Hemomycin (Capsules) Instructions for Use

Marketing Authorization Holder

Hemofarm, A.D. (Serbia)

Manufactured By

Hemofarm, A.D. (Serbia)

Or

Hemofarm A.D. Vrsac Branch Plant Sabac (Serbia)

Or

Hemofarm, LLC (Bosnia and Herzegovina)

Packaging and Quality Control Release

HEMOFARM, A.D. (Serbia)

Contact Information

NIZHPHARM group of companies (Russia)

ATC Code

J01FA10 (Azithromycin)

Active Substance

Azithromycin (Rec.INN WHO registered)

Dosage Forms

	Hemomycin	Capsules 250 mg: 6 pcs.
		Lyophilisate for preparation of concentrate for solution for infusion 500 mg: 1 fl.
		Film-coated tablets 500 mg: 3 pcs.
		Powder for oral suspension 100 mg/5 ml: 1 fl. with measuring spoon
		Powder for oral suspension 200 mg/5 ml: 1 fl. with measuring spoon

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 0, light blue; capsule contents – white powder.

Excipients: lactose anhydrous, corn starch, sodium lauryl sulfate, magnesium stearate.

Excipients (capsule): titanium dioxide (E171, C.I.77891), Patent Blue V (E131, C.I.42051), gelatin.

6 pcs. – blisters (1) – cardboard packs.

Film-coated tablets grayish-blue, round, biconvex; on cross-section the core is white or almost white.

Excipients: microcrystalline silicified cellulose, microcrystalline cellulose, sodium carboxymethyl starch (type A), povidone K90, magnesium stearate, talc, colloidal silicon dioxide.

Coating composition: titanium dioxide, talc, copovidone, ethylcellulose, macrogol 6000, indigo carmine (indigotine) E132, lake green 8% (indigo carmine (indigotine) E132, quinoline yellow E104).

3 pcs. – blisters (1) – cardboard packs.

Powder for oral suspension white or almost white, with a fruity odor; prepared suspension is almost white, with a fruity odor.

Excipients: xanthan gum, sodium saccharin, calcium carbonate, colloidal silicon dioxide, anhydrous sodium phosphate, sorbitol, apple flavor, strawberry flavor, cherry flavor.

11.43 g – dark glass bottles with a capacity of 60 ml, with first-opening control (1) in a set with a measuring spoon (volume 5 ml, with a mark for volume 2.5 ml) – cardboard packs.

Powder for oral suspension white or almost white, with a fruity odor; prepared suspension is almost white, with a fruity odor.

Excipients: xanthan gum, sodium saccharin, calcium carbonate, colloidal silicon dioxide, anhydrous sodium phosphate, sorbitol, apple flavor, strawberry flavor, cherry flavor.

10 g – dark glass bottles with a capacity of 60 ml, with first-opening control (1) in a set with a measuring spoon (volume 5 ml, with a mark for volume 2.5 ml) – cardboard packs.

Lyophilisate for solution for infusion in the form of a lyophilized powder or compacted cake, white or almost white.

* Each ml of concentrate contains 100 mg of azithromycin (in the form of dihydrate).

Excipients: citric acid monohydrate – 110 mg, mannitol – 146 mg, sodium hydroxide – q.s.

Glass bottles with a capacity of 13.5 ml (1) – cardboard packs.

Clinical-Pharmacological Group

Antibiotic of the macrolide group – azalide

Pharmacotherapeutic Group

Antibiotic-azalide

Pharmacological Action

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 peptidyltransferase at the translation stage and suppresses protein synthesis, slowing 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 may initially be resistant to the antibiotic or may acquire resistance to it.

Scale of microorganism susceptibility to azithromycin

* Minimum Inhibitory Concentration.

In most cases, the following are susceptible to azithromycin

• Aerobic gram-positive microorganisms: Staphylococcus aureus (methicillin-susceptible), Streptococcus pneumoniae (penicillin-susceptible), Streptococcus pyogenes;
• Aerobic gram-negative microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida, Neisseria gonorrhoeae;
• Anaerobic microorganisms: Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyromonas spp.;
• Other microorganisms: 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).

