Pharmacological properties

Pharmacodynamics

Azithromycin is a makrolidny antibiotic which belongs to group of azaleads. the molecule is formed as a result of introduction of a nitrogen atom to a lactonic ring of erythromycin and.

Mechanism of effect of azithromycin consists in suppression of synthesis of bacterial protein due to linking with a 50S-subunit of ribosomes and oppression of a translocation of peptides.

resistance Mechanism. The full cross resistance exists among Streptococcus pneumoniae, a beta and hemolytic streptococcus of group A, Enterococcus faecalis and Staphylococcus aureus, including metitsillinrezistentny golden staphylococcus (MRSA), to erythromycin, azithromycin, other macroleads and linkozamida.

Prevalence of the acquired resistance can be different depending on the area and time for the allocated types therefore local information on resistance is necessary, especially at treatment of heavy infections. In case of need it is possible to address for the qualified council if local prevalence of resistance such is that the efficiency of medicine at treatment of at least some types of infections is doubtful.

Range of antimicrobic effect of azithromycin

Usually sensitive types

Aerobic gram-positive bacteria:

Staphylococcus aureus metitsillinchuvstvitelny, Streptococcus pneumoniae penitsillinchuvstvitelny, Streptococcus pyogenes.

Aerobic gram-negative bacteria:

Haemophilus influenza, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida.

Anaerobic bacteria:

Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyriomonas spp.

Other microorganisms:

Chlamydia trachomatis, Chlamydia pneumoniae, Mycoplasma pneumonia.

Types for which the acquired resistance can be a problem

Aerobic gram-positive bacteria:

Streptococcus pneumonia with intermediate sensitivity to penicillin and penitsillinrezistentny.

Vrozhdennorezistentny organisms

Aerobic gram-positive bacteria:

Enterococcus faecalis, staphylococcus of MRSA, MRSE*.

Anaerobic bacteria:

group of Bacteroides fragilis bacteroids.

* Metitsillinrezistentny golden staphylococcus has very high prevalence of the acquired resistance to macroleads and was specified because of rare sensitivity to azithromycin here.

Pharmacokinetics

Bioavailability after oral administration makes about 37%. The C _max in blood plasma is reached in 2–3 h after administration of drug. At reception, azithromycin is distributed on all organism. In pharmacokinetic researches it is shown that concentration of azithromycin in fabrics is much higher (by 50 times), than in blood plasma that demonstrates strong linking of medicine with fabrics.

depending on plasma concentration and makes from 12% — at 0.5 mkg/ml up to 52% — at 0.05 mkg/ml in blood plasma. Distribution volume in an equilibrium state (the VV _ss ) was 31.1 l/kg.

Final T _½ from blood plasma completely reflects T _½ from fabrics during 2–4 days.

About 12% of a dose of azithromycin is allocated in not changed view with urine during the next 3 days. Especially high concentrations of not changed azithromycin are revealed in bile of the person. Also in bile 10 metabolites which were formed by means of N- and O-demethylation, hydroxylation of rings of a dezozamin and an aglikon and splitting of a kladinoza of a conjugate are revealed. Comparison of results of liquid chromatography and microbiological analyses showed that metabolites of azithromycin are not microbiological active.

Indication

• Infection, caused by the microorganisms sensitive to azithromycin: infections of ENT organs (bacterial pharyngitis / tonsillitis, sinusitis, average otitis); respiratory infections (bacterial bronchitis, not hospital pneumonia); infections of leather and soft tissues: the migrating erythema (initial stage of a disease of a lime), an ugly face, impetigo, secondary pyodermatoses; infections, sexually transmitted: the uncomplicated and complicated urethritis/cervicitis caused by chlamydia trachomatis; treatment at not severe forms of an acne vulgaris (also for a ziomitsin in the form of tablets of 500 mg).

Use

Drug should be used in the form of a single daily dose for 1 h to or in 2 h after a meal. to swallow of tablets without chewing. in case of the admission of reception of 1 dose of medicine the passed dose should be accepted as soon as possible, and the subsequent — with an interval of 24 h

Adults and children with the body weight of 45 kg

In infections of ENT organs, airways, skin and soft tissues (except the chronic migrating erythema) the general dose of azithromycin makes 1500 mg; on 500 mg of 1 times a day. Treatment duration — 3 days.

