Instructions for Azithromycin-Astrapharm capsules 500 mg No. 3
Composition
active ingredient: azithromycin;
1 capsule contains azithromycin (in the form of azithromycin dihydrate, calculated as 100% substance) 250 mg or 500 mg;
excipients: microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate;
capsule shell composition: gelatin, titanium dioxide (E 171), indigo carmine (E 132).
Dosage form
Capsules.
Main physicochemical properties: hard gelatin capsules of cylindrical shape with hemispherical ends, blue body and cap. Capsule contents – white or almost white powder.
Pharmacotherapeutic group
Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. ATX code J01F A10.
Pharmacological properties
Pharmacodynamics.
Azithromycin is a member of the macrolide azalide group of antibiotics with a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin is to inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide translocation without affecting polynucleotide synthesis.
The prevalence of acquired resistance of isolated species may vary depending on the location, therefore it is advisable to have local information on resistance, especially when treating severe infections. Expert advice should be sought if resistance is so prevalent in the area that the utility of the drug in at least several types of infections is questionable.
Azithromycin is active against aerobic gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, streptococci groups C, F and G, Staphylococcus aureus; aerobic gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Legionella pneumophila, Pasteurella multocida; anaerobic bacteria: Clostridium perfringens. The drug is also active against Chlamydia trachomatis.
Resistance to azithromycin can be natural or acquired: in rare cases, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus acquire resistance; Enterobacteriaceae, Pseudomonas spp are naturally resistant. Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.
Pharmacokinetics.
Azithromycin is rapidly absorbed from the gastrointestinal tract. After oral administration of 500 mg, the maximum concentration (Cmax) of azithromycin in the blood plasma is reached after 2.5–2.96 hours and is 0.4 mg/l. Bioavailability is approximately 37%. The elimination half-life (T½) is 14–20 hours (in the range of 8–24 hours after administration) and 41 hours (in the range of 24–72 hours). Food intake significantly changes the pharmacokinetics.
When taken orally, azithromycin is distributed throughout the body. The apparent volume of distribution at steady state is 31.1 l/kg. It penetrates well into the respiratory tract, organs and tissues of the genitourinary system (in particular, the prostate gland), into the skin and soft tissues. The concentration of the drug in tissues and cells is 10–100 times higher than in the blood. The high concentration in tissues and long T½ are due to the low binding of azithromycin to blood plasma proteins (from 12% to 52%). The drug accumulates in large quantities in phagocytes, which transport it to sites of infection and inflammation, where it is gradually released in the process of phagocytosis. Azithromycin is stored in bactericidal concentrations in the focus of inflammation for 5–7 days after taking the last dose.
It is metabolized in the liver (almost 35%), losing activity by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate.
More than 50% is excreted unchanged in the bile, approximately 4.5% in the urine within 72 hours.
In patients with mild/moderate renal/hepatic insufficiency, the pharmacokinetics of azithromycin do not change, in patients with severe renal insufficiency, the area under the concentration-time curve (AUC), Cmax and plasma clearance are significantly changed. In patients with mild/moderate hepatic insufficiency, an increase in the urinary clearance of azithromycin is possible to compensate for the reduced hepatic clearance.
In elderly patients, the AUC value is slightly higher than in the age group under 40 years, however, this is not clinically significant and therefore dose adjustment of the drug is not required.
Indication
Infections caused by microorganisms sensitive to azithromycin:
– upper respiratory tract infections (bacterial pharyngitis, tonsillitis, sinusitis, otitis media);
– lower respiratory tract infections (bacterial bronchitis and exacerbation of chronic bronchitis, community-acquired pneumonia);
– skin and soft tissue infections: chronic migratory erythema (stage I of Lyme disease), erysipelas, impetigo, secondary pyoderma;
– genital infections: uncomplicated and complicated urethritis/cervicitis caused by Chlamydia trachomatis.
Contraindication
Hypersensitivity to the components of the drug, to other antibiotics of the macrolide/ketolide group; severe liver or kidney dysfunction, liver failure, severe bradycardia, arrhythmia, severe heart failure; simultaneous use with ergot derivatives (possibility of ergotism).
Interaction with other medicinal products and other types of interactions
Azithromycin should be administered with caution to patients taking other drugs that may prolong the QT interval.