Inherently resistant microorganisms

• Aerobic gram-positive microorganisms: Enterococcus faecalis, Staphylococcus spp. (methicillin-resistant staphylococci very frequently have acquired resistance to macrolides);
• Gram-positive bacteria resistant to erythromycin;
• Anaerobic microorganisms: Bacteroides fragilis.

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

Pharmacokinetics

Absorption

When taken orally, Azithromycin is rapidly absorbed from the gastrointestinal tract, due to its stability in an acidic environment and lipophilicity. After oral administration of a 500 mg dose, the C_max of azithromycin in blood plasma is reached in 2-3 hours and is 0.4 mg/l. Bioavailability is 37%.

When administered parenterally, Azithromycin penetrates from blood plasma into tissues. In healthy volunteers receiving IV infusion of azithromycin at a dose of 500 mg (solution concentration 1 mg/ml) over 3 hours, the C_max of the drug in blood plasma was 1.1 µg/ml, with a baseline concentration of 0.18 µg/ml. Similar values were observed in patients with community-acquired pneumonia receiving the same therapy for 2 to 5 days (C_max 3.6 µg/ml, with a baseline concentration of 0.2 µg/ml).

Distribution

Azithromycin penetrates well into the respiratory tract, organs and tissues of the urogenital tract (particularly the prostate gland), skin and soft tissues. The high concentration in tissues (10-50 times higher than in plasma) and long T_1/2 are due to the low binding of azithromycin to plasma proteins, as well as its ability to penetrate eukaryotic cells and concentrate in the low pH environment surrounding lysosomes. This, in turn, determines the large apparent V_d (31.1 l/kg) and high plasma clearance. The ability of azithromycin to accumulate predominantly in lysosomes is particularly important for the elimination of intracellular pathogens. It has been proven that phagocytes deliver Azithromycin to the sites of infection, where it is released during phagocytosis. The concentration of azithromycin in foci of infection is significantly higher than in healthy tissues (on average by 24-34%) and correlates with the degree of inflammatory edema. Despite the high concentration in phagocytes, Azithromycin does not significantly affect their function.

Azithromycin persists in bactericidal concentrations for 5-7 days after the last dose, which allowed the development of short (3-day and 5-day) treatment courses.

Binding to plasma proteins decreases with increasing azithromycin concentration in the blood. The degree of azithromycin binding to proteins is 51% at a concentration of 0.02 µg/ml, and 7% at a concentration of 2 µg/ml.

Metabolism and Excretion

The main pathway of biotransformation is N-demethylation in the liver; the resulting metabolites are inactive.

Azithromycin has a very long T_1/2 – 35-50 hours, with parenteral administration – 65-72 hours. The T_1/2 from tissues is significantly longer. Azithromycin is excreted mainly unchanged – 50% via the intestine, 6% via the kidneys. With parenteral administration, 11% is excreted by the kidneys on the first day, and 14% of the IV administered dose after 5 days.

Indications

Capsules, tablets, powder

Infectious and inflammatory diseases caused by microorganisms susceptible 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 those caused by atypical pathogens);
• Infections of the skin and soft tissues (moderate acne vulgaris, erysipelas, impetigo, secondarily infected dermatoses);
• Infections of the genitourinary tract (urethritis and/or cervicitis) caused by Chlamydia trachomatis;
• Initial stage of Lyme disease (borreliosis) – migrating erythema (erythema migrans).

Lyophilisate for solution for infusion

• Severe community-acquired pneumonia caused by Chlamydia pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus or Streptococcus pneumoniae;
• Severe infectious and inflammatory diseases of the pelvic organs (endometritis and salpingitis) caused by Chlamydia trachomatis, Neisseria gonorrhoeae or Mycoplasma hominis.

ICD codes

Dosage Regimen

The drug in the form of capsules, tablets and suspension is taken orally, once a day, 1 hour before meals or 2 hours after meals. Capsules and tablets are swallowed whole, without chewing.

If one dose of the drug is missed, the missed dose should be taken as soon as possible, and subsequent doses – at intervals of 24 hours.

Capsules and tablets

Adults 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 – 500 mg (2 caps. or 1 tab.) once a day for 3 days (total course dose 1.5 g).

