PATIENT INFORMATION LEAFLET
INTERNATIONAL NONPROPRIETARY NAME
Description: white oblong biconvex film-coated tablets with a break line on one side.
Film-coated tablet contains
Active ingredient: azithromycin (as azithromycin dihydrate) 500 mg.
Excipients: calcium hydrogen phosphate dihydrate dibasic, pregelatinized starch, hydroxypropylcellulose, silica colloidal anhydrous, sodium laurilsulfate, croscarmellose sodium, magnesium stearate, lactose anhydrous.
Shell composition: Opadry® white Y-1-7000 (hypromellose, macrogol 400, titanium dioxide).
АТC CODE J01FA10
Antimicrobial drugs for systemic use. Macrolides and azalides.
PHARMACOLOGICAL PROPERTIES PHARMACODYNAMICS
Azithrosan (azithromycin) belongs to a subgroup of macrolide antibiotics azalides and has a broad antibacterial spectrum of action. By binding with the 50S-ribosomal subunit azithromycin inhibits protein synthesis in the microbial cell without affecting nucleic acid synthesis.
Azithromycin is active against the following microorganisms both in vitro and at clinical infections:
Other microorganisms: Chlamydia pneumoniae, Chlamydia trachomatis, Ureaplasma urealyticum, Legionella pneumophila, Borrelia burgdorferi (a causative agent of Lyme disease), Mycoplasma pneumoniae, Mycobacterium avium (MAC).
Azithromycin is active against Toxoplasma gondii. Azithromycin activity does not decrease in the presence of beta-lactose producing bacteria.
Gram-positive bacteria Enterococcus faecalis are resistant to the drug as well as the majority of Staphylococcus methicillin resistant strains.
Azithromycin easily passes histochematic barriers and penetratesinto the tissues. The concentrationsof antibioticin the lungs, respiratory passages and urogenital system (including prostate) tissues, skin and soft tissues are significantly higher (10-50 times) than its concentration in plasma and 24-34% higher in the site of infection than in the healthy tissues. It penetrates the cell membranes (it is effective against infections caused by the intracellular pathogens). It is transported by the phagocytes, polymorphonuclear leukocytes and macrophages to the site of infection, releasing during the process of phagocytosis. Azithromycin is rapidly absorbed from the plasma into the cells and tissues, penetrates into the phagocytic cells and then it is transported with them to the area of inflammation, creating high and stable therapeutic concentrations in infected tissues and remaining unchanged for 5-7 days after drug discontinuation.
It is stable in an acidic medium, lipophilic medium.
The absolute bioavailability of the tablet is 37%. The maximum concentration (Cmax) (0.4 mg/l) is achieved in 2-3 hours, the apparent volume of distribution is 31.1 l/kg, the protein binding is inversely proportional to the concentration in the blood and equal to 7-50%.
The administration of the drug during the meal increases Cmax by 23%, AUC does not change. Azithromycin is excreted mainly unchanged: 50% with the fel and 6% with the urine. It is demethylated in the liver. Plasma Cl is 630 ml/min. It has a long half-life of 34-68 hours. Pharmacokinetic parameters do not change in older men (65-85 years), Cmax increases in older women (by 30-50%), Cmax, half-life and AUC decrease in children aged 1-5 years.
Azithrosan is recommended for the treatment of the following infections in mild and moderate forms caused by microorganisms that are susceptible to the drug:
Infections of the upper divisions of respiratory tract and ENT organs: acute pharyngitis and tonsillitis caused by Streptococcus pyogenes; acute otitis media (inflammation of the middle ear cavity); laryngitis, sinusitis, scarlet fever.
Pelvic inflammatory diseases (PID): cervicitis, endometritis and salpingo-oophoritis caused by susceptible strains of Chlamydia trachomatis, Mycoplasma hominis and Neisseria gonorrhoeae.
DOSAGE AND ADMINISTRATION
Azithrosan can be administered regardless of meal. However, better tolerability is observed when the tablets are administered during the meal.
For adults and adolescents over 16 years with a body weight above 45 kg the following dosage regimen of the drug is recommended:
Gonococcal cervicitis and urethritis: a single dose of 2000 mg azithromycin (4 film-coated tablets).
Pharmacokinetic properties of azithromycin in elderly patients do not differ from pharmacokinetic properties of azithromycin of young patients. There is no need in adjustment of the dose.
Parameters below that show undesirable effect frequency are determined as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥1/1000 to
< 1/100); rarely (from ≥ 1/10000 to < 1/1000); very rarely (from < 10000); unknown frequency.
Infections and invasions: uncommon–candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infections, bacterial infections, pharyngitis, gastro- enteritis, respiratory diseases, rhinitis; unknown frequency pseudomembranous colitis.
Blood and lymphatic system disorders: uncommon- leukopenia, neutropenia, eosinophilia; unknown frequency hemolytic anemia, thrombocytopenia.
