Azithromycin Ecomed® tablets 250 mg

Instructions for use of Azithromycin Ecomed® tablets 250 mg

Registration number: LP-000268

Trade name: 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 to it.

Microorganism Susceptibility Scale to Azithromycin (Minimum Inhibitory Concentration (MIC), mg/ml)

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

Staphylococcus (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 in the body. The bioavailability after a single 500 mg dose is 37% (first-pass effect), the maximum concentration (0.4 mg/l) in the blood is reached in 2-3 hours, the apparent volume of distribution is 31.1 l/kg, plasma protein binding is inversely proportional to the concentration in the blood and ranges from 7-50 %. It penetrates cell membranes (effective against infections caused by intracellular pathogens).

It is transported by phagocytes to the site of infection, where it is released in the presence of bacteria. It easily passes tissue barriers and enters tissues. The concentration in tissues is 10 - 50 times higher than in plasma, and at the site of infection it is 24-34 % higher than in healthy tissues.

Azithromycin has a very long half-life - 35-50 hours. The half-life from tissues is significantly longer. The therapeutic concentration of azithromycin persists for up to 5-7 days after the last dose. Azithromycin is eliminated mainly unchanged - 50% via the intestines, 6%  via the kidneys. It is demethylated in the liver, losing activity.

Indications for Use

Infectious and inflammatory diseases caused by microorganisms susceptible to the drug:

• 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;
• Infections of the skin and soft tissues: moderate acne vulgaris, erysipelas, impetigo, secondarily infected dermatoses;
• Early stage of Lyme disease (borreliosis) – erythema migrans;
• Genitourinary tract infections caused by Chlamydia trachomatis (urethritis, cervicitis).

Contraindications

• Hypersensitivity to macrolide antibiotics;
• Hypersensitivity to other components of the drug;
• Severe hepatic failure
• Severe renal failure (creatinine clearance below 40 ml/min);
• Children under 12 years of age weighing less than 45 kg (for this dosage form);
• Breastfeeding;
• Concurrent use with ergotamine and dihydroergotamine.

Use with Caution

• Myasthenia gravis;
• Mild to moderate hepatic impairment;
• Mild to moderate renal impairment (creatinine clearance greater than 40 ml/min);
• In patients with proarrhythmic factors (especially elderly patients): with congenital or acquired QT interval prolongation, patients receiving therapy with class IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol) antiarrhythmic drugs, cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with water-electrolyte imbalances, especially in case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure;
• Concurrent use of terfenadine, warfarin, digoxin, cyclosporine.

Use During Pregnancy and Lactation.

Azithromycin during pregnancy is recommended only when the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding should be discontinued during azithromycin treatment.

Dosage and Administration

Azithromycin Ecomed^®  is taken orally, without chewing, once a day, regardless of meals. The drug should be taken at least 1 hour before or 2 hours after a meal.

Adults (including the elderly) and children over 12 years of age weighing more than 45 kg.

For infections of the upper and lower respiratory tracts, ENT organs, skin and soft tissues: 0.5 g once daily for 3 days (total course dose – 1.5 g).

For moderate acne vulgaris: 0.5 g once daily for 3 days, then 0.5 g once a week for 9 weeks. The first weekly tablet should be taken 7 days after taking the first daily tablet (day 8 from the start of treatment), the subsequent 8 weekly tablets – at 7-day intervals. Total course dose 6.0 g.

For erythema migrans: once daily for 5 days, 1.0 g on day 1, then 0.5 g from day 2 to day 5. Total course dose 3.0 g.

For genitourinary tract infections caused by Chlamydia trachomatis (urethritis, cervicitis): 1.0 g as a single 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 required. Caution should be exercised in elderly patients with persistent proarrhythmic factors due to the high risk of arrhythmias, including torsades de pointes.

Adverse Reactions

The frequency of adverse reactions is classified according to WHO recommendations: Very common - ≥ 10%; Common - ≥ 1%, but < 10%; Uncommon - ≥ 0.1%, but < 1%; Rare - ≥ 0.01%, but < 0.1%; Very rare -  < 0.01%; Frequency not known - cannot be estimated from available data.

Infections and infestations:

Uncommon - candidiasis, including of the oral mucosa and genitals, pneumonia, pharyngitis, gastroenteritis, respiratory diseases, 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.

Immune system disorders:

Uncommon - angioedema, hypersensitivity reaction; Frequency not known - anaphylactic reaction.