In an acne vulgaris the recommended general dose makes 6 g which should be accepted according to the following scheme: 1 tablet of 500 mg of 1 times a day within 3 days, then — 1 tablet of 500 mg once a week during 9 weeks. A dose of the second week it is necessary to take in 7 days after the first reception a pill, and 8 following doses — to accept at an interval of 7 days.

At the migrating erythema the general dose of azithromycin makes 3 g: in the 1st day it is necessary to accept 1 g, then on 500 mg — from the 2nd to the 5th day. Duration of treatment is 5 days.

In infections, sexually transmitted: the general dose of azithromycin makes 1 g

Patients of advanced age. Elderly people have no need for dose adjustment.

As patients of advanced age can enter into risk groups of violations of electric conductivity of heart, it is recommended to be careful at use of azithromycin in connection with risk of developing cardiac arrhythmia and arrhythmia of torsade de pointes.

Patients with a renal failure. At patients with insignificant renal failures (glomerular filtration rate of 10-80 ml/min.) it is possible to use the same dosage, as at patients with normal function of kidneys. Patients need to appoint azithromycin with care with a heavy renal failure (glomerular filtration rate of 10 ml/min.).

Patients with an abnormal liver function. As azithromycin is metabolized in a liver and removed with bile, medicament should not be used at patients with a heavy abnormal liver function. The researches connected with treatment of such patients using azithromycin were not conducted.

Contraindication

Hypersensitivity to azithromycin, erythromycin or other makrolidny or ketolidny antibiotic, or any component of medicine. because of a theoretical possibility of an ergotism it is not necessary to appoint azithromycin along with ergot derivatives.

Side effects

Infection and invasion: candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, rhinitis, pseudomembranous colitis.

from the system of blood and lymphatic system: leukopenia, neutropenia, eosinophilia, thrombocytopenia, hemolytic anemia.

from the immune system: hypersensitivity reactions, including anaphylactic reactions and a Quincke's disease.

from a metabolism: anorexia, adynamy.

from mentality: aggression, nervousness, uneasiness, insomnia, excitement, aggression, concern, delirium, hallucinations.

from nervous system: headache, dizziness, drowsiness, paresthesias, dysgeusia, syncope, spasms, psychomotor superactivity, anosmia, parosmiya, ageusia, myasthenia gravis, hypesthesia.

from an organ of sight: disorder of vision, deterioration in sight.

from an organ of hearing: a hearing disorder, deterioration in hearing, including deafness and/or a ring in ears, vertigo.

from heart: heart consciousness, palpitation, trembling/fibrillation of ventricles (torsde de pointes), arrhythmia, including ventricular tachycardia, increase in the Q-t-interval at the ECG.

from vessels: inflows, arterial hypotension.

from a respiratory system: short wind, breath dysfunction, nasal bleeding.

from digestive system: gastrointestinal discomfort, diarrhea, a frequent liquid chair, vomiting, an abdominal pain, nausea, gastritis, a lock, a meteorism, dyspepsia, a dysphagy, dryness in a mouth, an eructation, ulcers in an oral cavity, saliva hypersecretion, pancreatitis, discoloration of language, anorexia, gastrointestinal discomfort.

from a gepatobiliarny system: an abnormal liver function, cholestatic jaundice, a liver failure (which seldom led to a lethal outcome), hepatitis (including fulminantny hepatitis and necrotic hepatitis).

from skin and hypodermic cellulose: rash, an itch, urticaria, dermatitis, xeroderma, a hyperhidrosis, a photosensitization, Stephens's syndrome — Johnson, a toxic epidermal necrolysis, a polymorphic erythema.

from a musculoskeletal system: osteoarthritis, myalgia, dorsodynia, neck pain, arthralgia.

from an urinary system: dysuria, kidney pain, OPN, interstitial nephrite.

from a reproductive system and mammary glands: vaginitis, uterine bleeding, testicular violations.

General violations and local reactions: a stethalgia, an indisposition, an adynamy, increased fatigue, a hyperthermia, pain, hypostases, including a face edema and peripheral hypostases.

