Azithromycin-zdorov'ya

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMYCIN-ZDOROVYE (AZITHROMYCIN-ZDOROVYE)

Composition:

Active ingredient: azithromycin;

1 capsule contains azithromycin dihydrate equivalent to azithromycin 125 mg or 250 mg or 500 mg;

Excipients: microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate; capsule shell contains quinoline yellow (E 104), erythrosine (E 127), titanium dioxide (E 171), gelatin (for 125 mg dosage), or patent blue (E 131), titanium dioxide (E 171), gelatin (for 250 mg dosage), or indigo carmine (E 132), titanium dioxide (E 171), gelatin (for 500 mg dosage).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of yellow color (125 mg dosage), light blue to blue color (250 mg dosage), blue to light blue color (500 mg dosage). The capsule contents are white or almost white powder. Presence of powder particle agglomerates is permissible. The manufacturer's trademark "ZT" may be printed on the capsule.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics. Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50 S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance. Complete cross-resistance exists among Streptococcus pneumoniae, β*-haemolytic streptococcus group A,* Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance may vary depending on geographical location and time for isolated species; therefore, local information on resistance is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

Typically sensitive species

Aerobic Gram-positive bacteria: Staphylococcus aureus methicillin-sensitive, Streptococcus pneumoniae penicillin-sensitive, Streptococcus pyogenes.

Aerobic Gram-negative bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida.

Anaerobic bacteria: Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyriomonas spp.

Other microorganisms: Chlamydia trachomatis, Chlamydophila pneumoniae, Mycoplasma pneumoniae.

Species for which acquired resistance may be a problem

Aerobic Gram-positive bacteria: Streptococcus pneumoniae with intermediate sensitivity to penicillin and penicillin-resistant.

Inherently resistant organisms

Aerobic Gram-positive bacteria: Enterococcus faecalis, MRSA, MRSE*.

Anaerobic bacteria: Bacteroides fragilis group.

*Methicillin-resistant Staphylococcus aureus exhibits very high prevalence of acquired resistance to macrolides and is listed here due to its rare sensitivity to azithromycin.

Pharmacokinetics. Bioavailability after oral administration is approximately 37%. Maximum serum concentration (Cmax) is achieved within 2–3 hours after administration.

After oral intake, azithromycin is distributed throughout the body. Data indicate that azithromycin concentrations in tissues are significantly higher (up to 50 times) than in blood plasma, indicating strong tissue binding of the drug.

Protein binding in serum varies depending on plasma concentrations, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum. The apparent volume of distribution at steady state (Vss) is 31.1 L/kg.

The terminal plasma elimination half-life fully reflects the elimination half-life (T½) from tissues over 2–4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites were also detected in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of liquid chromatography and microbiological assay results showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications. Infections caused by microorganisms sensitive to azithromycin:

• infections of the ear, nose, and throat (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• skin and soft tissue infections: erythema migrans (early stage of Lyme disease), cat scratch disease, impetigo, secondary pyoderma, moderate severity acne vulgaris (common acne);
• sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications. Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, as well as to any other component of the drug. Due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although peak plasma concentrations of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine. It is known that in healthy volunteers, concomitant administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not result in pharmacokinetic interaction or significant changes in QT interval.

Didanosine. Available data indicate that in 6 HIV-positive volunteers, concomitant administration of 1200 mg daily doses of azithromycin with 400 mg daily doses of didanosine did not affect the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin. Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin has been reported to increase serum levels of P-glycoprotein substrates. Therefore, when azithromycin and digoxin are used concomitantly, the possibility of increased digoxin serum concentrations should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not established, but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is considered not to have pharmacokinetic drug interactions as observed with erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical possibility of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended.

Pharmacokinetic studies have been conducted on the co-administration of azithromycin with the following drugs, whose metabolism is largely mediated by cytochrome P450.

Atorvastatin. Concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter atorvastatin plasma concentrations (based on HMG-CoA reductase inhibition analysis). However, cases of rhabdomyolysis have been reported in patients taking azithromycin with statins.

Carbamazepine. Data are available showing that in a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cimetidine. It is known that in a pharmacokinetic interaction study, a single dose of cimetidine administered 2 hours prior to azithromycin had no effect on the pharmacokinetics of azithromycin.

Oral coumarin-type anticoagulants. Available data indicate that in a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. However, potentiation of anticoagulant effect has been reported 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. Data are available from a pharmacokinetic study in healthy volunteers who received 500 mg daily oral doses of azithromycin for 3 days, followed by a single 10 mg/kg oral dose of cyclosporine, demonstrating a significant increase in Cmax and AUC0-5 of cyclosporine. Therefore, caution should be exercised when co-administering these drugs. If concomitant use is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg daily doses of efavirenz for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole. Concomitant administration of a single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. Overall exposure and T½ of azithromycin were unchanged when co-administered with fluconazole, although a clinically insignificant reduction in Cmax (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not cause a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Methylprednisolone. It is known that in a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.

