Azithromycin-bhfs

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

Composition:

Active substance: azithromycin;

1 capsule contains azithromycin, as azithromycin dihydrate (calculated as 100% anhydrous substance) – 250 mg;

Excipients: microcrystalline cellulose, magnesium stearate, sodium lauryl sulfate; the capsule shell contains: Yellow West FCF (E 110), quinoline yellow (E 104), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard capsules with a white body and yellow cap. The contents of the capsules are powder, granules, or a solid plug of white or almost white color.

Pharmacotherapeutic group. Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. ATC Code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a representative of the macrolide antibiotics subgroup – azalides. It has a broad spectrum of antimicrobial activity. Its mechanism of action is based on inhibition of protein biosynthesis due to binding of azithromycin to the 50S ribosomal subunit and suppression of peptidyl transferase.

Azithromycin is active against Gram-positive aerobic bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus viridans, group C, F, and G streptococci, Staphylococcus aureus; some Gram-positive anaerobic bacteria: Clostridium perfringens; Gram-negative aerobic bacteria: Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Bordetella pertussis, Bordetella parapertussis, Neisseria gonorrhoeae, Gardnerella vaginalis, Campylobacter jejuni.

Azithromycin is also active against intracellular and other microorganisms: Legionella pneumophila, Chlamydia trachomatis, Mycoplasma pneumoniae, Ureaplasma urealyticum, Borrelia burgdorferi, Treponema pallidum.

It has no effect on Gram-positive microorganisms that are resistant to erythromycin.

Pharmacokinetics.

Azithromycin is rapidly and well absorbed from the gastrointestinal tract, due to its stability in an acidic environment and lipophilicity. It rapidly distributes throughout the body and penetrates well into the respiratory tract, organs and tissues of the urogenital tract, skin, and soft tissues. The high tissue concentration and prolonged elimination half-life are determined by the low binding of azithromycin to serum proteins, as well as its ability to penetrate eukaryotic cells and accumulate in low-pH environments surrounding lysosomes. This results in a large apparent volume of distribution (31.1 L/kg) and high plasma clearance. The ability of the drug to accumulate predominantly in lysosomes is particularly important for the elimination of intracellular pathogens.

Phagocytes deliver azithromycin to sites of infection, where it is released during the process of phagocytosis. High therapeutic concentrations, exceeding the minimum inhibitory concentration for infectious agents, are achieved at the site of inflammation within 12–72 hours.

The elimination half-life is prolonged, with slow release from tissues – 60–76 hours. Bactericidal concentrations of azithromycin are detectable at sites of inflammation for 5–7 days after the last dose, allowing once-daily dosing and short-course treatment (3 or 5 days). The drug is primarily excreted via bile, with a small portion eliminated in urine.

Clinical characteristics.

Indications.

Treatment of infectious diseases caused by pathogens sensitive to the drug:

• Infections of the ear, nose, and throat organs (sinusitis, otitis media, bacterial pharyngitis, tonsillitis);
• Lower respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• Skin and soft tissue infections (erysipelas, impetigo, secondary pyoderma);
• Migratory erythema (early stage Lyme disease);
• Sexually transmitted infections: uncomplicated genital infections caused by

Chlamydia trachomatis.

Contraindications.

• Hypersensitivity to azithromycin, erythromycin, or to any other macrolide or ketolide antibiotic, or to any component of the drug;
• Concomitant use with ergot derivatives due to the risk of ergotism.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be prescribed cautiously to patients receiving other drugs that may prolong the QT interval.

Antacids: In studies evaluating the effect of concomitant antacid administration on azithromycin pharmacokinetics, no overall changes in bioavailability were observed, although plasma peak concentrations of azithromycin were reduced by approximately 25%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid administration.

Oral anticoagulants of the coumarin type, warfarin: 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, post-marketing reports have described potentiation of the anticoagulant effect when azithromycin was used concomitantly with oral anticoagulants of the coumarin type. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin, warfarin type.

Cimetidine: No interaction was observed in pharmacokinetic studies.

Lincomycins reduce, while tetracycline and chloramphenicol increase the effectiveness of azithromycin.

Efavirenz: Concomitant administration of a single 600 mg dose of azithromycin and 400 mg of efavirenz for 7 days did not result in any clinically significant pharmacokinetic interactions.

Midazolam: Concomitant use of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics or pharmacodynamics of midazolam.

Cyclosporine: Some related macrolide antibiotics affect cyclosporine metabolism. The therapeutic situation should be carefully evaluated before prescribing concomitant use of these drugs. When used in combination, close monitoring of cyclosporine levels is required, with appropriate dose adjustments.

Methylprednisolone: In a pharmacokinetic interaction study, azithromycin did not show a significant effect on the pharmacokinetics of methylprednisolone.

Fluconazole: Concomitant administration of a single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. A clinically insignificant 18% reduction in azithromycin Cmax 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.

Nelfinavir: Increased azithromycin concentrations have been observed. Dose adjustment is not required, but close monitoring for possible azithromycin adverse reactions is recommended.

Terfenadine: Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. However, as with other macrolide antibiotics, azithromycin should be used cautiously in combination with terfenadine due to the risk of QT interval prolongation and arrhythmias.

Theophylline: Azithromycin did not affect the pharmacokinetics of theophylline when both drugs were administered concomitantly.