Laboratory indicators: reduction of quantity of leukocytes, increase in quantity of eosinophils, decrease in level of bicarbonate in blood, increase in level of basophiles, increase in level of monocytes, increase in level of neutrophils, the increased AsAT, AlAT, SF levels, bilirubin, urea, creatinine in blood, changes of indicators of potassium in blood, increase in levels of chloride, glucose, platelets, decrease in level of a hematocrit, increase in level of bicarbonate, a sodium level deviation.

Defeat and poisoning: complications after the procedure.

Special instructions

Allergic reactions. as well as in a case with erythromycin and other makrolidny antibiotics, it was reported about rare serious allergic reactions, including a Quincke's disease and an anaphylaxis (in rare instances — with a lethal outcome). some of these reactions caused by azithromycin provoked recurrent symptoms and demanded long observation and treatment.

Abnormal liver function. As the liver is the main way of discharge of azithromycin, it is necessary to appoint carefully azithromycin to patients with serious diseases of a liver. It was reported about cases of fulminantny hepatitis which causes a life-threatening abnormal liver function at intake of azithromycin.

, some patients in the anamnesis had diseases of a liver or applied other hepatotoxic medicines.

analyses/liver function test in case of development of signs and symptoms of dysfunction of a liver, for example an asthenia which quickly develops and followed by jaundice, dark urine, tendency to bleedings or hepatic encephalopathy.

in case of detection of an abnormal liver function use of azithromycin should be stopped.

ergot Alkaloids. At the patients accepting ergot derivatives, simultaneous application of makrolidny antibiotics contributes to the fast development of an ergotism. There are no interactions between alkaloids of an ergot and azithromycin given about an opportunity. However because of a theoretical possibility of an ergotism it is not necessary to appoint azithromycin along with ergot derivatives.

Superinfection. As well as in a case with other antibiotics, it is recommended to make observation concerning signs of the superinfection caused by insensitive organisms including mushrooms.

At intake of almost all antibacterial medicines, including azithromycin, it was reported about Clostridium difficile-associated to diarrhea (CDAD) which gravity varied from mild diarrhea to colitis with a lethal outcome. Treatment by antibacterial medicines changes normal flora in a large intestine that leads to the overgrowth of S. of difficile.

C. of difficile produces toxins A and B which contribute to the development of CDAD. S.'s strains of difficile which giperprodutsirut toxins are the reason of the increased incidence and lethality as these infections can be resistant to antimicrobic therapy and demand performing colectomy. It is necessary to consider the possibility of development of CDAD in all patients with the diarrhea caused by application of antibiotics. Careful maintaining a case history, as as it was reported, CDAD can arise within 2 months after intake of antibacterial medicines is necessary.

Renal failure. At patients with serious dysfunction of kidneys (glomerular filtration rate of 10 ml/min.) 33% increase in system exposure of azithromycin are noted.

Lengthening of warm repolarization and an interval of Q-T which increased risk of developing cardiac arrhythmia and trembling/fibrillation of ventricles (torsade de pointes), is noted at treatment by other makrolidny antibiotics. The similar effect of azithromycin cannot be excluded completely at patients with the increased risk of the extended warm repolarization therefore patients should appoint treatment with care: with the congenital or registered prolongation of an interval of Q-T; which now undergo treatment using other active agents which, as we know, increase the Q-t interval, for example antiarrhytmic medicines of classes _a (quinidine and procaineamide) and III (dofetilid, Amiodaronum and sotalol), tsizaprid and terfenadin, neuroleptics, such as Pimozidum; antidepressants, such, as to tsitalopra and also ftorkhinolona, such as moxifloxacin and levofloxacin; with violation of electrolytic exchange, especially in case of a hypopotassemia and a hypomagnesiemia; with clinically relevant bradycardia, arrhythmia or heavy heart failure.

Myasthenia gravis. It was reported about aggravation of symptoms of a myasthenia gravis or about new development of a myasthenic syndrome in the patients receiving therapy by azithromycin.

