Azithromycin, 500 mg 3 pcs

Pharmacotherapeutic group

Azolid antibiotic

ATX code: J01FA10

Pharmacokinetics

Azithromycin is well absorbed and rapidly distributed in the body after oral administration. After a single use of 500 mg bioavailability is 37% (first pass effect), maximum concentration (0.4 mg/l) in blood is achieved after 2-3 hours, apparent volume of distribution is 31.1 l/kg, protein binding is inversely proportional to blood concentration and is 7-50%. It penetrates through cell membranes (effective in 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 the histohematic barriers and enters the tissues. Concentration in tissues and cells is 10-50 times higher than in plasma and 24-34% higher in the focus of infection than in healthy tissues.

Asithromycin has a very long half-life of 35-50 h. The tissue elimination half-life is much longer. The therapeutic concentration of azithromycin is maintained up to 5-7 days after the last dose. Azithromycin is mainly excreted unchanged – 50% by the intestine, 6% by the kidneys. In the liver it is demethylated, losing activity.

Pharmacodynamics

Asithromycin is a bacteriostatic broad-spectrum antibiotic of macrolidovazalide group.‑ It has a broad spectrum of antimicrobial action. The mechanism of action of azithromycin is associated with inhibition of microbial cell protein synthesis. Binding to 50S-subunit ‑of ribosome, it inhibits peptide translocation stage and inhibits protein synthesis, slowing down the growth and reproduction of bacteria. In high concentrations it has a bactericidal effect.

It has activity against a number of Gram-positive, Gram-negative, anaerobic, intracellular and other microorganisms.

Microorganisms can be initially resistant to the action of the antibiotic or can become resistant to it.

The sensitivity scale for microorganisms to azithromycin (Minimum inhibitory concentration (MIC), mg/l):

In most cases, susceptible microorganisms

1. Gram-positive aerobes

Staphylococcus aureus methicillin-sensitive

Streptococcus pneumoniae penicillin-sensitive

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

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Chlamydia psittaci

Mycoplasma pneumoniae

Mycoplasma hominis

Borrelia burgdorferi

Microorganisms that can develop resistance to azithromycin

Gram-positive aerobes

Streptococcus pneumoniae penicillin-resistant

Intrinsically resistant microorganisms

Gram-positive aerobes

Enterococcus faecalis

Staphylococci (methicillin-resistant staphylococci have a very high frequency of acquired resistance to macrolides).

Gram-positive bacteria that are resistant to erythromycin.

The anaerobes

Basteasteides fragilis.

Indications

Infectious inflammatory diseases caused by microorganisms sensitive to azithromycin:

̶ infections of the upper respiratory tract and ENT organs (sinusitis, tonsillitis, pharyngitis, otitis media);

̶ Lower respiratory tract infections (acute bronchitis, exacerbation of chronic bronchitis, pneumonia, including that caused by atypical pathogens);

̶ Skin and soft tissue infections (rye, impetigo, secondary infected dermatoses, acne vulgaris of moderate severity);

̶ urinary tract infections caused by Chlamydia trachomatis (urethritis, cervicitis);

̶ Lyme disease (borreliosis) in the initial stage (erythema migrans).

Active ingredient

Composition

One tablet contains

The active ingredient

Azithromycin 500 mg (as azithromycin dihydrate – 524.05 mg);

Ancillary substances

Ancillary substances Calcium hydrophosphate dihydrate, hypromellose, corn starch, starch 1500, corn starch partially pregelatinized, sodium lauryl sulfate, magnesium stearate, microcrystalline cellulose, Opadray II (incl.including polyvinyl alcohol, talc, macrogol 3350, lecithin (soy), titanium dioxide E171, iron oxide yellow E172, indigo carmine-based aluminum lacquer E132).

How to take, the dosage

Adults and children over 12 years of age with a body weight of more than 45 kg:

̶ for infections of the upper respiratory tract and ENT organs (sinusitis, tonsillitis, pharyngitis, otitis media) – 500 mg/day in a single dose for 3 days (course dose – 1.5 g);

̶ for acne vulgaris moderately severe – 500 mg/day for 3 days, then 500 mg/day once a week for 9 weeks (course dose – 6.0 g). The first weekly tablet should be used 7 days after taking the first daily tablet (day 8 from the start of treatment), the next 8 weekly tablets at 7-day intervals;

̶ In lower respiratory tract infections (acute bronchitis, acute exacerbation of chronic bronchitis, pneumonia, including that caused by atypical pathogens) – 500 mg/day in a single dose for 3 days (course dose of 1.5 g);

̶ in infections of the skin and soft tissues (rye, impetigo, secondary infected dermatoses) – 500 mg/d at a single dose for 3 days (course dose – 1.5 g);

̶ in infections of the urinary tract caused by Chlamydia trachomatis (urethritis, cervicitis) – once 1.0 g;

̶ in Lyme disease (borreliosis) in the initial stage (erythema migrans) – 1.0 g on the first day and 500 mg daily from the second to the fifth day (course dose – 3.0 g).