Antacids: When studying the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin, there was generally no change in bioavailability, although peak plasma 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, concomitant administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not result in any pharmacokinetic interaction or significant changes in the QT interval.
Didanosine: Coadministration of daily doses of 1200 mg of azithromycin with didanosine had no effect on the pharmacokinetics of didanosine compared to placebo.
Digoxin and Colchicine: Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, the possibility of increased serum substrate concentrations should be considered when azithromycin is coadministered with a P-glycoprotein substrate such as digoxin.
Zidovudine. Single doses of 1000 mg and 1200 mg or multiple doses of 600 mg of azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, 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 may be useful for patients.
Ergot derivatives. Given the theoretical possibility of ergotism, the simultaneous administration of azithromycin with ergot derivatives is not recommended.
Azithromycin does not have a significant interaction with the hepatic cytochrome P450 system. It is believed that the drug does not have the pharmacokinetic drug interactions observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.
Pharmacokinetic studies have been conducted on the use of azithromycin and the following drugs, the metabolism of which occurs to a large extent with the participation of cytochrome P450.
Atorvastatin: Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on an HMG-CoA reductase inhibition assay).
Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers, azithromycin had no significant effect on the plasma levels of carbamazepine or its active metabolites.
Cimetidine: In a pharmacokinetic study of the effect of a single dose of cimetidine, taken 2 hours before azithromycin, on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were observed.
Oral Coumarin-Type 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 have been reports of potentiation of the anticoagulant effect following concomitant administration of azithromycin and oral coumarin-type anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin-type anticoagulants.
Cyclosporine. Some of the related macrolide antibiotics affect the metabolism of cyclosporine. Since pharmacokinetic and clinical studies of the possible interaction with the simultaneous use of azithromycin and cyclosporine have not been conducted, the therapeutic situation should be carefully considered before prescribing concomitant treatment with these drugs. If combination therapy is considered justified, cyclosporine levels should be carefully monitored and the dosage adjusted accordingly.
Efavirenz: Co-administration of a single dose of azithromycin 600 mg and efavirenz 400 mg daily for 7 days did not result in any clinically significant pharmacokinetic interaction.
Fluconazole: Coadministration of a single dose of 1200 mg azithromycin did not alter the pharmacokinetics of a single dose of 800 mg fluconazole. The total exposure and half-life of azithromycin were not altered by coadministration of fluconazole, but a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir: Coadministration of a single dose of azithromycin 1200 mg had no statistically significant effect on the pharmacokinetics of indinavir administered at a dose of 800 mg 3 times daily for 5 days.
Methylprednisolone: In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.
Midazolam: In healthy volunteers, concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam.
Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect the serum concentrations of these drugs. Neutropenia has been observed in patients receiving azithromycin and rifabutin concomitantly. Although neutropenia has been associated with rifabutin, a causal relationship to concomitant 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: No interaction has been reported in studies between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely excluded; however, there is no specific data on the existence of such an interaction.
Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction with the simultaneous use of azithromycin and theophylline.
Triazolam: Coadministration of azithromycin 500 mg on the first day and 250 mg on the second day with 0.125 mg of triazolam had no significant effect on all pharmacokinetic parameters of triazolam compared to triazolam and placebo.
Trimethoprim/sulfamethoxazole: Coadministration of trimethoprim/sulfamethoxazole at a double strength (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 had no significant effect on the maximum concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those observed in other studies.
Application features
Allergic reactions: As with erythromycin and other macrolide antibiotics, isolated reports of serious allergic reactions, including angioedema and anaphylaxis (rarely fatal), have been reported. Some of these reactions to azithromycin have resulted in recurrent symptoms and have required longer observation and treatment.
Hepatic impairment. Since the liver is the primary route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe liver disease. Cases of fulminant hepatitis leading to life-threatening hepatic failure have been reported with azithromycin. Liver function should be monitored if signs and symptoms of hepatic dysfunction develop, such as rapidly progressive asthenia accompanied by jaundice, dark urine, bleeding tendency, and hepatic encephalopathy.
If liver function impairment is detected, azithromycin should be discontinued.
Renal impairment: In patients with severe renal dysfunction (glomerular filtration rate < 10 mL/min), a 33% increase in systemic exposure to azithromycin was observed.