Nervous system disorders:

Common - headache; Uncommon - dizziness, taste perversion, paresthesia, somnolence, insomnia, nervousness; Rare - agitation; Frequency not known - hypoesthesia, anxiety, aggression, syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, delirium, hallucinations.

Eye disorders:

Uncommon - visual impairment.

Ear and labyrinth disorders:

Uncommon - hearing impairment, vertigo; Frequency not known - hearing impairment, including deafness and/or tinnitus.

Cardiac disorders:

Uncommon - palpitations, flushing; Frequency not known - decreased blood pressure, prolonged QT interval 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, mouth ulceration, increased salivary secretion; Very rare - tongue discoloration, pancreatitis.

Hepatobiliary disorders:

Uncommon - hepatitis; Rare - hepatic function disorder, cholestatic jaundice; Frequency not known - hepatic failure (in rare cases with fatal outcome, mainly against the background of severe liver dysfunction); liver necrosis, fulminant hepatitis.

Skin and subcutaneous tissue disorders:

Uncommon - skin 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 disorder.

General disorders and administration site conditions:

Uncommon - asthenia, malaise, fatigue, facial edema, chest pain, pyrexia, peripheral edema.

Investigations:

Common - decreased lymphocyte count, increased eosinophil count, increased basophil count, increased monocyte count, increased neutrophil count, decreased plasma bicarbonate concentration; Uncommon - increased AST, increased ALT, increased blood bilirubin, increased blood urea, increased blood creatinine, changes in blood potassium, increased alkaline phosphatase, increased blood chloride, increased blood glucose, increased platelet count, increased hematocrit, increased plasma bicarbonate concentration, changes in blood sodium.

Overdose

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

Treatment: symptomatic.

Drug Interactions.

Antacids

Antacids do not affect the bioavailability of azithromycin but reduce the maximum blood concentration by 30%, so the drug should be taken at least one hour before or two hours after taking these drugs and food.

Cetirizine

Concurrent administration for 5 days in healthy volunteers of azithromycin with cetirizine (20 mg) did not lead to pharmacokinetic interaction or significant change in the QT interval.

Didanosine

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

Digoxin (P-glycoprotein substrates)

Concurrent use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, leads to increased serum concentrations of the P-glycoprotein substrate. Thus, when azithromycin and digoxin are used concomitantly, the possibility of increased serum digoxin concentrations should be considered.

Zidovudine

Concurrent use of azithromycin (single 1000 mg dose and multiple 1200 or 600 mg doses) had a slight effect on the pharmacokinetics, including renal excretion, of zidovudine or its glucuronide metabolite. However, the use of azithromycin caused an increase in the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear.

Azithromycin interacts weakly with cytochrome P450 isoenzymes. Azithromycin has not been shown to participate in pharmacokinetic interactions similar to erythromycin and other macrolides. Azithromycin is not an inhibitor or inducer of cytochrome P450 isoenzymes.

Ergot Alkaloids

Given the theoretical possibility of ergotism, concurrent use of azithromycin with ergot alkaloid derivatives is not recommended.

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

Atorvastatin

Concurrent use of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not cause changes in atorvastatin plasma concentrations (based on HMG-CoA reductase inhibition analysis). However, in the post-marketing period, isolated reports of cases of rhabdomyolysis have been received in patients taking azithromycin and statins concomitantly.

Carbamazepine

In pharmacokinetic studies involving healthy volunteers, no significant effect on the plasma concentration of carbamazepine and its active metabolite was found in patients receiving azithromycin concomitantly.

Cimetidine

In pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were detected, provided cimetidine was administered 2 hours before azithromycin.

Coumarin-like oral anticoagulants

In pharmacokinetic studies, azithromycin did not affect the anticoagulant effect of a single 15 mg dose of warfarin taken by healthy volunteers. Potentiation of the anticoagulant effect after simultaneous use of azithromycin and coumarin-like oral anticoagulants has been reported. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when azithromycin is used in patients receiving coumarin-like oral anticoagulants.

Cyclosporine

In a pharmacokinetic study involving healthy volunteers who took oral azithromycin (500 mg/day as a single dose) for 3 days and then cyclosporine (10 mg/kg/day as a single dose), a significant increase in Cmax and AUC0–5 of cyclosporine in plasma was detected. Caution should be exercised when using these drugs concomitantly. If concomitant use of these drugs is necessary, plasma concentrations of cyclosporine should be monitored and the dose adjusted accordingly.

Efavirenz

Concurrent use of azithromycin (600 mg/day as a single dose) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.