In patients with impaired renal function

In patients with a GFR of 10-80 ml/min, no dose adjustment is required.

In patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment.

Elderly patients

Dose adjustment is not required. Because the elderly may already have current proarrhythmogenic conditions, caution should be exercised with Azithromycin due to the high risk of cardiac arrhythmias, including pirouette-type arrhythmias.

Interaction

The antacids do not affect the bioavailability of azithromycin, but decrease the maximum blood concentration by 30%; therefore, the drug should be taken at least one hour before or two hours after taking these drugs and meals.

Cetirizine

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

Didanosine (didezoxynosine)

The concomitant use of azithromycin (1200 mg/day) and didanosine (400 mg/day) in 6 HIV-infected patients showed no change in the pharmacokinetic readings of didanosine compared with the placebo group.

Digoxin and colchicine (P-glycoprotein substrates)

The concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine results in higher serum P-glycoprotein substrate concentration. Thus, when concomitant use of azithromycin and digoxin is necessary to consider the possibility of increasing the concentration of digoxin in the blood serum.

Zidovudine

The concomitant use of azithromycin (single administration of 1000 mg and multiple administration of 1200 mg or 600 mg) has little effect on the pharmacokinetics, including renal excretion of zidovudine or its glucuronide metabolite. However, azithromycin administration caused an increase in the concentration of phosphorylated zidovudine, the clinically active metabolite in peripheral blood mononuclear cells. The clinical significance of this fact is unclear.

Asithromycin interacts weakly with cytochrome P450 isoenzymes. Azithromycin has not been found to be involved in pharmacokinetic interactions similar to erythromycin and other macrolides. Azithromycin is not an inhibitor and inducer of cytochrome P450 isoenzymes.

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

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

Atorvastatin

Concomitant use of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not cause changes in plasma concentrations of atorvastatin (on the basis of HMK-CoA reductase inhibition assay). However, in the post-registration period there were isolated reports of cases of rhabdomyolysis in patients receiving azithromycin and statins simultaneously.

Carbamazepine

Pharmacokinetic studies with healthy volunteers showed no significant effect on plasma concentrations of carbamazepine and its active metabolite 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 found, provided that cimetidine was used 2 hours before azithromycin.

Indirect anticoagulants (coumarin derivatives)

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

Cyclosporine

. In a pharmacokinetic study involving healthy volunteers who received oral azithromycin (500 mg/day once daily) for 3 days followed by cyclosporine (10 mg/kg/day once daily), a significant increase in maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-5) of cyclosporine was found. Caution should be exercised when concomitant use of these drugs. In case of necessity of concomitant use of these drugs, it is necessary to monitor plasma concentrations of cyclosporine and adjust the dose accordingly.

Efavirenz

The concomitant use of azithromycin (600 mg/day once daily) and efavirenz (400 mg/day) daily for 7 days did not cause any clinically significant pharmacokinetic interaction.

Fluconazole

Concomitant use of azithromycin (1200 mg once daily) did not alter the pharmacokinetics of fluconazole (800 mg once daily). Total exposure and half-life of azithromycin were not altered by concomitant use of fluconazole, but there was a decrease in Cmax of azithromycin (by 18%), which had no clinical significance.

Indinavir

The concomitant use of azithromycin (1200 mg once) had no statistically significant effect on the pharmacokinetics of indinavir (800 mg three times daily for 5 days).

Methylprednisolone

Asithromycin has no significant effect on the pharmacokinetics of methylprednisolone.

Nelfinavir

The simultaneous use of azithromycin (1200 mg) and nelfinavir (750 mg 3 times daily) causes increased equilibrium serum concentrations of azithromycin. No clinically significant adverse effects have been observed and no dose adjustment of azithromycin is required when used concomitantly with nelfinavir.

Rifabutin

The concomitant use of azithromycin and rifabutin has no effect on the serum concentrations of either drug. Neutropenia was sometimes observed when azithromycin and rifabutin were used concomitantly. Although neutropenia has been associated with the use of rifabutin, a causal relationship between the use of a combination of azithromycin and rifabutin and neutropenia has not been established.

Sildenafil

There is 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 when used in healthy volunteers.

Terfenadine

In pharmacokinetic studies there has been no evidence of interaction between azithromycin and terfenadine. There have been isolated cases reported in which the possibility of such an interaction could not be completely ruled out, but there has not been any concrete evidence that this interaction has occurred.

The concomitant use of terfenadine and macrolides has been found to cause arrhythmias and prolongation of the QT interval.

Theophylline

There have been no identified interactions between azithromycin and theophylline.

Triazolam/midazolam

There are no significant changes in pharmacokinetic parameters when azithromycin is used simultaneously with triazolam or midazolam in therapeutic doses.