For moderate acne vulgaris – 500 mg (2 caps. or 1 tab.) once a day for 3 days, then 500 mg (2 caps. or 1 tab.) once a week (at 7-day intervals) for 9 weeks (total course dose 6 g).

For genitourinary tract infections (uncomplicated urethritis and/or cervicitis) caused by Chlamydia trachomatis – a single dose of 1 g (4 caps. or 2 tab.).

For Lyme disease (initial stage of borreliosis) – migrating erythema (erythema migrans) – once a day for 5 days: day 1 – 1 g (4 caps. or 2 tab.), then from day 2 to day 5 – 500 mg (2 caps. or 1 tab.) (total course dose 3 g).

Suspension 100 mg/5 ml and 200 mg/5 ml

Children for infections of the upper and lower respiratory tract, ENT organs, infections of the skin and soft tissues (except for chronic migrating erythema) the drug in the form of a suspension is prescribed at a rate of 10 mg/kg of body weight once a day for 3 days (total course dose – 30 mg/kg).

Recommended dosing regimens depending on the child’s body weight and suspension concentration

For pharyngitis/tonsillitis caused by Streptococcus pyogenes, Azithromycin is used at a dose of 20 mg/kg/day for 3 days (total course dose 60 mg/kg). The maximum daily dose is 500 mg.

Children with body weight less than 10 kg should take azithromycin preparations in the form of a powder for oral suspension with a concentration of 100 mg/5 ml.

For Lyme disease (borreliosis) for the treatment of the initial stage (erythema migrans) – once a day for 5 days: on the 1st day at a dose of 20 mg/kg of body weight, and then from the 2nd to the 5th day – 10 mg/kg of body weight (total course dose 60 mg/kg).

The following dosing regimen for Hemomycin suspension is recommended for children with erythema migrans

Day 1

From day 2 to day 5

Adults and children over 12 years of age with body weight over 45 kg

For infections of the upper and lower respiratory tract, ENT organs, skin and soft tissues, 500 mg (12.5 ml of 200 mg/5 ml suspension) is prescribed once a day for 3 days (total course dose – 1.5 g).

For Lyme disease (borreliosis) for the treatment of the initial stage (erythema migrans) – 1 g (25 ml of 200 mg/5 ml suspension)/day on the first day in a single dose, then 0.5 g (12.5 ml of 200 mg/5 ml suspension) per day daily from day 2 to day 5 (total course dose – 3 g).

Rules for suspension preparation

Add water (distilled or boiled and cooled) to the vial containing the powder up to the mark.

The contents of the vial are shaken thoroughly until a homogeneous suspension is obtained.

If the level of the prepared suspension is below the mark on the vial label, add water again up to the mark and shake.

The prepared suspension is stable at room temperature for 5 days.

The suspension should be shaken before use.

Immediately after taking the suspension, the child should be given a few sips of liquid (water, tea) to wash off and swallow the suspension remaining in the oral cavity.

Lyophilisate for solution for infusion

The drug should be used only in inpatient medical institutions.

For community-acquired pneumonia, 500 mg is prescribed once a day intravenously for at least 2 days (if necessary, at the discretion of the attending physician, the intravenous course of treatment can be extended, but should not exceed 5 days). Intravenous administration should be followed by subsequent oral administration of azithromycin as a single daily dose of 500 mg until the full completion of the 7-10-day general course of treatment.

For infectious and inflammatory diseases of the pelvic organs, 500 mg is prescribed once a day intravenously for at least 2 days (the intravenous course of treatment is no more than 5 days). Intravenous administration should be followed by subsequent oral administration of azithromycin as a single daily dose of 250 mg until the full completion of the 7-day general course of treatment.

The timing of the transition to oral treatment is determined in accordance with the data of the clinical examination.

Rules for solution preparation

The solution for infusion is prepared in 2 stages

• Stage 1 – preparation of the reconstituted solution – add 4.8 ml of sterile water for injections to the vial with 500 mg of the drug and shake thoroughly until the powder is completely dissolved. 1 ml of the resulting solution contains 100 mg of azithromycin. The prepared solution remains stable for 24 hours at room temperature;
• Stage 2 – dilution of the reconstituted solution (100 mg/ml) – is carried out immediately before administration in accordance with the table below.