Prolongation of cardiac repolarization and the QT interval, which increases the risk of cardiac arrhythmia and ventricular fibrillation (torsade de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be completely excluded in patients at increased risk of prolongation of cardiac repolarization, therefore, caution should be exercised when prescribing treatment to patients with congenital or documented prolongation of the QT interval; to patients currently receiving treatment with other active substances known to prolong the QT interval, such as antiarrhythmics of classes IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, neuroleptics (pimozide); antidepressants (citalopram), as well as fluoroquinolones (moxifloxacin and levofloxacin); to patients with electrolyte disturbances, especially in the case of hypokalemia and hypomagnesemia; patients with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.
Myasthenia: Exacerbation of myasthenia symptoms or new development of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Streptococcal infections. Penicillin is usually the drug of choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, and is also used for prophylaxis in acute rheumatic fever. Azithromycin is generally effective in the treatment of streptococcal oropharyngeal infections; however, there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever.
The safety and effectiveness of intravenous azithromycin for the treatment of infections in children have not been established.
Superinfections: As with other antibacterial drugs, there is a possibility of superinfection (mycosis).
Clostridium difficile-associated diarrhea, which can range from mild to fatal, can occur with virtually all antibacterial agents, including azithromycin. Antibacterial agents alter the normal flora of the large intestine, resulting in overgrowth of C. difficile (which produces toxins A and B, which contribute to diarrhea). C. difficile strains that overproduce toxins carry an increased risk of reinfection and mortality, as these infections may be resistant to antimicrobial agents and require colectomy. Diarrhea associated with C. difficile should be excluded in all patients receiving antibiotics. A detailed medical history should be obtained, as diarrhea associated with C. difficile may occur within 2 months of discontinuation of antibacterial agents.
Use during pregnancy or breastfeeding
Given the lack of data on the safety of azithromycin, it is not recommended to prescribe the drug during pregnancy or breastfeeding, except in cases where the expected positive effect for the mother outweighs the possible risk to the fetus/child.
Ability to influence reaction speed when driving vehicles or other mechanisms
There is no evidence that azithromycin can impair the ability to drive or operate machinery. However, the possibility of developing adverse reactions such as delirium, hallucinations, dizziness, drowsiness, fainting, and seizures, which may affect the ability to drive or operate machinery, should be taken into account.
Method of administration and doses
Adults and children weighing more than 45 kg
Azithromycin should be taken once a day, at least 1 hour before or 2 hours after a meal.
For infectious diseases of the respiratory tract and infectious diseases of the skin and soft tissues (except for chronic migratory erythema), the dose is 500 mg once a day for 3 days.
Chronic migratory erythema: on the 1st day 1 g (2 capsules of 500 mg at a time), from the 2nd to the 5th day 500 mg per day (1 capsule of 500 mg).
Uncomplicated and complicated urethritis/cervicitis: 1 g (2 capsules of 500 mg) once. Course dose – 1 g.
What to do if you miss a dose.
The missed dose should be taken as soon as possible, and subsequent doses should be taken 24 hours apart.
Kidney failure.
No dosage adjustment is necessary in patients with mild renal dysfunction (creatinine clearance > 40 mL/min). No studies have been conducted in patients with creatinine clearance < 40 mL/min. Accordingly, azithromycin should be used with caution in such patients.
Liver failure.
Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be used in patients with serious liver disease.
No dose adjustment is required for elderly patients.
Elderly patients: no dosage adjustment is necessary.
Since elderly patients may be at risk for cardiac conduction abnormalities, caution is recommended when using azithromycin due to the risk of cardiac arrhythmia and torsade de pointes.
Children.
The drug in this dosage form is not used in children weighing up to 45 kg.
It is recommended to prescribe azithromycin in other dosage forms for children under 6 years of age. The drug is prescribed to children over 6 years of age who can swallow the capsule.
Overdose
Clinical experience with azithromycin suggests that adverse reactions occurring at higher than recommended doses are similar to those seen at usual therapeutic doses and may include diarrhoea/frequent loose stools, nausea, abdominal pain or vomiting.
Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy aimed at maintaining vital functions of the body. There is no specific antidote.
Adverse reactions
The following adverse reactions have been identified during clinical trials and during post-marketing surveillance with all dosage forms of azithromycin, according to organ systems and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000), unknown (cannot be estimated from the available data).