Trimethoprim/sulfamethoxazole

The concomitant use of trimethoprim/sulfamethoxazole with azithromycin showed no significant effect on Cmax, total exposure or renal excretion of trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those found in other studies.

Special Instructions

If a dose of Azithromycin is missed, the missed dose should be taken as soon as possible, and subsequent doses should be taken 24 hours apart.

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

Azithromycin should be used with caution in patients with mild to moderate hepatic impairment because of the possibility of fulminant hepatitis and severe hepatic impairment.

In case of hepatic impairment

In the presence of symptoms of hepatic impairment, such as rapidly increasing asthenia, jaundice, darkened urine, tendency to bleeding, hepatic encephalopathy, therapy with azithromycin should be discontinued and liver function tests should be performed.

In patients with impaired renal function

In patients with a GFR of 10-80 ml/min, no dose adjustment is required.

As with other antibacterial agents, patients should be regularly evaluated during therapy with Azithromycin for the presence of non-susceptible microorganisms and signs of superinfections, including fungal infections.

Azithromycin should not be used for longer courses than directed, since the pharmacokinetic properties of azithromycin suggest a short and simple dosing regimen.

There are no data on possible interactions between azithromycin and ergotamine and dihydroergotamine derivatives, but because of the development of ergotism when using macrolides with ergotamine and dihydroergotamine derivatives simultaneously, this combination is not recommended. During long-term use of Azithromycin, pseudomembranous colitis caused by Clostridium difficile may develop, both as mild diarrhea and severe colitis. If antibiotic-associated diarrhea develops against the background of Azithromycin therapy, as well as 2 months after therapy termination, Clostridium difficile pseudomembranous colitis should be excluded. Drugs inhibiting intestinal peristalsis are contraindicated.

In treatment with macrolides, including azithromycin, prolongation of cardiac repolarization and QT interval have been observed, increasing the risk of cardiac arrhythmias, including pirouette-type arrhythmias.

We should use azithromycin with caution in patients with the presence of proarrhythmogenic factors (especially in elderly patients) including congenital or acquired prolongation of QT interval; in patients taking antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotics (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), in patients with electrolyte balance disorders, especially in case of hypokalemia or hypomagnesemia, clinically significant bradycardia, cardiac arrhythmia or severe heart failure. Administration of Azithromycin may provoke myasthenic syndrome or cause exacerbation of myasthenia gravis.

Hypersensitivity reactions

. Also when using erythromycin and other macrolides, rare cases of serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), skin reactions have been reported, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (rarely fatal), drug rash with eosinophilia and systemic manifestations (DRESS syndrome). Some of these reactions with azithromycin have been recurrent and require long-term treatment and monitoring.

If an allergic reaction develops, the drug should be discontinued and appropriate treatment initiated. It should be noted that after withdrawal of symptomatic therapy, symptoms of an allergic reaction may return.

Impact on driving, operating machinery

At the time of treatment, care must be taken when driving vehicles and engaging in other potentially dangerous activities requiring increased concentration and rapid psychomotor reactions. In case of undesirable effects of nervous system (dizziness, somnolence, syncope, convulsions) and eyesight (visual disturbances) one should not use the mentioned activities.

Contraindications

̶ Hypersensitivity to azithromycin and other drug components, erythromycin, other macrolides, ketolides, soy, and peanuts;

̶ severe hepatic impairment (Child-Pugh class C);

̶ children under 12 years of age with a body weight less than 45 kg;

̶ concurrent use with ergotamine and dihydroergotamine.

With caution

Terminal renal insufficiency with a GFR (glomerular filtration rate) less than 10 ml/min; mild to moderate hepatic impairment (Child-Pugh class A and B); in patients with proarrhythmogenic factors (especially in older patients): with congenital or acquired QT interval prolongation; 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 disorders of water-electrolyte balance, especially in case of hypokalemia or hypomagnesemia; with clinically significant bradycardia, cardiac arrhythmia or severe heart failure; simultaneous use of digoxin, warfarin, cyclosporine; myasthenia gravis.

Side effects

The frequency of side effects is classified in accordance with the recommendations of the World Health Organization: very common – at least 10%; common – at least 1%, but less than 10%; infrequent – 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 based on available data.

Infectious diseases

Infrequent – candidiasis, including oral mucosa, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory diseases, rhinitis;

An unknown frequency is pseudomembranous colitis.

Blood and lymphatic system disorders

Infrequent – leukopenia, neutropenia, eosinophilia;

Very rare – thrombocytopenia, hemolytic anemia.

Metabolism and nutrition disorders

Infrequent – anorexia.

Allergic reactions

Infrequent – angioedema, hypersensitivity reaction;

Unknown frequency – anaphylactic reaction.

Overdose

Symptoms

Temporary hearing loss, nausea, vomiting, diarrhea.

Treatment

Symptomatic (no specific antidote).

Pregnancy use

Prenatal use of the drug is possible only when the estimated benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding should be discontinued if it is necessary to use the drug during lactation.

Similarities