Azithromycin

General characteristics. Structure:

Active ingredient: 500 mg of azithromycin in 1 tablet.

Excipients: hydrophosphate calcium a dihydrate, a gipromelloz, starch corn, starch 1500, starch corn partially prezhelatinizirovanny, sodium lauryl sulfate, magnesium stearate, cellulose microcrystallic, Opadray of II (including polyvinyl alcohol, talc, a macrogoal 3350, lecithin (soy), titanium E 171 dioxide, ferrous oxide yellow E 172, an aluminum varnish on the basis of E 132 indigo carmine).

Pharmacological properties:

Pharmacodynamics. Action mechanism. Azithromycin is an antibiotic of a broad spectrum of activity, the first representative of new subgroup of the makrolidny antibiotics called azaleads. The molecule is designed by addition of oxygen atom to a lactone ring of erythromycin A. Chemical name of azithromycin: 9-деокси-9а-аза-9а-метил-9а-гомоэритромици A. Molekrulyarny weight makes 749,0.

The mechanism of effect of azithromycin - linkng with 50 S unit a ribosome that interferes with synthesis of bactericidal proteins and a translocation of peptides.

Resistance mechanism. Resistance to an azitrominii can be natural or acquired. Three main mechanisms of resistance at bacteria: alteration a target party, alteration in antibiotic transport and modification of an antibiotic.

Full cross resistance exists between the following microorganisms: Sreptococcuspneumoniae, a beta and hemolitic streptococcus of group A, Enterococcusfaecalisi Staphylococcusaureus, including Methicillinum, resistant Saureus (MRSA) to erythromycin, azithromycin, other macroleads and linkozamida.

Extreme concentration (Breakpoints). Extreme concentration of sensitivity to an azitromitsii for typical pathogens are:

EUCAST (EuropeanCommitteeonAntimicrobialSusceptibilityTesting) boundary values of the minimum overwhelming concentration (MOC):

Name of microorganisms	The extreme concentration connected with type (S /R)
	It is sensitive (S)	Rezistenten (R)
Staphylococcus	≤ 1 mg/l	> 2 mg/l
Sreptococcus A, B, C, G	≤0,25 mg/l	> 0,5 mg/l
Sreptococcus pneumoniae	≤ 0,25 mg/l	> 0,5 mg/l
Haemophilus influenzae	≤ 0,12 mg/l	> 4 mg/l
Moraxella cotarrhalis	≤0,5 mg/l	> 0,5 mg/l
Neisseria gonorrhoeae	≤0,25 mg/l	> 0,5 mg/l

For definition of sensitivity of these of a bacterium to other macroleads (azithromycin, кларитромицин and рокситромицин) erythromycin can be used.

At intravenous administration macroleads exert impact on Legionellupneumophila (the minimum overwhelming concentration of erythromycin <1 mg/l for strains of a dikogotip).

Macroleads are applied at treatment of the infections caused by Campylobacterjejuni (the minimum overwhelming concentration of erythromycin <1mg/l to strains of wild type). Azithromycin is used for treatment of the infections caused by S.typhy (the minimum overwhelming concentration ≤ 16 mg/l for strains of wild type) and Shigellaspp.

Sensitivity. Frequency of emergence of the acquired resistance can differ for the chosen samples as geographically, and in temporary parameter, and local information on resistance would be very desirable, especially at treatment of severe forms of an infection. It is necessary to consult to the specialist when the frequency of emergence of the acquired resistance such is what questionable to become use of medicine for several last types of infections.