Streptococcal infections. Azithromycin in general is effective in treatment of a streptococcal infection in a stomatopharynx, concerning prevention of the rheumatic attack there are no data which would show efficiency of azithromycin. Germicide with anaerobic activity needs to be taken in a combination with azithromycin if it is supposed that anaerobic microorganisms cause development of an infection.

Another. Safety and efficiency for prevention or treatment of Mycobacterium Av_um Complex at children are not established.

Use during pregnancy and feeding by a breast. Pregnancy. Researches of influence on reproductive function of animals are executed at introduction of the doses corresponding to moderate toxic doses for a maternal organism. In these researches the evidence of toxic impact of azithromycin on a fruit is not obtained. However there are no adequate and well controlled researches at pregnant women. As researches of influence on reproductive function of animals not always correspond to effect at the person, it is necessary to appoint azithromycin during pregnancy only according to vital indications.

Feeding by a breast. It was reported, that azithromycin gets into breast milk, but corresponding and properly controlled clinical trials which would give the chance to characterize pharmacokinetics of excretion of azithromycin in breast milk, was not carried out. Use of azithromycin during feeding by a breast perhaps only in cases when the expected advantage for mother exceeds potential risk for the child.

Fertility. The research of fertility was conducted on rats; frequency of approach of pregnancy after administration of azithromycin decreased. The relevance of these data on the person is unknown.

Children. Drug should be used at children with body weight 45 kg. Children with the body weight of 45 kg are recommended to use azithromycin medicaments in the corresponding dosage.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Proofs that azithromycin can worsen ability to steer vehicles or to work with mechanisms, no, but it is necessary to consider a possibility of development of such side reactions as dizziness, drowsiness, a disorder of vision.

Interaction

with care azithromycin to patients together with other medicines which can extend q–t interval.

Antacids. When studying influence of simultaneous application of antacids on azithromycin pharmacokinetics, changes in bioavailability are generally not revealed though plasma peak concentration of azithromycin decreased approximately by 25%. Azithromycin needs to be taken at least for 1 h to or in 2 h after reception of an antacid.

Tsetirizin. At healthy volunteers at simultaneous use of azithromycin within 5 days from tsetiriziny 20 mg in an equilibrium state the phenomena of pharmacokinetic interaction or significant changes of an interval of Q-T are noted.

Didanozin. At simultaneous application of daily doses of 1200 mg of azithromycin with didanoziny the influence on pharmacokinetics of a didanozin in comparison with placebo is not revealed.

Digoksin. It was reported that simultaneous application of makrolidny antibiotics, including azithromycin, and substrates of the R-glycoprotein, such as digoxin, leads to increase in level of substrate of the R-glycoprotein in blood plasma. Therefore, at simultaneous use of azithromycin and digoxin it is necessary to consider a possibility of increase in concentration of digoxin in blood plasma.

Zidovudin. Single doses of 1000 and 1200 mg or reusable doses of 600 mg of azithromycin did not influence plasma pharmacokinetics or removal with urine of a zidovudine or its glyukuronidny metabolites. However intake of azithromycin increased concentration of a fosforilirovanny zidovudine, clinically active metabolite in mononukleara in peripheric circulation. The clinical importance of these data is not established, but can be useful to patients.

ergot Alkaloids. Taking into account theoretical possibility of an ergotism the simultaneous introduction of azithromycin with derivatives of an ergot is not recommended.

Azithromycin has no significant interaction with the hepatic system of P450 cytochrome. It is considered that medicine has no pharmacokinetic medicinal interaction which is noted with erythromycin and other macroleads. Azithromycin does not cause induction or an inactivation of P450 cytochrome through cytochrome-metabolitny a complex.

conducted pharmacokinetic researches of use of azithromycin and the following medicines which metabolism substantially happens to P450 cytochrome participation.

Atorvastatin. Simultaneous application of an atorvastatin (10 mg/days) and azithromycin (500 mg/days) did not cause change of concentration of an atorvastatin in blood plasma (on the basis of the analysis of inhibition of GMG-KoA-reduktazy).

Karbamazepin. In a research of pharmacokinetic interaction at healthy volunteers azithromycin did not show considerable influence on plasma levels of carbamazepine or its active metabolites.