The reconstituted solution is introduced into the vial with the solvent (0.9% sodium chloride solution, 5% dextrose solution, Ringer’s solution) to obtain a final concentration of azithromycin of 1.0-2.0 mg/ml in the infusion solution.

Before administration, the solution is subjected to visual inspection. If the finished solution contains particles of the substance, it should not be used.

The prepared solution is stable at room temperature for 24 hours.

Hemomycin solution should not be administered intravenously as a bolus or intramuscularly.

It is recommended to administer the prepared solution intravenously by drip over 3 hours – infusion solution at a concentration of 1 mg/ml, over 1 hour – at a concentration of 2 mg/ml. Administration of higher concentrations should be avoided due to the risk of reactions at the injection site.

Special patient groups

In patients with impaired renal function with GFR 10-80 ml/min, dose adjustment is not required.

When used in patients with mild to moderate hepatic impairment, dose adjustment is not required.

In elderly patients, dose adjustment is not required. Since elderly individuals may already have existing proarrhythmic conditions, caution should be exercised when using azithromycin due to the high risk of developing cardiac arrhythmias, including torsades de pointes arrhythmia.

Adverse Reactions

The frequency of adverse effects is classified according to WHO recommendations: very common – at least 10%, common – at least 1%, but less than 10%, uncommon – at least 0.1%, but less than 1%, rare – at least 0.01%, but less than 0.1%, very rare – less than 0.01%; unknown frequency – cannot be estimated from the available data.

Infections uncommon – candidiasis, including oral mucosal candidiasis, vaginal infection, pneumonia, pharyngitis, gastroenteritis, respiratory diseases, rhinitis, fungal infection, bacterial infection; unknown frequency – pseudomembranous colitis.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia, eosinophilia; very rare – thrombocytopenia, hemolytic anemia.

Allergic reactions: uncommon – angioedema, hypersensitivity reaction; unknown frequency – anaphylactic reaction.

Nervous system disorders: common – headache; uncommon – dizziness, taste disturbance, paresthesia, somnolence, insomnia, nervousness; rare – agitation; unknown frequency – hypoesthesia, anxiety, aggression, syncope, convulsions, psychomotor hyperactivity, loss of smell, parosmia, ageusia, myasthenia, delirium, hallucinations.

Eye disorders: uncommon – visual impairment.

Ear and labyrinth disorders: uncommon – hearing disorder, vertigo; unknown frequency – hearing impairment, including deafness and/or tinnitus.

Cardiac disorders: uncommon – palpitations, flushing; unknown frequency – decreased blood pressure, prolonged QT interval on ECG, torsades de pointes arrhythmia, 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 ulcers, increased salivary gland secretion; very rare – tongue discoloration, pancreatitis.

Hepatobiliary disorders: uncommon – hepatitis; rare – impaired liver function, cholestatic jaundice; unknown frequency – hepatic failure (in rare cases with a 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, acute generalized exanthematous pustulosis; unknown frequency – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

Musculoskeletal and connective tissue disorders uncommon – osteoarthritis, myalgia, back pain, neck pain; unknown frequency – arthralgia.

Renal and urinary disorders: uncommon – dysuria, renal pain; unknown frequency – interstitial nephritis, acute renal failure.

Reproductive system and breast disorders: uncommon – metrorrhagia, testicular dysfunction.

General disorders and administration site conditions uncommon – anorexia, edema, asthenia, malaise, feeling of fatigue, facial edema, chest pain, neck pain, back pain, pyrexia, peripheral edema.

Administration site reactions (with intravenous drip administration): pain and inflammation at the injection site.

Investigations common – decreased lymphocyte count, increased eosinophil count, increased basophil count, increased monocyte count, increased neutrophil count, decreased plasma bicarbonate concentration; uncommon – increased AST activity, increased 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, decreased hematocrit, increased plasma bicarbonate concentration, change in plasma sodium content.

Contraindications

• Severe hepatic impairment;
• Concomitant use with ergotamine, dihydroergotamine;
• Age under 18 years (for the lyophilisate);
• Children under 12 years of age with body weight less than 45 kg (for tablets and capsules);
• Children under 6 months of age (for the suspension);
• Lactase deficiency, lactose intolerance, glucose-galactose malabsorption (for capsules);
• Fructose intolerance (for the suspension);
• Hypersensitivity to azithromycin or other components of the drug;
• Hypersensitivity to erythromycin, other macrolides, ketolides.

