For medical use of preparation
active substances: azithromycin;
1 tablet contains azithromycin dihydrate equivalent to 250 mg of azithromycin;
excipients: Microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, povidone К 90, talc, magnesium stearate, coating Opadry 04B52069 Yellow: polyethylene glycol, hypromellose, quinoline yellow (Е 104), titanium dioxide (Е 171).
Pharmaceutical form. Film coated tablets.
Main physical and chemical properties: Capsule-shaped, film-coated, yellow tablets, with logo «А 250» on one side and smooth - on the other.
Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. АТС code J01F A10.
Azithromycin is a macrolide antibiotic of azalide group. The molecule is formed as a result of the introduction of nitrogen atom into the lactone ring of erythromycin A.
Azithromycin mechanism of action is a result of protein synthesis inhibition due to binding with 50S-subunit of ribosomes and inhibition of peptides translocation.
The mechanism of resistance.
The complete cross-resistance exists among Streptococcus рпеитопіае, group A beta-hemolytic streptococci, Enterococcus faecalis and Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), to erythromycin, azithromycin, other macrolides and lincosamides.
The prevalence of acquired resistance may vary depending on location and time for selected species, local information on resistance is desirable, particularly when treating severe infections. If necessary, expert advice should be sought when the local prevalence of resistance is such as efficacy of the agent in at least some types of infections is questionable.
The spectrum of azithromycin antimicrobial activity
Usually sensitive species
Aerobic gram-positive bacteria
Streptococcus рпеитопіае penicillin-sensitive
Aerobic gram-negative bacteria
Species for which acquired resistance may be a problem
Aerobic gram-positive bacteria
Streptococcus pneumonia with intermediate penicillin resistance and penicillin-resistant
Congenitally resistant organisms
Aerobic gram-positive bacteria
Staphylococci МRSА, МRSЕ*
Bacteroides fragilis group
*Methycillin-resistant staphylococcus has a very high prevalence of acquired resistance to macrolides and has been mentioned here because it is rarely susceptible to azithromycin.
Bioavailability after oral administration is approximately 37 %. Peak blood serum concentration is attained 2-3 hours after taking the medicinal product. Orally administered azithromycin is widely distributed throughout the body. In pharmacokinetic studies it has been demonstrated that the concentrations of azithromycin measured in tissues are noticeably higher (as much as 50 times) than those measured in blood plasma, which indicates that the agent strongly binds to tissues.
Binding to blood serum proteins varies according to plasma concentrations and ranges from 12 % at 0.5 microgram/ml up to 52% at 0.05 microgram/ml in blood serum. Apparent volume of distribution at steady state (VVss) has been calculated to be 31.1 l/kg.
The terminal plasma elimination half-life closely reflects the elimination half-life from tissues within 2-4 days.
Approximately 12 % of an intravenously administered dose of azithromycin is excreted unchanged in urine within the following three days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also in bile, ten metabolites were detected, which were formed through N- and O- demethylation, hydroxylation of desosamine – and aglycone rings and cleavage of cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses has shown that the metabolites of azithromycin are not microbiologically active.
Infections caused by microorganisms, sensitive to azithromycin:
• ENT- organs infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• respiratory tract infections (bacterial bronchitis, community acquired pneumonia);
• skin and soft tissues infections: erythema migrans (initial stage of Lyme disease), erysipelas, impetigo, secondary pyoderma;
• sexually transmitted infections: uncomplicated and complicated urethritis/cervicitis, caused by Chlamydia trachomatis.
Hypersensitivity to azithromycin, erythromycin or any of the macrolide or ketolide antibiotics, or to any excipient.
Through theoretical ergotism possibility, azithromycin should not be administered simultaneously with ergot derivatives.
Interaction with other medicinal products and other forms of interactions.
Azithromycin should be carefully prescribed to patients simultaneously with other drugs that may prolong the QT interval.
Antacids. In a pharmacokinetic study investigating the effects of simultaneous administration of antacid with azithromycin, no effect on overall bioavailability was seen, although peak serum concentrations of azithromycin were reduced by approximately 25 %. Azithromycin should be taken at least 1 hour before or 2 hours after taking an antacid.