Antimicrobic range of azithromycin: usually sensitive microorganisms:

- aerobic gram-positive microorganisms:

- Staphylococcus aureus (Methicillinum – sensitive);

- Sreptococcus pneumoniae (penicillin – sensitive);

- Sreptococcus pyogenes;

- aerobic gram-negative microorganisms:

- Haemuphilis influenzae;

- Haemophilus parainfluenzae;

- Legionella pneumophila;

- Moraxella calarrhalls;

- Moraxella catarrhalis;

- Pasteurela multocida;

- anaerobic microorganisms:

- Clostridium perfrmgens;

- Fusobacterium spp.;

- Prevotella spp.;

- Porphyriomonas spp.;

- Other microorganisms:

- Chlamydia trachomatis;

Microorganisms with the acquired resistance:

- Aerobic gram-positive microorganisms: Sreptococcus pneumoniae (penicillin - intermediarno резистентен, penicillin – резистентен).

Naturally resistant microorganisms: aerobic gram-positive microorganisms:

- Enterococcus faecalis;

- Staphylococcus MRSA, MRSE (Methicillinum-resistant staphylococcus have the acquired resistance to macroleads, and here are specified because they are seldom sensitive to azithromycin).

- Anaerobic microorganisms:

- Bacteriodis fragilis group.

Pharmacokinetics. Absorption. After intake azithromycin is well soaked up and quickly distributed in an organism. After a single dose of 500 mg bioavailability makes 37% due to effect of the first passing through a liver. Cmax in a blood plasma is reached in 2-3 h and makes 0.4 mg/l.

Distribution. Linkng with proteins in inverse proportion to concentration in a blood plasma also makes 7-50%. The seeming Vd makes 31.1 l/kg. Gets through membranes of cells (it is effective at the infections caused by intracellular activators). It is transported by phagocytes to the place of an infection where it is released in the presence of bacteria. Easily gets through gistogematichesky barriers and comes to fabrics. Concentration in fabrics and cells 10-50 times higher, than in plasma, and in the infection center - is 24-34% more, than in healthy fabrics.

Metabolism. In a liver it demetilirutsya, losing activity.

Removal. T½ long - 35-50 p. T1/2 from fabrics much more. Therapeutic concentration of azithromycin remains up to 5-7 days after reception of the last dose. Azithromycin is removed, generally in not changed look - 50% through intestines, 6% by kidneys.

Indications to use:

Infections of upper parts of respiratory tracts (acute and chronic tonzillofaringit, acute and chronic recurrent sinusitis, acute average otitis).

Infections of lower parts of respiratory tracts (acute bacterial bronchitis, exacerbation of chronic bronchitis, community-acquired bacterial pneumonia).

Infections of skin and soft tissues: the uncomplicated acne vulgaris forms, the migrating chronic erythema (an initial stage of a disease of Lyme), an ugly face, impetigo, a pyoderma.

Diseases, sexually transmitted (urethritis, cervicitis).

The diseases of a stomach and 12-perstny gut associated with Helicobacter pylori.

Route of administration and doses:

Inside, once a day, in 1 hour prior to meal or in 2 hours after it, washing down with water.

At infections of upper and lower respiratory tracts, skin and soft tissues (except for the chronic migrating erythema): 500 mg once a day within 3 days; the total dose makes 1500 mg.

At the uncomplicated acne vulgaris forms: The course dose makes 6 g. The first 3 days appoint on 1 tablet 500 mg once a day, in the next 9 weeks - on 1 tablet of 500 mg once a week, and in the second week take a pill in 7 days after the previous reception. At the chronic migrating erythema: 1 g (2 tablets on 500 mg at the same time) in the first day and on 500 mg daily once a day from the second to the fifth day.

At infections, sexually transmitted: an uncomplicated urethritis / cervicitis — 1 g once.

The diseases of a stomach and 12-perstny gut associated with Helicobacter pylori: 1 g (2 tablets on 500 mg) daily, in a combination with anti-secretory drugs and other medicines, on doctor's orders.

Azithromycin tablets on 500 mg children can appoint more than 45 kg with body weight.

Risk on a tablet it is not intended for division into two equal doses.

Insufficiency of renal function. The patient with clearance of creatinine> 40 ml/min., corrections of a dose are not required. Researches of patients with clearance of creatine <40 ml/min., were not carried out. Such patients need to apply azithromycin with care.

