Azibiot^® (Tablets) Instructions for Use

Marketing Authorization Holder

Krka d.d., Novo mesto (Slovenia)

Labeled By

KRKA d.d., Novo mesto (Slovenia)

Or

KRKA-RUS, LLC (Russia)

ATC Code

J01FA10 (Azithromycin)

Active Substance

Azithromycin (Rec.INN registered by WHO)

Dosage Forms

	Azibiot®	Film-coated tablets, 250 mg: 6 pcs.
		Film-coated tablets, 500 mg: 3 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, capsule-shaped, engraved with “S19” on one side; cross-sectional view: a rough mass of white or almost white color with a film coating of white or almost white color.

Excipients: microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Film coating composition: Opadry white Y-1-7000 (hypromellose, titanium dioxide (E171), macrogol 400).

6 pcs. – blisters made of PVC/PVDF/aluminum foil (1) – cardboard packs.

Film-coated tablets white or almost white, capsule-shaped, engraved with “S5” on one side and with a score on the other; cross-sectional view: a rough mass of white or almost white color with a film coating of white or almost white color.

Excipients: microcrystalline cellulose, pregelatinized starch, sodium lauryl sulfate, hypromellose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate.

Film coating composition: Opadry white Y-1-7000 (hypromellose, titanium dioxide (E171), macrogol 400).

3 pcs. – blisters made of PVC/PVDF/aluminum foil (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the macrolide group – azalide

Pharmacotherapeutic Group

Antibiotic-azalide

Pharmacological Action

An antibiotic of the macrolide group, a representative of azalides. 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 at the translation stage, suppresses protein synthesis, and slows down the growth and reproduction of bacteria. In high concentrations, it has a bactericidal effect.

It is active against a number of gram-positive, gram-negative, anaerobic, intracellular and other microorganisms.

Microorganisms sensitive to azithromycin include gram-positive cocci: Streptococcus pneumoniae (penicillin-sensitive strains), Streptococcus pyogenes, Staphylococcus aureus (methicillin-sensitive strains); aerobic gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida, Neisseria gonorrhoeae; some anaerobic microorganisms: Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyriomonas spp.; as well as Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, Mycoplasma hominis, Borrelia burgdorferi.

Microorganisms with acquired resistance to azithromycin: aerobic gram-positive microorganisms – Streptococcus pneumoniae (penicillin-resistant strains and strains with intermediate sensitivity to penicillin).

Microorganisms with natural resistance: aerobic gram-positive microorganisms – Enterococcus faecalis, Staphylococcus aureus, Staphylococcus epidermidis (methicillin-resistant strains), anaerobic microorganisms – Bacteroides fragilis.

Cases of cross-resistance have been described between Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococcus), Enterococcus faecalis and Staphylococcus aureus (methicillin-resistant strains) to erythromycin, azithromycin, other macrolides and lincosamides.

Pharmacokinetics

After oral administration, Azithromycin is well absorbed and rapidly distributed in the body. After a single dose of 500 mg, bioavailability is 37% due to the first-pass effect through the liver. C_max in blood plasma is reached after 2-3 hours and is 0.4 mg/l.

Protein binding is inversely proportional to the concentration in plasma and is 7-50%. The apparent V_d is 31.1 l/kg. 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 through histohematic barriers and enters tissues. The concentration in tissues and cells is 10-50 times higher than in plasma, and at the site of infection it is 24-34% higher than in healthy tissues.

Azithromycin is metabolized in the liver. Metabolites do not have antimicrobial activity.

T_1/2 is very long – 35-50 hours. T_1/2 from tissues is significantly longer. The therapeutic concentration of azithromycin persists for up to 5-7 days after the last dose. Azithromycin is excreted mainly unchanged – 50% through the intestines, 6% by the kidneys.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to azithromycin: infections of the upper respiratory tract and ENT organs (sinusitis, tonsillitis, pharyngitis, otitis media); infections of the lower respiratory tract (acute bronchitis, exacerbation of chronic bronchitis, pneumonia, including that caused by atypical pathogens); skin and soft tissue infections (moderate acne vulgaris, erysipelas, impetigo, secondarily infected dermatoses); uncomplicated infections of the genitourinary tract caused by Chlamydia trachomatis (urethritis and/or cervicitis); the initial stage of Lyme disease (borreliosis) – erythema migrans.

ICD codes

Dosage Regimen

Take Azibiot^® tablets orally, once daily, at least 1 hour before or 2 hours after a meal.