With caution myasthenia gravis, mild to moderate hepatic impairment, end-stage renal failure with GFR less than 10 ml/min, in patients with proarrhythmic factors (especially elderly patients): with congenital or acquired prolongation of the QT interval, in patients receiving therapy with antiarrhythmic drugs 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 case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia or severe heart failure; concomitant use of digoxin, warfarin, cyclosporine.

Use in Pregnancy and Lactation

During pregnancy and breastfeeding, the drug is used only if the intended benefit to the mother outweighs the potential risk to the fetus and child.

If it is necessary to use azithromycin during breastfeeding, it is recommended to discontinue breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment.

The drug should be used with caution in mild to moderate hepatic impairment.

Use in Renal Impairment

The drug should be prescribed with caution in end-stage renal failure (GFR less than 10 ml/min).

Pediatric Use

Contraindications: children under 12 years of age with body weight less than 45 kg (for capsules and tablets); children under 6 months of age (for the suspension); age under 18 years (lyophilisate).

Geriatric Use

In elderly patients, dose adjustment is not required. Since elderly individuals may already have existing proarrhythmic conditions, caution should be exercised when using azithromycin due to the high risk of developing cardiac arrhythmias, including torsades de pointes arrhythmia.

Special Precautions

The drug should not be administered in longer courses than indicated in the instructions, because the pharmacokinetic properties of azithromycin allow the use of a short dosing regimen.

Superinfection (including fungal) may occur during treatment with Hemomycin (as with any antibiotic therapy).

Also, as with the use of erythromycin and other macrolides, rare cases of serious allergic reactions have been reported, including angioedema and anaphylaxis (in rare cases with fatal outcome), skin reactions, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (in rare cases with fatal outcome), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Some of these reactions that developed during the use of azithromycin had a recurrent course and required prolonged treatment and observation.

If an allergic reaction occurs, the drug should be discontinued and appropriate treatment should be prescribed. It should be borne in mind that after discontinuation of symptomatic therapy, a recurrence of allergic reaction symptoms is possible, which requires specific therapy under medical supervision.

Azithromycin in oral dosage forms should be taken at least 1 hour before or 2 hours after taking antacid preparations. 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.

Azithromycin 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 occur, 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 renal impairment: in patients with GFR 10-80 ml/min, dose adjustment is not required; therapy with Hemomycin should be carried out with caution under monitoring of renal function in patients with GFR less than 10 ml/min.

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 in longer courses than indicated in the instructions, because the pharmacokinetic properties of azithromycin recommend a short and simple dosing 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, ranging from mild diarrhea to severe colitis. In this regard, patients with diarrhea should be carefully monitored. If antibiotic-associated diarrhea occurs during drug administration, as well as within 2 months after the end of therapy, clostridial pseudomembranous colitis should be ruled out. The use of drugs that inhibit intestinal peristalsis in the development of pseudomembranous colitis is contraindicated.

During treatment 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, which can lead to cardiac arrest.

Caution should be exercised when using the drug in patients with proarrhythmic factors (especially elderly patients): with congenital or acquired prolongation of the QT interval, in patients receiving therapy with antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotic drugs (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), with water-electrolyte imbalance, 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.

Patients on a sodium-restricted diet should take into account that one vial of Hemomycin lyophilisate for solution for infusion contains 6.2 mg of sodium (sodium hydroxide is an excipient).

Use in pediatrics

The safety and efficacy of the injectable form of Hemomycin in children and adolescents under 18 years of age have not been established.

Effect on ability to drive vehicles and operate machinery

Due to the possible development of adverse reactions from the central nervous system and the organ of vision during treatment, caution should be exercised when driving vehicles and performing other activities that require increased concentration and speed of psychomotor reactions.

Overdose

Symptoms nausea, temporary hearing loss, vomiting, diarrhea, abdominal pain, impaired liver function.

Treatment symptomatic therapy.