Cetirizine. In healthy volunteers, co-administration of a 5-day regimen of azithromycin with cetirizine 20 mg at steady-state resulted in no pharmacokinetic interaction and no significant changes in the QT interval.
Didanosine. Co-administration of 1200 mg/day azithromycin with didanosine did not appear to affect the pharmacokinetics of didanosine as compared with placebo.
Digoxin. It was reported, that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin, leads to increased substrate of P-glycoprotein in blood serum. Consequently, in a case of the concurrent use of azithromycin and digoxin, the possibility of increased blood serum concentration of digoxin should be considered.
Zidovudine. Single 1000 mg and 1200 mg doses or multiple 600 mg doses of azithromycin had no effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, administration of azithromycin increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is unclear, but it may be useful for patients.
Ergots. Due to the theoretical possibility of ergotism, the concurrent use of azithromycin with ergot derivatives is not recommended.
Azithromycin does not interact significantly with the hepatic cytochrome P450 system. It is not believed to undergo the pharmacokinetic drug interactions as seen with erythromycin and other macrolides. Hepatic cytochrome P450 induction or inactivation via cytochrome-metabolite complex does not occur with azithromycin.
Pharmacokinetic studies have been conducted between azithromycin and the following drugs known to undergo significant cytochrome P450 mediated metabolism.
Atorvastatin. Co-administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter the blood plasma concentrations of atorvastatin (based on a HMG CoA-reductase inhibition analysis).
Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, no significant effect was observed on the plasma levels of carbamazepine or its active metabolites.
Cimetidine. In a pharmacokinetic study investigating the effects of a single dose of cimetidine, given 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no alteration of azithromycin pharmacokinetics was observed.
Coumarin-type oral anticoagulants. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. There is data on potentiated anticoagulation subsequent to co-administration of azithromycin and coumarin-type oral anticoagulants. Although a causal connection has not been established, consideration should be given to the frequency of monitoring prothrombin time when azithromycin is used in patients receiving coumarin-type oral anticoagulants.
Ciclosporin. Some of the related macrolide antibiotics affect the metabolism of cyclosporine. Since there is no data on possible interactions while simultaneous administration of azithromycin with ciclosporin, the therapeutic situation before initiating co-administration should be carefully weighed. If co-administration of these drugs is necessary, ciclosporin levels should be monitored and the dose adjusted accordingly.
Efavirenz. Co-administration of a 600 mg single dose of azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interactions.
Fluconazole. Co-administration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. Total exposure and half-life of azithromycin were unchanged by the co-administration of fluconazole, however, a clinically insignificant decrease in Cmax (18 %) of azithromycin was observed.
Indinavir. Co-administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered as 800 mg three times daily for 5 days.
Methylprednisolone. In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the pharmacokinetics of methylprednisolone.
Midazolam. In healthy volunteers, co-administration of azithromycin 500 mg/day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.
Nelfinavir. Co-administration of azithromycin (1200 mg) and nelfinavir at steady state (750 mg three times daily) resulted in increased azithromycin concentrations. No clinically significant adverse effects were observed and no dose adjustment is required.
Rifabutin. Co-administration of azithromycin and rifabutin did not affect the serum concentrations of these drugs. Neutropenia was observed in subjects receiving concomitant treatment of azithromycin and rifabutin. Although neutropenia has been associated with the use of rifabutin, a causal relationship to combination with azithromycin has not been established.
Sildenafil. In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.
Terfenadine. Pharmacokinetic studies have reported no evidence of an interaction between azithromycin and terfenadine. In some cases the possibility of such an interaction could not be entirely excluded; however there was no specific evidence that such an interaction had occurred.
Theophylline. There is no data on a clinically significant pharmacokinetic interaction when azithromycin and theophylline are co-administered.
Triazolam. Co-administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg of triazolam had no significant effect on any of the pharmacokinetic variables for triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole. Co-administration of trimethoprim/sulfamethoxazole double concentration (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 had no significant effect on peak concentrations, total exposure or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were similar to those seen in other studies.
Allergic reactions. As with erythromycin and other macrolide antibiotics, rare serious allergic reactions including angioneurotic oedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions with azithromycin have resulted in recurrent symptoms and required a longer period of observation and treatment.