Infections and infestations: uncommon – candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory failure, rhinitis, oral candidiasis; unknown – pseudomembranous colitis.
From the blood system: infrequently - leukopenia, neutropenia, eosinophilia; unknown - thrombocytopenia, hemolytic anemia.
Immune system disorders: infrequently - angioedema, hypersensitivity reactions; unknown - anaphylactic reaction.
Metabolic: infrequently - anorexia.
Nervous system: often - headache; infrequently - dizziness, drowsiness, dysgeusia, paresthesia; unknown - fainting, convulsions (it has been found that they are also caused by other macrolide antibiotics), hypoesthesia, psychomotor hyperactivity, distortion or loss of taste and smell, ageusia, parosmia, myasthenia gravis, syncope, asthenia, neurosis, lethargy.
On the part of the organs of vision: infrequently - visual impairment.
Hearing disorders: uncommon - hearing disorders, vertigo; unknown - hearing impairment, including deafness and/or tinnitus. Most of these cases are associated with experimental studies in which azithromycin was used in high doses for a long time. According to the available information on further medical observation, most of these problems were reversible.
Cardiovascular system: infrequently - palpitations, hot flashes; unknown - ventricular flutter-fibrillation (torsade de pointes), QT prolongation; ventricular arrhythmia, including ventricular tachycardia (it has been found that they are also caused by other macrolide antibiotics), chest pain.
From the respiratory system: infrequently - dyspnea, epistaxis.
On the part of the digestive tract: very often - diarrhea; often - vomiting, abdominal discomfort (pain/cramps), nausea; infrequently - loose stools, constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, oral ulcers, hypersecretion of saliva; unknown - pancreatitis, tongue discoloration, pseudomembranous colitis, anorexia.
Hepatobiliary system: rarely - liver dysfunction; hepatitis and cholestatic jaundice, including altered liver function tests; severe hepatitis and liver dysfunction; unknown - hepatic failure (which rarely resulted in death), fulminant hepatitis, liver necrosis.
Skin and subcutaneous tissue disorders: uncommon - rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis; rare - photosensitivity, acute generalized eczematous pustulosis; not known - Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms.
Musculoskeletal system: infrequently - osteoarthritis, myalgia, back pain, neck pain; unknown - arthralgia, weakness.
From the urinary system: infrequently - dysuria, kidney pain; unknown - acute renal failure, interstitial nephritis.
From the reproductive system: infrequently - uterine bleeding, testicular disorders, vaginitis.
General disorders and local reactions: infrequently - edema, asthenia, malaise, fatigue, facial edema, chest pain, hyperthermia, pain, peripheral edema.
Laboratory parameters: often - decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil level, increased monocyte level, increased neutrophil level; infrequently - increased aspartate aminotransferase level, increased alanine aminotransferase level, increased bilirubin level in the blood, increased urea level in the blood, increased creatinine level in the blood, changes in blood potassium levels, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet level, decreased hematocrit, increased bicarbonate level, abnormal sodium level.
Injury and poisoning: uncommon – complications after the procedure.
Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on clinical trial data and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with the immediate-release and long-release formulations.
Adverse reactions that may be associated with the prevention and treatment of Mycobacterium Avium Complex
Metabolic: often - anorexia.
From the nervous system: often - dizziness, headache, paresthesia, dysgeusia; infrequently - hypoesthesia.
On the part of the organs of vision: often - visual impairment.
On the part of the auditory organs: often - deafness; infrequently - hearing impairment, tinnitus.
Cardiac: infrequently - palpitations.
On the part of the digestive tract: very often - diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.
Hepatobiliary system: infrequently - hepatitis.
Skin and subcutaneous tissue disorders: common: rash, itching; uncommon: Stevens-Johnson syndrome, photosensitivity.
Musculoskeletal system: often - arthralgia.
General disorders and local disorders: often - increased fatigue; infrequently - asthenia, malaise.
Expiration date
3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging
Capsules of 250 mg - 6 capsules in a blister; 1 blister in a box.
Capsules of 500 mg - 3 capsules in a blister; 1 blister in a box.
Vacation category
By prescription.
Producer
"ASTRAPHARM" LLC.
Location of the manufacturer and address of its place of business.
08132, Ukraine, Kyiv region, Kyiv-Svyatoshynskyi district, Vyshneve, Kyivska st., 6.
