment with azithromycin.

Dosage and Administration

Azithromycin Ecomed^® is taken orally, once daily, without chewing, regardless of meals. It should be taken at least 1 hour before or 2 hours after food.

For adults (including elderly patients) and children over 12 years of age weighing more than 45 kg:

For infections of the upper and lower respiratory tract, ENT organs, and skin/soft tissues: 500 mg once daily for 3 days (total course dose: 1.5 g).

For moderate acne vulgaris: 500 mg once daily for 3 days, followed by 500 mg once weekly for 9 weeks. The first weekly dose should be taken on day 8 (i.e., 7 days after the last daily dose), with subsequent weekly doses administered at 7-day intervals. Total course dose: 6.0 g.

For erythema migrans (early Lyme disease): 1.0 g on day 1, followed by 500 mg once daily on days 2–5. Total course dose: 3.0 g.

For genitourinary infections caused by Chlamydia trachomatis (urethritis, cervicitis): single 1.0 g dose.

No dose adjustment is required in patients with mild renal impairment.

No dose adjustment is required in patients with mild to moderate hepatic impairment or in elderly patients.

Elderly patients: No dose adjustment is required. However, caution is advised in elderly patients with persistent proarrhythmic risk factors due to the increased risk of arrhythmias, including torsades de pointes.

Adverse Reactions

Adverse reaction frequencies are classified according to WHO recommendations: very common (≥10%); common (≥1% to <10%); uncommon (≥0.1% to <1%); rare (≥0.01% to <0.1%); very rare (<0.01%); frequency not known (cannot be estimated from available data).

Infections and infestations:

Uncommon: candidiasis (including oropharyngeal and genital), pneumonia, pharyngitis, gastroenteritis, respiratory tract infections, rhinitis; frequency not known: pseudomembranous colitis.

Blood and lymphatic system disorders:

Uncommon: leukopenia, neutropenia, eosinophilia; very rare: thrombocytopenia, hemolytic anemia.

Metabolism and nutrition disorders:

Uncommon: anorexia.

Hypersensitivity reactions:

Uncommon: angioedema, hypersensitivity reactions; frequency not known: anaphylactic reaction.

Nervous system disorders:

Common: headache; uncommon: dizziness, taste disturbances, paresthesia, somnolence, insomnia, nervousness; rare: agitation; frequency not known: hypaesthesia, anxiety, aggression, syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia, delirium, hallucinations.

Eye disorders:

Uncommon: visual disturbances.

Ear and labyrinth disorders:

Uncommon: hearing impairment, vertigo; frequency not known: hearing loss (including deafness) and/or tinnitus.

Cardiac disorders:

Uncommon: palpitations, facial flushing; frequency not known: hypotension, QT interval prolongation on ECG, torsades de pointes, ventricular tachycardia.

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnea, epistaxis.

Gastrointestinal disorders:

Very common: diarrhea; common: nausea, vomiting, abdominal pain; uncommon: flatulence, dyspepsia, constipation, gastritis, dysphagia, abdominal distension, dry mouth, eructation, oral mucosal ulceration, increased salivation; very rare: tongue discoloration, pancreatitis.

Hepatobiliary disorders:

Uncommon: hepatitis; rare: hepatic function abnormalities, cholestatic jaundice; frequency not known: hepatic failure (including fatal cases, primarily in patients with pre-existing severe liver disease), hepatic necrosis, fulminant hepatitis.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis; rare: photosensitivity reaction; frequency not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders:

Uncommon: osteoarthritis, myalgia, back pain, neck pain; frequency not known: arthralgia.

Renal and urinary disorders:

Uncommon: dysuria, renal pain; frequency not known: interstitial nephritis, acute renal failure.

Reproductive system and breast disorders:

Uncommon: metrorrhagia, testicular dysfunction.

General disorders and administration site conditions:

Uncommon: asthenia, malaise, fatigue, facial edema, chest pain, fever, peripheral edema.