Insufficiency of hepatic function. To apply with care the patient with the expressed liver failure.

Features of use:

Allergic reactions: heavy allergic reactions, anaphylactic hypostasis and an anaphylaxis were in rare instances registered. Some of these reactions are followed by recurrent symptoms and demand longer observation and treatment.

Abnormal liver functions: Azithromycin should be used with care at patients with a serious illness of a liver. It is necessary to carry out an inspection of function of a liver at emergence of symptoms of dysfunction, such as bystry development of the adynamy connected with jaundice, dark urine, tendency to bleedings or hepatic encephalopathy.

Ergotamine: at the patients accepting derivatives of alkaloids of an ergot in parallel with some macroleads cases of development of an ergotoksichnost were noted. It is not proved that Azitromitsin at joint reception with derivatives of alkaloids of an ergot causes an ergotoksichnost to appoint, nevertheless, these medicines together does not follow.

Consecutive infection: as well as in a case with other antibiotics, monitoring of signs of consecutive infections by insensitive organisms, including fungi is recommended.

Clostridium Difficile-associated diarrhea: the diarrhea connected with Clostridium difficile organisms was noted at reception of almost all antibacterial drugs, including azithromycin. Severity can vary from slight diarrhea to acute colitis. Antibacterial therapy changes normal intestinal microflora and leads to organism overgrowth With difficile.

Renal failure: at patients with a heavy renal failure (SKF <10 ml/min.) system influence of an azitromitsii increases by 33%.

Lengthening of repolarization and QT interval of a myocardium which bears in itself risk of development of cardiac arrhythmia and piruetny tachycardia were registered at treatment by other macroleads. The similar effect cannot be excluded completely at use of an azitromntsin for patients who are in group of the increased risk of the extended repolarization of a myocardium therefore extra care at treatment of patients is necessary with:

· the hereditary or documentary confirmed lengthening of a QT interval;

· a concomitant use of other medicines which, as we know, extend a QT interval, for example, of an antiaritmika of the classes IA and III, тизаприд and терфенадин;

· disturbances of electrolytic balance, especially in case of development of a hypopotassemia and a hypomagnesiemia;

· clinically significant bradycardia, cardiac arrhythmia or heavy heart failure.

It was reported about an aggravation of symptoms of a myasthenia or a new myasthenic syndrome, at the patients receiving therapy by azithromycin.

Streptococcal infections: penicillin, as a rule, is choice drug in treatment of the pharyngitis/tonsillitis caused by Streptococcus pyogenes and as prevention of acute rheumatic fever. Azithromycin is, as a rule, effective in treatment of acute pharyngitis, but there are no data on efficiency in prevention of acute rheumatic fever.

Pregnancy and lactation. The previous experience of use of HP does not indicate harmful effects of azithromycin on a fruit. Despite it, medicine can be appointed only in emergency cases.

Influence on ability to manage motor transport and to service mechanical devices. There are no data on influence of drug on ability to manage motor transport and to service mechanical devices.

Side effects:

Azithromycin seldom causes side reactions. In the table side effects on diseases and frequency of manifestation are specified. Side effects are classified by frequency as follows: very often (≥ 1/10); often (≥ 1/100 to <1/10); infrequently (≥ 1/1.000 to <1/100); seldom (≥ 1/10 000 to <1/1 000); very seldom (<1/10 000), it is unknown (it is impossible to estimate on the basis of the available data). Side effects concerning frequency are specified in each group on a scale from more frequent to less frequent.