Cimetidinum. In a pharmacokinetic research of influence on pharmacokinetics of azithromycin of the single dose of Cimetidinum taken for 2 h before use of azithromycin, any changes of pharmacokinetics of azithromycin are noted.

Oral anticoagulants of coumarinic type. In a research of pharmacokinetic interaction azithromycin did not change anticoagulating effect of a single dose of 15 mg of the warfarin appointed to healthy volunteers. There are data on potentiation of anticoagulating effect after simultaneous use of azithromycin and oral anticoagulants of type of coumarin. Though the causal relationship is not established, it is necessary to consider need of carrying out frequent monitoring of a prothrombin time when prescribing azithromycin to patients who receive oral anticoagulants, such as coumarin.

Cyclosporine. Some of related makrolidny antibiotics influence cyclosporine metabolism. As there are no data on possible interaction at a concomitant use of azithromycin and cyclosporine, it is necessary to weigh carefully a therapeutic situation before purpose of a concomitant use of these drugs. If the combined treatment is considered justified, it is necessary to carry out careful monitoring of level of cyclosporine and to respectively regulate a dosage.

Efavirents. Simultaneous application of a single dose of azithromycin 600 and 400 of mg of efavirenets daily within 7 days did not cause any clinically significant pharmacokinetic interactions.

Flukonazol. Simultaneous application of a single dose of azithromycin of 1200 mg does not lead 800 mg to change of pharmacokinetics of a single dose of a flukonazol. The general exposure and T _½ azithromycin did not change at simultaneous application of a flukonazol, however clinically insignificant decrease in the C _max (18%) azithromycin was observed.

Indinavir. Simultaneous application of a single dose of azithromycin of 1200 mg does not cause statistically reliable influence on pharmacokinetics of an indinavir who 3 times a day within 5 days accept in a dose 800 mg.

Methylprednisolonum. In a research of pharmacokinetic interaction at healthy volunteers azithromycin significantly did not influence Methylprednisolonum pharmacokinetics.

Midazolam. Simultaneous use of azithromycin of 500 mg within 3 days did not cause clinically significant changes of pharmacokinetics and a pharmacodynamics of midazolam in healthy volunteers.

Nelfinavir. Simultaneous use of azithromycin (1200 mg) and a nelfinavir in equilibrium concentration (750 mg 3 times a day) leads to increase in concentration of azithromycin. Clinically significant by-effects are noted, respectively, there is no need for dose adjustment.

Rifabutin. Simultaneous use of azithromycin and a rifabutin did not affect concentration of these medicines in blood plasma. The neutropenia is revealed at persons who accepted at the same time azithromycin and rifabutin. Though the neutropenia was connected with application of a rifabutin, the causal relationship is not established with a concomitant use of azithromycin.

Sildenafil. At male healthy volunteers the evidence of influence of azithromycin (500 mg/days within 3 days) on max AUC and C _value a sildenafil or its main circulating metabolite is not obtained.

Terfenadin. In pharmacokinetic researches it was not reported about interaction between azithromycin and terfenadiny. In certain cases it is impossible to exclude a possibility of such interaction completely; however there are no special data on existence of such interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interaction at simultaneous use of azithromycin and theophylline.

to Triazoles. Simultaneous use of azithromycin of 500 mg in the 1st day and 250 mg in the 2nd day from 0.125 mg of midazolam significantly did not influence all pharmacokinetic indicators of a triazolam in comparison with triazolamy and placebo.

Trimethoprimum/sulfamethoxazole. Simultaneous use of Trimethoprimum/sulfamethoxazole of double concentration (160 mg / 800 mg) within 7 days with azithromycin of 1200 mg for the 7th day did not show significant effect on the C _max , the general exposure or excretion with urine of Trimethoprimum or sulfamethoxazole. Concentration of azithromycin in blood plasma corresponded to that in other researches.

Overdose

Symptoms: side effects which develop at reception of doses above recommended are similar that arise at application of usual therapeutic doses, namely: they can include diarrhea, nausea, vomiting, a reversible hearing loss.

Treatment: if necessary intake of activated carbon and performing the general symptomatic and supporting treatment is recommended.

Storage conditions

At a temperature not above 25 °C.