Drug Interactions

Antacid preparations

Antacid preparations do not affect the bioavailability of azithromycin, but reduce C_max in the blood by 30%, so the drug should be taken at least 1 hour before or 2 hours after taking these preparations and food.

Cetirizine

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

Didanosine (dideoxyinosine)

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

Digoxin and colchicine (P-glycoprotein substrates)

Concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates, such as digoxin and colchicine, leads to an increase in the serum concentration of the P-glycoprotein substrate. Thus, when azithromycin and digoxin are used concomitantly, the possibility of increased serum digoxin concentrations should be considered.

Zidovudine

Concomitant administration of azithromycin (single 1000 mg dose and multiple 1200 mg or 600 mg doses) has a slight effect on the pharmacokinetics, including the renal excretion of zidovudine or its glucuronide metabolite. However, the administration 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 the cytochrome P450 enzyme system. Azithromycin has not been shown to be involved in pharmacokinetic interactions similar to those of erythromycin and other macrolides. Azithromycin is not an inhibitor or inducer of cytochrome P450 enzymes.

Ergot alkaloids

Given the theoretical possibility 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 the cytochrome P450 enzyme system.

Atorvastatin

Concomitant administration 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, isolated cases of rhabdomyolysis have been reported post-marketing in patients receiving Azithromycin and statins concomitantly.

Carbamazepine

Pharmacokinetic studies in healthy volunteers did not reveal a significant effect on the plasma concentrations of carbamazepine and its active metabolite in patients receiving Azithromycin concomitantly.

Cimetidine

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

Indirect anticoagulants (coumarin derivatives)

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 has been reported after concomitant use of azithromycin and indirect anticoagulants (coumarin derivatives). Although a causal relationship has not been established, the need for frequent monitoring of prothrombin time should be considered when using azithromycin in patients receiving oral indirect anticoagulants (coumarin derivatives).

Cyclosporine

In a pharmacokinetic study involving healthy volunteers who took Azithromycin orally (500 mg/day as a single dose) for 3 days, followed by cyclosporine (10 mg/kg/day as a single dose), a significant increase in the C_max and AUC_0-5 of cyclosporine in plasma was revealed. Caution should be exercised when these drugs are used concomitantly. If concomitant use of these drugs is necessary, monitoring of cyclosporine plasma concentrations and appropriate dose adjustment should be performed.

Efavirenz

Concomitant administration 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

Concomitant administration of azithromycin (1200 mg as a single dose) did not alter the pharmacokinetics of fluconazole (800 mg as a single dose). The total exposure and T_1/2 of azithromycin were not changed with concomitant fluconazole use, however, a decrease in the C_max of azithromycin (by 18%) was observed, which was not clinically significant.

Indinavir

Concomitant administration of azithromycin (1200 mg as a single dose) did not cause a statistically significant effect on the pharmacokinetics of indinavir (800 mg 3 times/day for 5 days).

Methylprednisolone

Azithromycin does not have a significant effect on the pharmacokinetics of methylprednisolone.

Nelfinavir

Concomitant administration of azithromycin (1200 mg) and nelfinavir (750 mg 3 times/day) causes an increase in the C_ss 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

Concomitant administration of azithromycin and rifabutin does not affect the serum concentration of either drug. Neutropenia was sometimes observed with the concomitant use of azithromycin and rifabutin. Although neutropenia has been 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

No evidence of an effect of azithromycin (500 mg/day daily for 3 days) on the AUC and C_max of sildenafil or its main circulating metabolite was obtained in healthy volunteers.

Terfenadine

Pharmacokinetic studies have provided no evidence of an interaction between azithromycin and terfenadine. 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 concomitant use of terfenadine and macrolides can cause arrhythmia and QT interval prolongation.

Theophylline

No interaction between azithromycin and theophylline has been identified.

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

Concomitant administration of trimethoprim/sulfamethoxazole with azithromycin did not reveal a significant effect on the C_max, total exposure, or renal excretion of trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those detected in other studies.

Storage Conditions

The drug should be stored in the original packaging, in a place inaccessible to children, at a temperature not exceeding 25°C (77°F) (lyophilisate – at a temperature from 10°C (50°F) to 25°C (77°F)).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.