For adults and children over 12 years of age weighing 45 kg or more, the standard total course dose is 1500 mg.

For infections of the upper and lower respiratory tract, skin, and soft tissues, take 500 mg once daily for 3 days.

For uncomplicated urethritis/cervicitis caused by Chlamydia trachomatis, take a single 1000 mg dose.

For the initial stage of Lyme disease (erythema migrans), take 1000 mg on the first day, followed by 500 mg once daily on days 2 through 5 (total dose 3000 mg).

For children aged 3 to 12 years with a body weight under 45 kg, use the 250 mg tablet.

The recommended pediatric dosage is 10 mg per kg of body weight once daily for 3 days.

Alternatively, for children, administer 10 mg/kg on day 1, then 5 mg/kg on days 2 through 5.

Do not use the 500 mg tablet in children under 12 years of age or weighing less than 45 kg.

In patients with mild to moderate renal impairment (GFR ≥10 mL/min), no dosage adjustment is required.

Use with caution in patients with end-stage renal disease (GFR <10 mL/min).

Contraindicated in patients with severe hepatic impairment; use with caution in mild to moderate hepatic impairment.

Complete the full prescribed course of therapy, even if symptoms improve.

Adverse Reactions

From the hematopoietic system: infrequently – leukopenia, neutropenia, eosinophilia; very rarely – thrombocytopenia, hemolytic anemia.

Allergic reactions rarely – skin rash, angioedema and anaphylaxis (in rare cases with fatal outcome) erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS syndrome). Some of these reactions that developed with the use of azithromycin became recurrent and required prolonged treatment and observation.

From the skin and subcutaneous tissues: infrequently – skin rash, itching, urticaria, dermatitis, dry skin, sweating; rarely – photosensitivity reaction; frequency unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

From the nervous system: frequently – headache; infrequently – dizziness, taste disturbance, paresthesia, somnolence, insomnia, nervousness; rarely – agitation; frequency unknown – hypoesthesia, anxiety, aggression, syncope, convulsions, psychomotor hyperactivity, loss of smell, smell distortion, loss of taste, myasthenia, delirium, hallucinations.

From the organ of vision: infrequently – visual impairment.

From the organ of hearing and labyrinthine disorders: infrequently – hearing disorder, vertigo; frequency unknown – hearing impairment up to deafness and/or tinnitus.

From the cardiovascular system: infrequently – palpitations, flushing; frequency unknown – decreased blood pressure, prolonged QT interval on ECG, torsades de pointes arrhythmia, ventricular tachycardia.

From the respiratory system infrequently – dyspnea, epistaxis.

From the digestive system: very frequently – diarrhea; frequently – nausea, vomiting, abdominal pain; infrequently – flatulence, dyspepsia, constipation, gastritis, dysphagia, abdominal distension, dry mouth, belching, oral mucosa ulcers, increased salivary gland secretion; very rarely – tongue discoloration, pancreatitis.

From the liver and biliary tract: infrequently – hepatitis; rarely – impaired liver function, cholestatic jaundice; frequency unknown – hepatic failure (in rare cases with fatal outcome mainly against the background of severe liver dysfunction), liver necrosis, fulminant hepatitis.

From the musculoskeletal system infrequently – osteoarthritis, myalgia, back pain, neck pain; frequency unknown – arthralgia.

From the kidneys and urinary tract: infrequently – dysuria, renal pain; frequency unknown – interstitial nephritis, acute renal failure.

From the reproductive system: infrequently – metrorrhagia, testicular dysfunction.

Infectious diseases infrequently – candidiasis (including oral and genital mucosa); frequency unknown – pseudomembranous colitis.

From laboratory parameters frequently – decreased lymphocyte count, increased eosinophil count, increased basophil count, increased monocyte count, increased neutrophil count, decreased plasma bicarbonate concentration; infrequently – increased AST activity, ALT activity, increased plasma bilirubin concentration, increased plasma urea concentration, increased plasma creatinine concentration, change in plasma potassium content, increased plasma alkaline phosphatase activity, increased plasma chloride content, increased blood glucose concentration, increased platelet count, increased hematocrit, increased plasma bicarbonate concentration, change in plasma sodium content.

Other infrequently – asthenia, malaise, anorexia, feeling of tiredness, facial edema, chest pain, fever, peripheral edema.