Liver function abnormality. Since the liver is the principal route of elimination for azithromycin, the use of azithromycin should be undertaken with caution in patients with significant hepatic disease. Cases of fulminant hepatitis potentially leading to life-threatening liver failure have been reported with azithromycin.
Some patients may have had a history of liver disease or may have been taking other hepatotoxic medicinal products.
In case of signs and symptoms of liver dysfunction, such as rapid developing asthenia associated with jaundice, dark urine, bleeding tendency or hepatic encephalopathy, liver function tests / investigations should be performed immediately.
In case of abnormal liver function azithromycin should be discontinued.
Ergots. In patients receiving ergot derivatives, ergotism has been precipitated by co-administration of some macrolide antibiotics. There are no data concerning the possibility of an interaction between ergot and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be co-administrated.
Superinfection. As with any antibiotic preparation, observation for signs of superinfection with non-susceptible organisms including fungi is recommended.
Clostridium difficile-associated diarrhoea (CDAD) has been reported with use of nearly all antibacterial agents, including azithromycin, and may range in severity from mild diarrhoea to fatal colitis. Treatment with antibacterial agents alters the normal flora in the colon leading to overgrowth of C. difficile.
C. difficile produces the toxins A and B that develop CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be resistant to antimicrobial therapy and may require colectomy. Therefore, CDAD must be considered in patients with diarrhoea associated with the administration of any antibiotics. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents
Renal impairment. In patients with severe renal impairment (glomerular filtrate rate
Prolonged cardiac repolarisation and QT interval, imparting a risk of developing cardiac arrhythmia and atrial fibrillation or flutter (torsade de pointes), have been seen in treatment with other macrolide antibiotics. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization, therefore caution is required when treating patients:
• with congenital or documented QT prolongation;
• currently receiving treatment with other active substances known to prolong QT interval such as antiarrhythmic of classes IA (procainamide and quinidine) and III (amiodarone, sotalol, dofetilide), cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones, such as moxifloxacin and levofloxacin;
• with electrolyte disturbance, particularly in case of hypokalemia and hypomagnesemia;
• with clinically relevant bradycardia, cardiac arrhythmia or severe cardiac insufficiency.
Myasthenia gravis. Exacerbations of the symptoms of myasthenia gravis and new onset of myasthenia syndrome have been reported in patients receiving azithromycin therapy.
Streptococcal infections. Azithromycin is in general effective against streptococcus in the oropharynx, but no data are available that demonstrate the efficacy of azithromycin in preventing acute rheumatic fever. Antimicrobial agent with anaerobic activity should be taken in combination with azithromycin if it is assumed that the development of anaerobic organisms causes infections.
Safety and efficacy for the prevention or treatment Мусоbacteriит АvіитСотрlехin children have not been established.
Use in pregnancy and lactation.
Animal reproduction studies have been performed at doses up to moderately maternally toxic dose concentrations. In these studies, no evidence of toxic effects on the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.
It was reported that azithromycin penetrates into the human milk, but there are no adequate and well-controlled studies that allows to characterize the pharmacokinetics of azithromycin excretion into human breast milk. Azithromycin should not be used in the treatment of a lactating woman unless the potential benefits justify the potential risks to the infant.
Fertility studies were conducted in rats; reduced pregnancy rates were noted following administration of azithromycin. The relevance of this finding to humans is unknown.
Influence on velocity reactions in driving motor transport or operating other machines.
There is no evidence to suggest that azithromycin may impair the ability to drive a car or operate other mechanisms, but the possibility of adverse reactions such as dizziness, drowsiness, blurred vision should be considered.
Dosage and administration.
The drug should be used once daily regardless of meals. Swallow the tablets without chewing. If one drug dose has been missed it should be taken as soon as possible, and the next - at intervals of 24 hours.
Adults and children weighing > 45 kg.
In case of ENT- organs infections, respiratory tract and skin and soft tissues infections (except chronic migrating erythema) total dose of azithromycin is 1500 mg: 500 mg (two tablets) OD. Treatment duration is 3 days.
In the treatment of erythema migrans the total dose of azithromycin is 3 g: 1 g (4 tablets as a single dose) on the first day, followed by 500 mg (2 tablets as a single dose) on the second till fifth day.
Treatment duration is 5 days.
