Azithromycin, 250 mg capsules 6 pcs

Pharmacotherapeutic group:

Azalid antibiotic

ATX code:

J01FA10

Pharmacological Action

Pharmacodynamics
Azithromycin is a broad spectrum bacteriostatic antibiotic from the macrolide-azalid group. It has a broad spectrum of antimicrobial action. Azithromycin mechanism of action is associated with inhibition of microbial cell protein synthesis. Binding to 50S-subunit of ribosomes, 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):

Staphylococcus

In most cases, susceptible microorganisms
1. Gram-positive aerobes
Staphylococcus aureus (methicillin-sensitive strains),
Streptococcus pneumoniae (penicillin-sensitive strains),
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 that can develop resistance to azithromycin
Gram-positive aerobes
Streptococcus pneumoniae (penicillin-resistant strains).

Initially resistant microorganisms
Gram-positive aerobes
Enterococcus faecalis,
Staphylococcus spp. (methicillin-resistant strains of Staphylococcus spp. show very high resistance to macrolides), Gram-positive bacteria that are resistant to erythromycin.

The anaerobes
Basteuris fragilis.

Pharmacokinetics
Absorption
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.

Distribution
Apparent volume of distribution is 31.1 l/kg, binding to proteins is inversely proportional to the concentration in the blood 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. Easily passes the histohematic barriers and enters the tissues. Concentration in tissues and cells is 10-50 times higher than in plasma, and in the focus of infection – 24-34% higher than in healthy tissues.

Metabolism
Azithromycin is demethylated in the liver, losing activity.

Elimation
Azithromycin has a very long half-life of 35-50 hours. 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 excreted mainly unchanged – 50% by the intestine, 6% by the kidneys.

Indications

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

Active ingredient

Composition

1 capsule contains:

The active ingredient:

azithromycin dihydrate (equivalent to anhydrous azithromycin) – 250 mg.

excipients:

Microcrystalline cellulose – 40.6 mg,

povidone low molecular weight (polyvinylpyrrolidone low molecular weight) – 1.0 mg,

magnesium stearate – 3.7 mg,

sodium lauryl sulfate – 0.7 mg,

lactose monohydrate – until the contents of the capsule weigh 370 mg;

solid gelatin capsules:

titanium dioxide 2%,

gelatin to 100%.

How to take, the dosage

Overly, once daily at least 1 hour before or 2 hours after meals.

Infections of the upper and lower respiratory tract, ENT organs, skin and soft tissues – 1 tablet (500 mg) 1 time daily for 3 days (course dose -1.5 g).

In Lyme disease (initial stage of Borreliosis) – erythema migrans – once daily for 5 days: 1st day – 1.0 g (2 tablets of 500 mg), then from 2nd to 5th day – 1 tablet (500 mg) daily (course dose – 3.0 g).

In case of urogenital tract infections caused by Chlamydia trachomatis (urethritis, cervicitis) – 1 g once (2 tablets of 500 mg).

In acne vulgaris of moderate severity – 1 tablet (500 mg) once a day for 3 days, then 1 tablet (500 mg) once a week for 9 weeks (course dose of 6.0 g). The first weekly tablet should be taken 7 days after the first daily tablet (day 8 from the start of treatment), the next 8 weekly tablets should be taken 7 days apart.

Special patient groups
With impaired renal function:
In patients with a GFR of 10-80 ml/min, no dose adjustment is required.

In patients with hepatic impairment:
In patients with mild to moderate hepatic impairment, dosage adjustment is not required.

Elderly patients:
Dose adjustment is not required. Because elderly people may already have current proarrhythmogenic conditions, caution should be exercised when using the drug because of the high risk of cardiac arrhythmias, including pirouette-type arrhythmias.

Interaction

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

Cetirizine
Simultaneous use of azithromycin with cetirizine (20 mg) for 5 days in healthy volunteers did not result in pharmacokinetic interaction and significant QT interval changes.