Laboratory findings:

Common: decreased lymphocyte count, increased eosinophil, basophil, monocyte, and neutrophil counts, decreased plasma bicarbonate concentration; uncommon: increased AST and ALT activity, increased plasma bilirubin, increased plasma urea and creatinine, electrolyte imbalances (potassium), increased alkaline phosphatase, increased plasma chloride, hyperglycemia, increased platelet count, increased hematocrit, increased plasma bicarbonate, sodium imbalances.

Overdose

Symptoms: temporary hearing loss, nausea, vomiting, diarrhea.

Treatment: symptomatic.

Drug Interactions

Antacids

Antacids do not affect the bioavailability of azithromycin but reduce its peak plasma concentration by 30%. Therefore, azithromycin should be taken at least 1 hour before or 2 hours after antacids and food.

Cetirizine

Concomitant administration of azithromycin and cetirizine (20 mg) for 5 days in healthy volunteers did not result in pharmacokinetic interaction or clinically significant QT interval changes.

Didanosine

Concomitant use of azithromycin (1200 mg/day) and didanosine (400 mg/day) in 6 HIV-infected patients did not alter the pharmacokinetic parameters of didanosine compared to placebo.

Digoxin (P-glycoprotein substrates)

Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin may increase serum concentrations of the substrate. Therefore, increased serum digoxin levels should be considered when azithromycin and digoxin are used together.

Zidovudine

Concomitant administration of azithromycin (single 1000 mg dose or multiple doses of 1200 mg or 600 mg) had minimal effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite. However, azithromycin increased the concentration of phosphorylated zidovudine—the clinically active metabolite—in peripheral blood mononuclear cells. The clinical significance of this finding is unknown.

Azithromycin exhibits weak interaction with cytochrome P450 isoenzymes. Unlike erythromycin and other macrolides, azithromycin does not appear to be involved in significant pharmacokinetic interactions and is neither an inhibitor nor an inducer of cytochrome P450 isoenzymes.

Ergot alkaloids

Due to the theoretical risk of ergotism, concomitant use of azithromycin with ergot alkaloid derivatives is not recommended.

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin and drugs metabolized by cytochrome P450 isoenzymes.

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 assays). However, post-marketing reports have noted isolated cases of rhabdomyolysis in patients receiving azithromycin and statins concomitantly.

Carbamazepine

Pharmacokinetic studies in healthy volunteers showed no clinically significant effect of azithromycin on plasma concentrations of carbamazepine or its active metabolite.

Cimetidine

Pharmacokinetic studies showed no effect of a single dose of cimetidine (administered 2 hours before azithromycin) on the pharmacokinetics of azithromycin.

Coumarin-type oral anticoagulants

In pharmacokinetic studies, azithromycin did not affect the anticoagulant effect of a single 15 mg dose of warfarin in healthy volunteers. However, there have been post-marketing reports of potentiated anticoagulant effects when azithromycin was co-administered with coumarin-type oral anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time is recommended in patients receiving oral anticoagulants when azithromycin is prescribed.

Cyclosporine

In a pharmacokinetic study in healthy volunteers who received azithromycin (500 mg once daily for 3 days) followed by cyclosporine (10 mg/kg once daily), a statistically significant increase in cyclosporine C_max and AUC_0–5 was observed. Caution is advised when these drugs are used concomitantly. If co-administration is necessary, cyclosporine plasma concentrations should be monitored, and the dose adjusted accordingly.

Efavirenz

Concomitant administration of azithromycin (600 mg once daily) and efavirenz (400 mg once 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 half-life of azithromycin were unchanged with concomitant fluconazole, although a 18% reduction in azithromycin C_max was observed, which was not clinically significant.

Indinavir

A single 1200 mg dose of azithromycin had no statistically significant effect on the pharmacokinetics of indinavir (800 mg three times daily for 5 days).

Methylprednisolone

Azithromycin does not significantly affect the pharmacokinetics of methylprednisolone.

Nelfinavir

Concomitant administration of azithromycin (1200 mg) and nelfinavir (750 mg three times daily) increased steady-state serum concentrations of azithromycin. No clinically significant adverse effects were observed, and dose adjustment of azithromycin is not required when used with nelfinavir.

Rifabutin

Concomitant use of azithromycin and rifabutin did not affect serum concentrations of either drug. Neutropenia was occasionally observed during co-administration. Although neutropenia has been associated with rifabutin use, a causal relationship between the combination of azithromycin and rifabutin and neutropenia has not been established.