In genital infections the total dose of azithromycin is 1g (4 tablets as a single dose).
Dose adjustment is not required in elderly patients.
Azithromycin should be used with caution in patients with a risk of cardiac conduction disease, because of the possibility of cardiac arrhythmias, including torsade de pointes.
Patients with renal failure.
In patients with slightly impaired renal function (glomerular filtration rate is 10-80 ml/min) the dose may be the same as for patients with normal renal function. Azithromycin should be used with caution in patients with severe renal impairment (glomerular filtration rate
Patients with hepatic failure.
Since azithromycin is metabolised in the liver and excreted in the bile, the drug should not be given to patients suffering from severe liver disease. No studies have been conducted regarding treatment of such patients with azithromycin.
The drug should be used in children > 45 kg body weight. For children under 45 kg body weight an appropriate dosage of azithromycin may be used.
Symptoms: adverse events experienced in higher than recommended doses were similar to those seen at normal doses, such as: they may include diarrhea, nausea, vomiting and reversible hearing loss.
Treatment: the administration of medicinal charcoal and general symptomatic treatment and supportive measures are indicated as required.
Infections and infestations: candidiasis, oral candidiasis, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, rhinitis, pseudomembranous colitis.
Blood and lymphatic system disorders: leukopenia, neutropenia, eosinophilia, thrombocytopenia, hemolytic anemia.
Immune system disorders: hypersensitivity reactions, including anaphylactic reactions and angioedema.
Metabolism disorders: anorexia, asthenia.
Psychiatric disorders: aggression, nervousness, anxiety, insomnia, agitation, aggression, anxiety, delirium, hallucinations.
CNS disorders: headache, dizziness, somnolence, paresthesia, dysgeusia, fainting, syncope, seizures, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypoesthesia.
Eye disorders: visual disturbances, blurred vision.
Ear disorders: hearing impairment, amblyacousia, including deafness and/or tinnitus, vertigo.
Cardiac disorders: heart consciousness palpitation, atrial fibrillation or flutter (torsade de pointes), arrhythmias, including ventricular tachycardia, prolongation of QT-interval on the ECG.
Vascular disorders: flushing, arterial hypotension.
Respiratory system disorders: dyspnea, respiratory dysfunction, nosebleeds.
Gastro-intestinal tract disorders: gastrointestinal discomfort, diarrhea, frequent softened stools, vomiting, abdominal pain, nausea, gastritis, constipation, flatulence, dyspepsia, dysphagia, dry mouth, belching, sores in the mouth, hypersecretion of saliva, pancreatitis, tongue discoloration, anorexia, gastrointestinal discomfort.
Hepatobiliary disorders: abnormal liver function, cholestatic jaundice, hepatic failure, (which is often resulted in fatal outcome), hepatitis (including fulminant hepatitis, necrotizing hepatitis).
Skin and subcutaneous tissue disorders: rash, itching, hives, dermatitis, dry skin, hyperhidrosis, photosensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema polymorph.
Musculoskeletal disorders: osteoarthritis, myalgia, back pain, neck pain, arthralgia.
Urinary system disorders: dysuria, renal pain, acute renal failure, interstitial nephritis.
Reproductive system and breast disorders: vaginitis, uterine bleeding, testicular disorders.
General disorders and administration site conditions: chest pain, malaise, asthenia, fatigue, pyrexia, pain, swelling, including facial swelling and peripheral edema.
Laboratory findings: reduced number of white blood cells, increased number of eosinophils, reduced blood bicarbonate, increased basophils, increased monocytes, increased neutrophils, elevated levels of aspartate aminotransferase, alanine aminotransferase increased level, elevated blood levels of bilirubin, elevated blood levels of urea, elevated blood levels of creatinine, changes in rates of potassium blood indicants, increased alkaline phosphatase, increased chloride level, increased blood glucose, increased platelet level, decreased hematocrit level, increased bicarbonate, sodium deviation.
Lesions and poisoning: post procedural complication.
Shelf- life.3 years.
Store at a temperature NMT 25 °C.
Keep out of reach of children.
6 or 21 tablets are in a blister, 1 blister is in a carton pack №6 (6x1) or №21 (21x1).
Conditions of supply.
KUSUM HEALTHCARE PVT LTD.
SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.