Central nervous system disorders: common-dizziness, headache, paresthesia, taste-perversion; uncommon hypesthesia, drowsiness; rarely syncope, convulsions, psychomotor hyperactivity, anosmia, ageusia, myasthenia.
Mental disorders: uncommon-nervosity; unknown frequency-excitation, anxiety, aggression.
Disorders of sensory organs: common - visual disturbances, deafness; uncommon - ear disorders, hearing disorders, tinnitus; rarely-dizziness.
Cardiovascular system disorders: uncommon-palpitations, hot flushes; unknown frequency-arrhythmia, ventricular tachycardia, QT interval prolongation, torsade de pointes, hypotension.
Gastrointestinaldisorders: very common-nausea, diarrhoea, flatulence, abdominal pain/spasms; common-vomiting, dyspepsia; uncommon-gastritis, constipation, dysphagia, abdominal distension, dry mouth, eructation; unknown frequency- pancreatitis, tongue discoloration.
Hepatobiliary disorders: uncommon-hepatitis; unknown frequency-hepatic insufficiency, hepatic necrosis, cholestatic jaundice.
Skin and subcutaneous tissue disorders: common-rash, pruritus; uncommon - Stevens Johnson syndrome, photosensitivity reactions, urticaria, dermatitis, skin dryness; rarely-allergic reactions, including angioedema; unknown frequency - toxic epidermal necrolysis, erythema multiforme. Musculoskeletal system disorders: common arthralgia.
Urogenital system disorders: uncommon - dysuria, nephralgia; unknown frequency-interstitial nephritis, acute renal insufficiency.
General disorders and local reactions: common-fatigue; uncommon-weakness, asthenia, edema, chest pain.
Azithromycin should not be used in patients with moderate to severe pneumonia who are judged to be inappropriate for outpatient therapy and if the following risk factors are observed:
During treatment with azithromycin, rare serious allergic reactions, angioedema and anaphylaxis have been reported.
Treatment cessation may lead to relapses although reactions may be observed as a response to symptomatic treatment. Such reactions may result from a prolonged azithromycin accumulation in the body.
Administration of Azithrosan may lead to hepatic necrosis, hepatitis, hepatic insufficiency that may result in a lethal out come in some cases.
Azithromycin may induce pancreatitis, pyloric stenosis, pseudomembranous colitis, tongue discoloration.
Treatment with Azithrosan (azithromycin) may induce a QT interval prolongation syndrome/ torsades de pointes. Therefore it's not recommended to prescribe this medication to patients with a diagnosis or suspected QT interval prolongation syndrome/ torsades de pointes. A risk of polymorphic ventricular tachycardia is higher in women as compared with men.
INFLUENCE ON ABILITY TO DRIVE AND OPERATE MECHANISMS
Azithrosan does not affect the ability to drive and operate mechanisms.
PREGNANCY AND LACTATION
The product should be used during pregnancy only when the expected benefit overweighs a potential risk.
If the product is to be administered during lactation, a decision shall be made to stop breast-feeding.
This dosage form is not recommended for use in children and adolescents under 16 years old with body weight lower than 45 kg.
Antacids: antacid preparations do not alter bioavailability of azithromycin, but reduce the peak blood concentration by 25%, therefore Azithrosan should be taken at least one hour before or two hour after administration of these drugs. Cetirizine: normal volunteers, concomitantly administering azithromycin and cetirizine 20 mg for 5 days, demonstrated no statistically significant interaction or essential influence on alteration of the QT interval.
Didanosine: simultaneous prescription of azithromycin in a dose of 1200 mg/day and didanosinein a dose of 400 mg/day in 6 HIV-positive patients did not reveal statisticallysignificant alteration of didanosine pharmacokinetics compared to placebo.
Digoxin: some macrolides in concomitantadministrationmay disturb cell metabolism of digoxin in some patients, which may lead to an increase in its concentration.This should be borne in mind while prescribingazithromycin.
Zidovudine: simultaneous administration of azithromycin (a single dose administration of 1000 mg and multidose administration of 1200 or 600 mg) has a negligible effect on pharmacokinetics, including renal elimination of zidovudine or its glucuronide metabolite. Nevertheless, administration of azithromycin induced an increase in the concentration of phosphorylated zidovudine, the clinically active metabolite in mononuclear cells of peripheral blood. Clinical significance of this fact is unclear.
Azithromycin weakly interacts with cytochrome P450 isoenzymes. It has not been revealed that azithromycin is involved in pharmacokinetic interactions similarly to erythromycin and other macrolides. Azithromycin does not inhibit or induce cytochrome P450 isoenzymes.
Ergot alkaloids: taking into consideration theoretical possibility of ergotism development, simultaneous administration of azithromycin with ergot alkaloid derivatives is not recommended.
Pharmacokinetic studies of concomitant administration of azithromycin and preparations, metabolism of which involves cytochrome P450 isoenzymes, have been performed.