Disturbances and diseases	Side effects	Frequency
Infectious and parasitic diseases	Candidiasis, oral candidiasis, vaginal infection Pseudomembranous colitis	Infrequently It is unknown
Disturbances from blood and lymphatic system	Leukopenia, neutropenia Thrombocytopenia, hemolitic anemia	Infrequently It is unknown
Disturbances from immune system	Quincke's edema, hypersensitivity Anaphylactic reactions	Infrequently It is unknown
Disturbances of mentality	Neurosis Concern Aggression, uneasiness	Infrequently Seldom It is unknown
Disturbances from a nervous system	Dizziness, headache, paresthesia, dysgeusia Hypesthesia, drowsiness, sleeplessness To syncope, convulsion, psychomotor hyperactivity. anosmia, ageusia, parosomiiya, myasthenia гравис	Often Infrequently It is unknown
Disturbances from an organ of sight	Vision disorder	Often
Disturbance of an acoustic organ and labyrinth disturbances	Deafness Hearing disorder, sonitus Dizziness	Often Infrequently Seldom
Disturbances from heart	Heartbeat Torsadedepointes (piruetny tachycardia), arrhythmia, including ventrikulyarny tachycardia	Infrequently It is unknown
Disturbances from vessels	Hypotension	It is unknown
Disturbances from digestive tract	Diarrhea, abdominal pains, nausea, meteorism Vomiting, dyspepsia Gastritis, lock Pancreatitis, the decoloured language	Very often Often Infrequently  It is unknown
Disturbance from a liver and biliary tract	Hepatitis Disturbances of work of a liver Liver failure, liver necrosis, cholestatic jaundice	Infrequently Seldom It is unknown
Disturbances from skin and hypodermic fabrics	Rash, itch Stephens-Johnson's syndrome, photosensitivity, small tortoiseshell Toxic epidermal necrolysis, multiformny erythema	Often Infrequently It is unknown
Disturbances from skeletal and muscular and connecting fabric	Arthralgia	Often
Disturbances from kidneys and urinary tract	Acute inflammation of kidneys, intersticial nephrite	It is unknown
The general frustration and disturbances in an injection site	Fatigue Stethalgia, hypostasis, weakness, adynamy	Often Infrequently
Laboratory and tool data	Reduction of number of lymphocytes, increase in number of eosinophils of blood, reduction of content  of bicarbonates in blood serum; Increase in level of aspartate aminotransferase, alaninaminostransferaza, reduction of content of bilirubin in blood serum; increase in level of creatinine, urea in blood serum, changes of amount of potassium in blood serum. Increase in an interval of QT at an ECG	Often   Infrequently         It is unknown

Interaction with other medicines:

Food reduces azithromycin absorption.

Antacids: antacids slow down azithromycin absorption. The recommended interval between administration of drug and antacids not less than two hours.

Tsetirizin: healthy patients did not lead a concomitant use of azithromycin and a tsetirizin in a dose of 20 mg within 5 days to change of pharmacokinetics or considerable change of an interval of QT.

Didanozin: simultaneous use of azithromycin at a day dose of 1200 mg and a didanozina at 6 examinees did not influence pharmacokinetics of a didanozin in comparison with placebo.

Digoxin: as patients who accept makrolidny antibiotics have data on change of metabolism of digoxin, at their concomitant use care is necessary.

Zidovudine: Azithromycin at a single dose in a dose in 1000 mg and at repeated doses from 1200 mg did not exert impact on pharmacokinetics, and also allocation of a zidovudine and its metabolites.

Ergotamine derivatives: because of a theoretical possibility of manifestation of an ergotism it is impossible to apply azithromycin together with ergotamine derivatives.

Atorvastatin: at simultaneous use of an atorvastatin (10 mg a day) and azithromycin (500 mg a day) azithromycin did not exert impact on concentration of an atorvastatin in plasma.

Carbamazepine: in the pharmacokinetic researches conducted on healthy volunteers, azithromycin had no significant effect on the level of carbamazepine or its active metabolite in plasma.

Cimetidinum: at reception of Cimetidinum in two hours prior to reception of azithromycin changes in azithromycin pharmacokinetics were not observed.

Peroral anticoagulants of coumarin: in a research of pharmacokinetic interaction azithromycin did not change effect of anticoagulants of warfarin at reception in a dose of 15 mg at healthy patients. After joint reception of azithromycin and anticoagulants of coumarin the anticoagulating effect amplified. Though relationship of cause and effect is not established, it is necessary to consider the frequency of check of a prothrombin time when azithromycin is accepted by the patients accepting coumarin anticoagulants.