Contraindications

Hypersensitivity to azithromycin, erythromycin, other macrolides or ketolides; severe hepatic impairment; simultaneous use with ergotamine and dihydroergotamine; children under 6 months of age (for the powder for oral suspension dosage form); children under 3 years of age (for the 125 mg tablet dosage form), children under 12 years of age with body weight less than 45 kg (for the 500 mg tablet dosage form).

With caution: myasthenia gravis; mild to moderate hepatic impairment; end-stage renal failure with GFR less than 10 ml/min; patients with proarrhythmic factors (especially in the elderly) – with congenital or acquired prolongation of the QT interval, patients receiving therapy with antiarrhythmic agents of classes IA (quinidine, procainamide) and III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotic drugs (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with water-electrolyte imbalance, especially in hypokalemia or hypomagnesemia, with clinically significant bradycardia, arrhythmia or severe heart failure; simultaneous use of digoxin, warfarin, cyclosporine.

Use in Pregnancy and Lactation

Use during pregnancy is possible only in cases where the intended benefit to the mother outweighs the potential risk to the fetus. If it is necessary to use azithromycin during lactation, the issue of discontinuing breastfeeding should be decided.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

Use with caution in mild to moderate hepatic impairment.

Use in Renal Impairment

Use with caution in end-stage renal failure with GFR less than 10 ml/min.

Pediatric Use

Contraindicated in children under 6 months of age (for the powder for oral suspension dosage form); in children under 3 years of age (for the 125 mg tablet dosage form), in children under 12 years of age with body weight less than 45 kg (for the 500 mg tablet dosage form).

Geriatric Use

Elderly patients may have proarrhythmic conditions, Azithromycin should be used with caution due to the high risk of arrhythmias, including torsades de pointes ventricular arrhythmia.

Special Precautions

It 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, azithromycin therapy should be discontinued and a study of the functional state of the liver should be conducted.

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.

Azithromycin should not be used for longer courses than indicated in the instructions, because the pharmacokinetic properties of azithromycin allow recommending a short and simple dosing regimen.

With prolonged use of azithromycin, the development of pseudomembranous colitis caused by Clostridium difficile is possible, ranging from mild diarrhea to severe colitis. If antibiotic-associated diarrhea develops during the use of azithromycin, as well as 2 months after the end of therapy, pseudomembranous colitis caused by Clostridium difficile should be excluded. Drugs that inhibit intestinal peristalsis are contraindicated.

During treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and the QT interval has been observed, increasing the risk of cardiac arrhythmias, including torsades de pointes arrhythmia.

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

Isolated cases of serious allergic reactions, including angioedema and anaphylaxis (rarely with fatal outcome), dermatological reactions, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug rash with eosinophilia and systemic symptoms (DRESS syndrome) have been noted. Some of the reactions were recurrent and required longer observation and treatment.

Effect on the Ability to Drive Vehicles and Operate Machinery

If adverse effects on the nervous system and the organ of vision develop, patients should exercise caution when performing activities requiring increased concentration and speed of psychomotor reactions.

Drug Interactions

Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates, such as digoxin, leads to an increase in the serum concentration of the P-glycoprotein substrate. When digoxin or digitoxin is used concomitantly with azithromycin, a significant increase in the plasma concentration of cardiac glycosides and the risk of glycoside intoxication are possible.

Cases of enhanced effects of the latter have been reported with the concomitant use of azithromycin and warfarin.

Azithromycin interacts weakly with the cytochrome P450 system isoenzymes.

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

Concomitant 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 rhabdomyolysis have been received in patients receiving Azithromycin and statins concomitantly.

Pharmacokinetic studies on the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin did not reveal changes in the pharmacokinetics of azithromycin, provided that cimetidine was administered 2 hours before azithromycin.

Potentiation of the anticoagulant effect has been reported after the concomitant use of azithromycin and indirect anticoagulants (coumarin derivatives). The need for frequent monitoring of prothrombin time should be considered when using azithromycin in patients receiving oral indirect anticoagulants (coumarin derivatives).

Caution should be exercised with concomitant use with cyclosporine. If concomitant use is necessary, monitoring of cyclosporine plasma concentration and appropriate dose adjustment should be performed.

Concomitant use of terfenadine and macrolides has been found to cause arrhythmia and QT interval prolongation.

A case of ventricular fibrillation has been described with concomitant use with disopyramide.

Cases of rhabdomyolysis have been reported with concomitant use with lovastatin.

Concomitant use with rifabutin increases the risk of neutropenia and leukopenia.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.