Atorvastatin: simultaneous administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma atorvastatin concentrations(based on the analysis of HMG-CoA-reductase inhibition). Nevertheless, cases of rhabdomyolysis in patients, concomitantly receiving azithromycin and statins, were reported in the postmarketing period.
Carbamazepine: pharmacological studies in normal volunteers did not reveal essential influence on the concentration of carbamazepine and its active metabolite in plasma of patients, simultaneously receiving azithromycin. Cimetidine: pharmacological studies of the influence of a single dose of cimetidine on pharmacokinetics of azithromycin revealed no alterations of azithromycin pharmacokinetics on condition that cimetidine is administered 2 hours before azithromycin.
Indirect acting anticoagulants (coumarin derivatives): pharmacological studies demonstrated the absence of influence of azithromycin on the anticoagulant effect of a
single 15 mg dose of warfarin administered by normal volunteers. There were reports of potentiation of the anticoagulant effect after concomitant administration of azithromycin and indirect acting anticoagulants (coumarin derivatives). Although the causative relation has not been established, the need to perform close monitoring of prothrombin time should be considered in case of administration of azithromycin in patients receiving indirect- acting anticoagulants (coumarin derivatives).
Cyclosporine: pharmacological studies in normal volunteers receiving azithromycin orally (a single 500 mg/day dose) for 3 days, followed by cyclosporine (a single 10 mg/kg/day dose), revealed a significant increase in plasma Cmax and AUC0-5 of cyclosporine. Caution should be exercised in simultaneous administration of these drugs. If concomitant administration of these preparations is required, plasma cyclosporine concentrations should be monitored and the dose should be adequately adjusted.
Efavirenz: simultaneous administration of azithromycin (a single 600 mg/day dose) and efavirenz (400 mg/day) for
7 successive days did not cause a clinically significant pharmacokinetic interaction.
Fluconazole: concomitant administration of azithromycin (a single 1200 mg dose) did not alter pharmacokinetics of fluconazole (a single 800 mg dose). Total exposure and elimination half-life of azithromycin did not alter in simultaneous administration of fluconazole, although a decrease in azithromycin Cmax (by 18%) was observed, which had no clinical significance.
Indinavir: simultaneous administration of azithromycin (a single 1200 mg dose) had no statistically significant influence on pharmacokinetics of indinavir (800 mg 3 times daily for 5 days).
Methylprednisolone: azithromycin has no significant influence on pharmacokinetics of methylprednisolone.
Nelfinavir: concomitant administration of azithromycin (1200 mg) and nelfinavir (750 mg 3 times daily) induces an increase in serum azithromycin concentration. No clinically significant adverse effects have been observed; no azithromycin dose adjustment in concomitant administration with nelfinavir is required.
Rifabutin: simultaneous administration of azithromycin and rifabutin does not influence serum concentration of each drug. Sometimes parallel administration of azithromycin and rifabutin induced neutropenia. Although neutropenia was associated with administration of rifabutin, no causative relation was established between treatment with the combination of azithromycin and rifabutin and neutropenia. Sildenafil: administration in normal volunteers produced no evidence of influence of azithromycin (500 mg/day for 3 days) on AUC and Cmax of sildenafil or its main circulating metabolite. Terfenadine: pharmacokinetic studies produced no evidence of interaction between azithromycin and terfenadine. There were reports of individual cases when the possibility of such interaction could not be absolutely ruled out, although there was not a single specific proof of such interaction. It was found that simultaneous administration of terfenadine and macrolides may induce arrhythmia and prolongation of the QT interval.
Theophylline: no interaction between azithromycin and theophylline was revealed.
Triazolam/midazolam: no significant alterations of pharmacokinetic parameters in concomitant administration of azithromycin with triazolam or midazolam in therapeutic doses were found.
Tr imethoprim/ sulfamethoxazole: s i m u l t a n e o u s administration of trimethoprim/sulfamethoxazole with azithromycin revealed no significant influence on Cmax, total exposure or renal excretion of t r imethoprim or sulfamethoxazole. Serum azithromycin concentrations corresponded to those revealed in other studies.
Adverse effects observed in azithromycin overdose are similar to those observed in administration of the drug in recommended therapeutic doses. Characteristic symptoms of overdose are: nausea, vomiting, diarrhea, temporary loss of hearing. General symptomatic and supportive treatment is administered in case of overdose. No antidote is available.
Film-coated tablets. 3 tablets in a blister.
1 blister with the enclosed leaflet in a carton box.
Store in a protected from moisture place at temperature not exceeding 25°C.
Keep out of reach of children!
5 years from the manufacturing date. Do not use after expiry date.
Sold under prescription.
AZITHROSAN is a product and a trade mark of "Sanolife", Great Britain.
“WORLD MEDICINE İLAÇ SAN. VE TİC. А.Ş.”, TURKEY