Cyclosporine: some makrolidny antibiotics influence cyclosporine metabolism. At a concomitant use of azithromycin and cyclosporine it is necessary to control concentration of cyclosporine.

Efavirents: joint reception of one dose of azithromycin of 600 mg and 400 mg of efavirenets a day within 7 days did not lead to clinically significant pharmacokinetic interaction.

Flukonazol: Simultaneous use of one dose of 1200 mg of azithromycin does not change pharmacokinetics of a single dose of 800 mg of a flukonazol. The general concentration and an elimination half-life of azithromycin did not change at simultaneous use of a flukonazol. Nevertheless, clinically significant decrease in Cmax (18%) of azithromycin was noted.

Indinavir: simultaneous use of one dose of 1200 mg of azithromycin has no significant effect on pharmacokinetics of an indinavir at reception in a dose of 800 mg three times a day within 5 days.

Methylprednisolonum: at a pharmacokinetic research of medicinal interactions at healthy patients azithromycin had no considerable influence on Methylprednisolonum pharmacokinetics.

Midazolam: the concomitant use of azithromycin of 500 mg daily within 3 days does not cause clinically significant changes of pharmacokinetics and a pharmacodynamics of midazolam at reception in healthy patients once of 15 mg.

Nelfinavir: simultaneous use of azithromycin (1200 mg) and a nelfinavira (750 mg three times a day) leads to increase in concentration of azithromycin. No clinically significant side effects were revealed. There is no need to adjust a dose.

Rifabutin: simultaneous use of azithromycin and a rifabutin did not influence concentration of any of two drugs in blood serum. At simultaneous use of azithromycin and a rifabutin for patients the neutropenia was observed. The neutropenia is connected using a rifabutin, the causal relationship at reception in combination with azithromycin is not established.

Sildenafil: no proofs of influence of azithromycin (were revealed at reception of 500 mg daily within 3 days) on AUC and Cmax values of a sildenafil or its main metabolites in blood.

Terfenadin: interaction of a terfenadin and azithromycin is not revealed. In certain cases such interaction cannot be excluded completely. And still there are no proofs of such reaction. As well as at use of other macroleads at the same time it is necessary to apply azithromycin and терфенадин with care.

Theophylline: Azithromycin does not influence theophylline pharmacokinetics at healthy patients. Simultaneous use of theophylline and other makrolidny antibiotics sometimes leads to increase in concentration of theophylline in blood serum.

To triazoles: for the 1st day and 250 mg for the 2nd day and 0,125 mg of a triazolam for the 2nd day 14 healthy patients have a simultaneous use of azithromycin of 500 mg, had no significant effect on pharmacokinetic parameters of a triazolam in comparison with a concomitant use of a triazolam and placebo.

Trimethoprimum / сулъфаметоксазол: the concomitant use of DS Trimethoprimum / sulfamethoxazole (160 mg / 800 mg) within 7 days and 1200 mg of azithromycin for the 7th day has no significant effect on peak concentration, the general influence or removal of Trimethoprimum and sulfamethoxazole.

Contraindications:

Hypersensitivity to makrolidny antibiotics.

Because of a theoretical possibility of an ergotism, azithromycin should not be applied along with ergotamine derivatives.

Overdose:

There are no data on overdose by azithromycin. The overdose by makrolidny antibiotics is followed by a temporary hearing loss, severe nausea, vomiting and diarrhea. At suspicion on overdose it is necessary to cause vomiting and to resort immediately to medical assistance.

Storage conditions:

In the place protected from light and moisture the place, at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 2 years. Not to use medicine upon termination of a period of validity.

Issue conditions:

According to the recipe

Packaging:

3 or 10 tablets in a blister strip packaging, in packaging No. 3×1, No. 3×2, No. 10х1 together with a leaf insert.