Didanosine (didezoxinosine)
Simultaneous 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 (P-glycoprotein substrates)
Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin results in higher serum P-glycoprotein substrate concentrations. 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
Concomitant use of azithromycin (single administration of 1000 mg and multiple administration of 1200 mg or 600 mg) has little effect on 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 finding 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.

Given the theoretical possibility of ergotism, concomitant use of azithromycin with ergot derivatives is not recommended.
Pharmacokinetic studies have been performed on concomitant use of azithromycin and drugs whose metabolism involves cytochrome P450 isoenzymes.

Atorvastatin
Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not cause changes in plasma concentrations of atorvastatin (based on 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-acting 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 anticoagulant effect has been reported after concomitant use of azithromycin and indirect anticoagulants (coumarin derivatives). Despite the fact that causal relationship has not been established, the need for frequent monitoring of prothrombin time when using azithromycin in patients receiving oral anticoagulants of indirect action (coumarin derivatives) should be considered.

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 (Stakh) 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
Simultaneous 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
Simultaneous 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 Stache of azithromycin (by 18%), which had no clinical significance.

Indinavir
Concurrent 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
Azithromycin has no significant effect on the pharmacokinetics of methylprednisolone.

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

Rifabutin
Concomitant use of azithromycin and rifabutin has no effect on the serum concentrations of either drug. Neutropenia has occasionally been observed with concomitant use of azithromycin and rifabutin.
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
When used in healthy volunteers, there is no evidence of an effect of azithromycin (500 mg/day daily for 3 days) on the AUC and Stache of sildenafil or its major circulating metabolite.

Terfenadine
No evidence of interaction between azithromycin and terfenadine has been obtained in pharmacokinetic studies. Single cases have been reported in which the possibility of such an interaction cannot be completely ruled out, but there has been no specific evidence that such an interaction has occurred.
It has been found that concomitant use of terfenadine and macrolides can cause arrhythmias and QT interval prolongation.

Theophylline
No interaction between azithromycin and theophylline has been identified.

Triazolam/midazolam
No significant changes in pharmacokinetic parameters were found in concomitant use of azithromycin with triazolam or midazolam in therapeutic doses.

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

Special Instructions

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

Asithromycin 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 because of the possibility of fulminant hepatitis and severe hepatic failure.

In patients with hepatic impairment, if there are symptoms of hepatic impairment, such as rapidly increasing asthenia, jaundice, darkened urine, increased bleeding, and renal encephalopathy, therapy with azithromycin should be discontinued and liver function testing 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.

The drug should not be used for longer courses than indicated, since the pharmacokinetic properties of azithromycin recommend a short and simple dosing regimen.

There are no data on possible interaction between azithromycin and derivatives of ergotamine and dihydroergotamine, but because of the development of ergotism when using macrolides with derivatives of ergotamine and dihydroergotamine simultaneously, this combination is not recommended.

The development of pseudomembranous colitis caused by Clostridium difficile is possible with long-term administration of azithromycin, both as mild diarrhea and severe colitis. If antibiotic-associated diarrhea develops against the background of the drug, as well as 2 months after therapy termination, clostridial pseudomembranous colitis should be excluded. Drugs that inhibit 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.

Cautions should be taken when using the drug in patients with the presence of proarrhythmogenic factors (especially in elderly patients), including congenital or acquired prolongation of the QT interval; in patients taking antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotic drugs (pimozide), antidepressants (citalopram), fluoroquinolones (moxifloxacin and levofloxacin), in patients with electrolyte and water balance disorders, especially in case of hypokalemia or hypomagnesemia, clinically significant bradycardia, cardiac arrhythmia or severe heart failure.

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

When the adverse effects of the drug on nervous system and eyesight are observed, care must be taken when performing activities requiring high concentration and rapid psychomotor reaction.