Fluconazole

Concurrent use of azithromycin (1200 mg single dose) did not alter the pharmacokinetics of fluconazole (800 mg single dose). The total exposure and T1/2 of azithromycin were not changed with concurrent use of fluconazole, however, a decrease in Cmax of azithromycin (by 18%) was observed, which was not of clinical significance.

Indinavir

Concurrent use of azithromycin (1200 mg single dose) did not have a 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

Concurrent use of azithromycin (1200 mg) and nelfinavir (750 mg three times daily) causes an increase in Css of azithromycin in serum. Clinically significant side effects were not observed, and no dose adjustment of azithromycin is required when used concomitantly with nelfinavir.

Rifabutin

Concurrent use of azithromycin and rifabutin does not affect the concentration of each drug in the serum. Neutropenia was sometimes observed with the concomitant use of azithromycin and rifabutin. Although neutropenia was associated with the use of rifabutin, a causal relationship between the use of the combination of azithromycin and rifabutin and neutropenia has not been established.

Sildenafil

In studies in healthy volunteers, no evidence of an effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite was obtained.

Terfenadine

In pharmacokinetic studies, no evidence of interaction between azithromycin and terfenadine was obtained. Isolated cases have been reported where the possibility of such an interaction could not be completely excluded, but there was no specific evidence that such an interaction occurred. It has been established that the concomitant use of terfenadine and macrolides can cause arrhythmia and QT prolongation.

Theophylline

No interaction between azithromycin and theophylline was detected.

Triazolam/Midazolam

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

Trimethoprim/Sulfamethoxazole

Concurrent use of trimethoprim/sulfamethoxazole with azithromycin did not reveal a significant effect on Cmax, total exposure, or renal excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations corresponded to those detected in other studies.

Special Instructions

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.

The drug should be taken at least one hour before or two hours after taking antacids.

The drug should be used with caution in patients with mild to moderate hepatic impairment due to the possibility of developing fulminant hepatitis and severe hepatic failure.

If symptoms of liver dysfunction appear, such as rapidly increasing asthenia, jaundice, dark urine, tendency to bleed, hepatic encephalopathy, therapy with the drug should be discontinued and a study of the functional state of the liver should be conducted.

In case of mild to moderate renal impairment (creatinine clearance more than 40 ml/min), therapy with azithromycin should be carried out with caution under monitoring of renal function.

As with the use of other antibacterial drugs, during therapy with azithromycin, patients should be regularly examined for the presence of non-susceptible microorganisms and signs of superinfections, including fungal ones.

The drug should not be used for longer courses than indicated in the instructions, as the pharmacokinetic properties of azithromycin allow recommending a short and simple dosage regimen.

There are no data on a possible interaction between azithromycin and ergotamine and dihydroergotamine derivatives, but due to the development of ergotism with the simultaneous use of macrolides with ergotamine and dihydroergotamine derivatives, this combination is not recommended.

With long-term use of azithromycin, the development of pseudomembranous colitis caused by Clostridium difficile is possible, both in the form of mild diarrhea and severe colitis. If antibiotic-associated diarrhea occurs during drug administration, as well as within 2 months after the end of therapy, clostridial pseudomembranous colitis should be excluded.

When treated with macrolides, including azithromycin, prolongation of cardiac repolarization and the QT interval has been observed, increasing the risk of developing cardiac arrhythmias, including torsades de pointes.

Caution should be exercised when using the drug in patients with proarrhythmic factors (especially elderly patients): with congenital or acquired QT interval prolongation, patients taking antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with water-electrolyte imbalances, especially in case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

The use of azithromycin may provoke the development of myasthenic syndrome or cause an exacerbation of myasthenia gravis.

Effects on Ability to Drive and Operate Machinery.

If adverse reactions from the nervous system and organs of vision occur, caution should be exercised when performing activities requiring increased concentration and speed of psychomotor reactions.

Packaging

Film-coated tablets,  250 mg, 500 mg.

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

1 blister strip along with the instructions for use is placed in a cardboard carton.

Shelf Life

2 years.  Do not use after the expiration date.

Storage Conditions

In a dry, light-protected place, at a temperature not exceeding 25 ^oC.

Keep out of reach of children.

Legal Status

Prescription only.

Marketing Authorization Holder / Organization for Claims:

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

ul. Krylatskie Kholmy, 30, building 9.

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

avva.com.ru

ecobantibiotic.ru

Production Site Address:

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

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

General Director

JSC "AVVA RUS" A.G. Egorov