Sildenafil

In studies with healthy volunteers, azithromycin (500 mg once daily for 3 days) did not affect the AUC or C_max of sildenafil or its primary circulating metabolite.

Terfenadine

Pharmacokinetic studies have not demonstrated an interaction between azithromycin and terfenadine. Although isolated post-marketing reports could not entirely exclude such an interaction, no definitive evidence has confirmed it. However, it is established that concurrent use of terfenadine and macrolides can cause arrhythmias and QT interval prolongation.

Theophylline

No interaction has been observed between azithromycin and theophylline.

Triazolam/Midazolam

No significant changes in pharmacokinetic parameters were observed with concomitant use of azithromycin and triazolam or midazolam at therapeutic doses.

Trimethoprim/Sulfamethoxazole

Concomitant administration of trimethoprim/sulfamethoxazole with azithromycin did not significantly affect C_max, total exposure, or renal excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Special Instructions

If a dose is missed, it should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Azithromycin should be taken at least 1 hour before or 2 hours after antacids.

Use with caution in patients with mild to moderate hepatic impairment due to the risk of fulminant hepatitis and severe hepatic failure.

If symptoms of liver dysfunction occur—such as rapidly developing asthenia, jaundice, dark urine, bleeding tendency, or hepatic encephalopathy—azithromycin therapy should be discontinued and liver function tests performed.

In patients with mild to moderate renal impairment (creatinine clearance >40 mL/min), azithromycin should be used with caution and under monitoring of renal function.

As with other antibacterial agents, patients should be monitored for the development of superinfections (including fungal) or overgrowth of non-susceptible organisms during azithromycin therapy.

The drug should not be used for longer durations than indicated, as the pharmacokinetic properties of azithromycin allow for a short and simple dosing regimen.

Although no specific interaction data exist between azithromycin and ergotamine or dihydroergotamine derivatives, concomitant use is not recommended due to the risk of ergotism observed with other macrolides and these agents.

Prolonged use of azithromycin may lead to Clostridium difficile-associated diarrhea, ranging from mild diarrhea to severe colitis. Clostridium difficile-associated pseudomembranous colitis should be considered in any patient developing diarrhea during or up to 2 months after completion of azithromycin therapy.

Macrolide antibiotics, including azithromycin, have been associated with prolongation of cardiac repolarization and the QT interval, which may increase the risk of cardiac arrhythmias, including torsades de pointes.

Caution should be exercised when using azithromycin in patients with proarrhythmic risk factors (especially elderly patients): congenital or acquired QT prolongation; concurrent use of Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin, levofloxacin); electrolyte disturbances, especially hypokalemia or hypomagnesemia; clinically significant bradycardia; cardiac arrhythmias; or severe heart failure.

Azithromycin may trigger myasthenic syndrome or exacerbate myasthenia gravis.

Effects on Ability to Drive and Operate Machinery

If adverse reactions affecting the nervous system or vision occur, caution should be exercised when driving or operating machinery, as these activities require heightened attention and rapid psychomotor responses.

Dosage Form

Film-coated tablets, 250 mg, 500 mg.

6 tablets of 250 mg or 3 tablets of 500 mg per blister strip made of PVC film and printed lacquered aluminum foil.

1 blister strip with the package leaflet enclosed in a cardboard carton.

Shelf Life

2 years. Do not use after the expiration date.

Storage Conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 °C.

Keep out of reach of children.

Legal Status

Prescription only.

Marketing Authorization Holder / Organization for Claims:

JSC "AVVA RUS", Russia, 121614, Moscow,

Krylatskie Kholmy St., 30, Bldg. 9.

Tel/Fax: +7 (495) 956-75-54.

www.avva-rus.ru

www.ecoantibiotic.ru

Production Site Address:

JSC "AVVA RUS", Russia, 610044, Kirov region, Kirov, Luganskaya St., 53a.

Tel.: +7 (8332) 25-12-29; +7 (495) 956-75-54.

Chief Executive Officer

JSC "AVVA RUS" A.G. Egorov