Midazolam. Available data indicate that 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 administered as a single 15 mg dose.

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) results in increased azithromycin concentrations. No clinically significant adverse events were observed; therefore, dose adjustment is not necessary.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect serum concentrations of either drug. Neutropenia was observed in subjects taking both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

Sildenafil. It is known that in healthy male volunteers, no evidence was found of the effect of azithromycin (500 mg daily for 3 days) on AUC and Cmax values of sildenafil or its main circulating metabolite.

Terfenadine. Data are available indicating that pharmacokinetic studies did not report interaction between azithromycin and terfenadine. In some cases, the possibility of such interaction cannot be completely excluded; however, there are no specific data confirming such interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interaction when azithromycin and theophylline are administered concomitantly to healthy volunteers.

Triazolam. Available data indicate that in healthy volunteers, concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam with placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 did not show a significant effect on Cmax, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Special precautions.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases fatal), and dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for azithromycin, azithromycin should be administered with caution in patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin use. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

Liver function tests should be performed if signs or symptoms of hepatic dysfunction develop, such as rapidly developing asthenia associated with jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If hepatic dysfunction is suspected, azithromycin should be discontinued.

Ergot derivatives. In patients receiving ergot derivatives, concomitant use of certain macrolide antibiotics may lead to rapid development of ergotism. There are no data available on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections. As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of Clostridium difficile.

Clostridium difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxigenic strains of Clostridium difficile may lead to increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is necessary, as CDAD has been reported to occur up to two months after antibiotic administration.

Renal function impairment. In patients with severe renal impairment (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed.

Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachycardia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired QT prolongation;
• currently receiving treatment with other medicinal products known to prolong the QT interval, such as Class IA (quinidine, procainamide) and Class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, neuroleptics such as pimozide, antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

Myasthenia gravis. Worsening of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Streptococcal infections. Azithromycin is generally effective in the treatment of streptococcal pharyngitis; however, there are no data demonstrating efficacy of azithromycin in preventing rheumatic fever.

Other. Safety and efficacy for the prevention or treatment of Mycobacterium avium complex in children have not been established.

The product contains methylparaben (E 218) and propylparaben (E 216), which may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding.

Pregnancy. There are insufficient data on the use of azithromycin in pregnant women. Reproductive toxicity studies in animals have not shown teratogenic or harmful effects of azithromycin on the fetus, although the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding. Azithromycin has been reported to be excreted in human milk, but adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Use of azithromycin during breastfeeding is possible only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility. Fertility studies conducted in rats showed a reduced pregnancy rate after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery. There is no evidence that azithromycin impairs the ability to drive or operate machinery; however, the possibility of adverse reactions such as dizziness, somnolence, and visual disturbances should be taken into account.

Method of Administration and Dosage.

The drug should be taken orally once daily, at least 1 hour before or 2 hours after a meal. Capsules must be swallowed whole. If a dose is missed, it should be taken as soon as possible, and the next dose administered 24 hours later.

Adults and children with body weight ≥45 kg.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema): the total dose of azithromycin is 1500 mg: 500 mg once daily. The duration of treatment is 3 days.

For migrating erythema: the total dose of azithromycin is 3 g: 1 g on day 1, followed by 500 mg once daily from day 2 to day 5. The duration of treatment is 5 days.

For vulgar acne: the recommended total dose of azithromycin is 6 g, administered as follows: 1 capsule of 500 mg once daily for 3 days, followed by 1 capsule of 500 mg once weekly for 9 weeks. The second weekly dose should be taken 7 days after the first capsule, and the subsequent 8 doses should be taken at 7-day intervals.

For sexually transmitted infections: a single dose of 1 g.

Elderly patients. Dosage adjustment is not required in elderly individuals. However, since elderly patients may be at risk for cardiac conduction disturbances, caution is recommended when using azithromycin due to the potential risk of cardiac arrhythmia, including torsade de pointes.

Patients with renal impairment. The same dosage regimen as for patients with normal renal function may be used in patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min). Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate <10 mL/min).

Patients with hepatic impairment. Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be used in patients with severe hepatic dysfunction. Clinical studies on azithromycin use in such patients have not been conducted.

Children. Azithromycin in other pharmaceutical forms is recommended for children under 6 years of age. The drug may be administered to children aged 6 years and older who are able to swallow capsules. Children with body weight over 45 kg should receive adult doses.

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema): the total dose of azithromycin is 30 mg/kg body weight (10 mg/kg body weight once daily). The duration of treatment is 3 days.