Contraindications

Myasthenia; mild to moderate hepatic dysfunction; terminal renal failure with glomerular filtration rate less than 10 ml/min; in patients with proarrhythmogenic factors (especially in 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 electrolyte balance disorders, especially in case of hypokalemia or hypomagnesemia, with clinically significant bradycardia, cardiac arrhythmia or severe heart failure; concomitant use of digoxin, warfarin, cyclosporine.

Side effects

The frequency of side effects listed below was determined according to the following (classification of the World Health Organization): very common (more than 10%), common (more than 1% and less than 10%), infrequent (more than 0.1% and less than 1%), rare (more than 0.01% and less than 0.1%), very rare (less than 0.01%), including individual reports; frequency is unknown (cannot be estimated using available data).

Infectious diseases:
infrequent – candidiasis, including oral mucosa, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory diseases, rhinitis;
frequency unknown – pseudomembranous colitis.

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

Mechanism and nutrition disorders:
infrequent – anorexia.

Nervous system disorders:
frequent – headache; infrequent – dizziness, impaired sense of taste, paresthesias, somnolence, insomnia, nervousness; rare – agitation; frequency unknown – hypoesthesia, anxiety, aggression, fainting, seizures, psychomotor hyperactivity, loss of sense of smell, perversion of smell, loss of sense of taste, myasthenia, delirium, hallucinations.

Visual organ disorders:
infrequently – visual impairment.

Hearing and labyrinth disorders:
infrequent – hearing disorder, vertigo;
frequency unknown – hearing disorder, including deafness and/or tinnitus.

Heart disorders:
infrequent – sensation of palpitations;
frequency unknown – prolongation of the QT interval on electrocardiogram, “pirouette” type arrhythmia, ventricular tachycardia.

Vascular disorders:
infrequent – “flushes” of blood to the face;
frequency unknown – decreased blood pressure.

Respiratory system, thorax and mediastinum disorders:
infrequently – shortness of breath, nasal bleeding.

Gastrointestinal tract disorders:
very common – diarrhea; common – nausea, vomiting, abdominal pain; infrequent – flatulence, dyspepsia, constipation, gastritis, dysphagia, bloating, dry oral mucosa, belching, oral mucosa ulcers, increased salivary gland secretion; very rare – color change of tongue, pancreatitis.

Hepatic and biliary tract disorders:
infrequent – hepatitis; rare – hepatic dysfunction, cholestatic jaundice; frequency unknown – hepatic failure (in rare cases with fatal outcome, mainly with severe liver dysfunction), liver necrosis, fulminant hepatitis.

Dermal and subcutaneous tissue disorders:
infrequent – skin rash, itching, urticaria, dermatitis, dry skin, sweating; rarely – photosensitization reaction, acute generalized exanthematous pustulosis (OGEP); frequency unknown – Stephen-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug rash with eosinophilia and systemic manifestations (DRESS syndrome).

Musculoskeletal disorders:
infrequent – osteoarthritis, myalgia, back pain, neck pain; frequency unknown – arthralgia.

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

Gender and mammary gland disorders:
infrequent – metrorrhagia, impaired testicular function.

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

General disorders:
infrequent – edema, asthenia, malaise, feeling of fatigue, facial edema, chest pain, fever, peripheral edema.

Impact on the results of laboratory and instrumental studies:
often – decreased lymphocyte count, increased eosinophil count, increased basophil count, increased monocyte count, increased neutrophil count, decreased plasma bicarbonate concentration; infrequent – increased activity of aspartate aminotransferase, alanine aminotransferase, increased concentration of bilirubin in blood plasma, increased concentration of urea in blood plasma, increased concentration of creatinine in blood plasma, changes in plasma potassium content, increased plasma alkaline phosphatase activity, increased plasma chloride concentration, increased blood glucose concentration, increased platelet count, decreased hematocrit, increased plasma bicarbonate concentration, change in plasma sodium concentration.

Overdose

Pregnancy use

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