Azithromycin has been shown to be effective in the treatment of streptococcal pharyngitis in children, administered either as a single dose of 10 mg/kg or 20 mg/kg daily for 3 days. When comparing these two regimens, similar clinical efficacy was observed, although bacterial eradication was greater with the 20 mg/kg daily dose. However, penicillin remains the drug of choice for the prevention of pharyngitis caused by Streptococcus pyogenes and for the prevention of secondary rheumatic polyarthritis.

For migrating erythema: the total dose of azithromycin is 60 mg/kg body weight: 20 mg/kg body weight on day 1, followed by 10 mg/kg body weight once daily from day 2 to day 5. The duration of treatment is 5 days.

Overdose. Clinical experience with azithromycin indicates that adverse effects associated with overdose are similar to those observed with standard therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, activated charcoal may be administered if necessary, along with general symptomatic and supportive treatment measures.

Adverse Reactions.

The adverse reaction described below is classified by organs and systems and by frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000); unknown (cannot be estimated from available data).

Infections and infestations: uncommon – candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, pharyngitis, gastroenteritis, respiratory tract disorders, rhinitis; unknown – pseudomembranous colitis.

Blood and lymphatic system disorders: uncommon – leukopenia, neutropenia, eosinophilia; unknown – thrombocytopenia, hemolytic anemia.

Immune system disorders: uncommon – angioedema, hypersensitivity reactions; unknown – anaphylactic reaction.

Metabolism and nutrition disorders: uncommon – anorexia.

Psychiatric disorders: uncommon – nervousness, insomnia; rare – agitation; unknown – aggression, restlessness, delirium, hallucinations.

Nervous system disorders: common – headache; uncommon – dizziness, somnolence, paraesthesia, dysgeusia; unknown – loss of consciousness, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis, hypesthesia.

Eye disorders: uncommon – visual disturbances.

Ear and labyrinth disorders: uncommon – hearing disorders, vertigo; unknown – worsening of hearing, including deafness and/or tinnitus.

Cardiac disorders: uncommon – palpitations; unknown – ventricular fibrillation/torsade de pointes, arrhythmia, including ventricular tachycardia, QT interval prolongation on ECG.

Vascular disorders: uncommon – flushing; unknown – arterial hypertension.

Respiratory, thoracic and mediastinal disorders: uncommon – dyspnea, epistaxis.

Gastrointestinal disorders: very common – diarrhea; common – vomiting, abdominal pain, nausea; uncommon – gastritis, constipation, flatulence, dyspepsia, dysphagia, dry mouth, belching, oral ulcers, hypersalivation; unknown – pancreatitis, change in tongue color.

Hepatobiliary disorders: rare – liver function abnormalities, cholestatic jaundice; unknown – liver failure (rarely leading to fatal outcome), fulminant hepatitis, necrotic hepatitis.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis; rare – photosensitivity, acute generalized exanthematous pustulosis; unknown – Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms (DRESS).

Musculoskeletal and connective tissue disorders: uncommon – osteoarthritis, myalgia, back pain, neck pain; unknown – arthralgia.

Renal and urinary disorders: uncommon – dysuria, kidney pain; unknown – acute renal failure, interstitial nephritis.

Reproductive system and breast disorders: uncommon – uterine bleeding, testicular disorders.

General disorders and administration site conditions: uncommon – chest pain, swelling, malaise, asthenia, fatigue, facial swelling, hyperthermia, pain, peripheral edema.

Investigations: common – decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count; uncommon – increased aspartate aminotransferase level, increased alanine aminotransferase level, increased blood bilirubin level, increased blood urea level, increased blood creatinine level, potassium level abnormalities, increased alkaline phosphatase level, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit level, increased bicarbonate level, sodium level abnormalities.

Injury and poisoning: uncommon – procedural complications.

Information on adverse reactions possibly associated with prophylaxis and treatment of Mycobacterium Avium Complex. These adverse reactions differ in type or frequency from those occurring with the use of immediate-release and extended-release dosage forms:

Metabolism and nutrition disorders: common – anorexia.

Psychiatric disorders: common – dizziness, headache, paraesthesia, dysgeusia; uncommon – hypesthesia.

Eye disorders: common – visual impairment.

Ear and labyrinth disorders: common – deafness; uncommon – hearing impairment, tinnitus.

Cardiac disorders: uncommon – palpitations.

Gastrointestinal disorders: very common – diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.

Hepatobiliary disorders: uncommon – hepatitis.

Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – Stevens-Johnson syndrome, photosensitivity.

Musculoskeletal and connective tissue disorders: common – arthralgia.

General disorders and administration site conditions: common – increased fatigue; uncommon – asthenia, malaise.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of the reach of children.

Packaging. Capsules 125 mg or 250 mg, pack of 6 in blister pack in a carton; capsules 500 mg, pack of 3 in blister pack in a carton.

Prescription category. Prescription only.

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVIYA".

Manufacturer's address and place of business. Ukraine, 61013, Kharkiv, Kharkiv region, Shevchenko Street, 22.