Cisapride: Concomitant use may cause QT prolongation, ventricular arrhythmia, and "torsade de pointes"; therefore, these drugs should not be used together.

Carbamazepine: Azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Atorvastatin: Concomitant use with azithromycin did not affect atorvastatin plasma concentrations.

Astemizole, alfentanil: Caution should be exercised when using these drugs concomitantly with azithromycin due to the potential for enhanced effects.

Cetirizine: No pharmacokinetic interaction at steady state, but significant changes in QT interval may occur.

Zidovudine: Azithromycin does not affect the pharmacokinetics or excretion of zidovudine. However, azithromycin administration increases the concentration of phosphorylated zidovudine in peripheral blood mononuclear cells. The clinical significance of this phenomenon is not fully understood, but it may be beneficial for the patient.

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

Didanosine: No effect on the pharmacokinetics of didanosine was observed when 1200 mg/day of azithromycin was administered concomitantly, compared to placebo.

Triazolam: No evidence of significant effects on pharmacokinetic parameters was found when azithromycin and triazolam were used concomitantly.

Rifabutin: Plasma concentrations of these drugs are not altered, but neutropenia has been observed, likely related to rifabutin use. A causal relationship with concomitant azithromycin use has not been established.

Trimethoprim/sulfamethoxazole: The plasma concentration of azithromycin is not altered when administered concomitantly with trimethoprim or sulfamethoxazole.

Sildenafil: No effect of azithromycin on AUC and Cmax of sildenafil or its major circulating metabolites was observed in male subjects.

Ergot derivatives: When azithromycin is used concomitantly with dihydroergotamine or other ergot derivatives, the possibility of ergotism and vasoconstrictive effects with perfusion disturbances leading to tissue damage in fingers and toes cannot be excluded; therefore, concomitant use should be avoided.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that the drug does not exhibit the pharmacokinetic drug interactions commonly associated with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via a cytochrome-metabolite complex. Pharmacokinetic studies have been conducted on the co-administration of azithromycin with drugs whose metabolism is primarily mediated by cytochrome P450.

Special precautions for use.

Hypersensitivity reactions.

There have been rare reports of macrolide antibiotics, including azithromycin, causing severe adverse reactions (rarely fatal), such as angioedema and anaphylaxis. Some of these reactions were recurrent in nature and required prolonged observation and treatment.

Hepatotoxicity.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to 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 concomitant use of other hepatotoxic medicinal products.

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

Azithromycin therapy should be discontinued if hepatic dysfunction is suspected.

Alcohol consumption should be avoided during treatment with this medicinal product.

Ergot derivatives.

In patients receiving ergot derivatives, concomitant use of certain macrolide antibiotics may lead to rapid development of ergotism. Data on the potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections.

As with other antibacterial agents, there is a possibility of superinfections caused by microorganisms not susceptible to azithromycin, including fungi.

Clostridium difficile-associated diarrhea (CDAD).

Antibacterial therapy, including macrolides, may lead to antibiotic-associated diarrhea, such as Clostridium difficile-associated diarrhea (CDAD), with severity ranging from mild diarrhea to colitis, including pseudomembranous colitis, sometimes fatal. Therefore, CDAD, including pseudomembranous colitis, should be considered in patients who develop diarrhea during or after azithromycin therapy. Azithromycin should be discontinued in cases of severe and/or bloody diarrhea, and appropriate therapy should be initiated. Without adequate treatment, toxic megacolon, peritonitis, and shock may develop.

Renal impairment.

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

Prolonged cardiac repolarization and QT interval, which may increase the risk of cardiac arrhythmias, including torsade de pointes, have been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be entirely excluded in patients at increased risk of prolonged cardiac repolarization; therefore, caution is advised when prescribing azithromycin to patients:

• with congenital or acquired QT prolongation;
• who are receiving treatment with other drugs that prolong the QT interval, e.g., 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, arrhythmias, or severe heart failure.

Myasthenia gravis.

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

Streptococcal infections.

Azithromycin is generally effective in the treatment of streptococcal pharyngitis; however, there are no data confirming its efficacy in the prevention of rheumatic fever.

If anaerobic microorganisms are suspected to contribute to the infection, an antimicrobial agent with anaerobic activity should be used in combination with azithromycin.

Other.

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

The product contains the colouring agent sunset yellow FCF (E 110), which may cause allergic reactions, including bronchial asthma. The risk of allergy is higher in patients with hypersensitivity to acetylsalicylic acid.

Use during pregnancy or breastfeeding.

Pregnancy.

Reproductive toxicity studies in animals were conducted at doses corresponding to moderately toxic levels for the maternal organism. These studies provided no evidence of teratogenic effects of azithromycin. However, adequate and well-controlled studies in pregnant women are lacking. Since animal reproductive studies do not always predict effects in humans, azithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

breastfeeding.

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

Fertility.

Fertility studies were conducted in rats; pregnancy rates decreased after administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

Due to the possibility of adverse reactions (e.g., dizziness, somnolence) in patients hypersensitive to azithromycin, patients should refrain from driving or operating machinery during treatment with this medicinal product.

Method of Administration and Dosage

Prior to prescribing the medication, the sensitivity of the causative microflora should be determined. Azithromycin-BHFZ should be taken once daily, 1 hour before or 2 hours after meals, since concomitant intake with food reduces azithromycin absorption.

Adults, children with body weight over 45 kg.

For infections of the ear, nose, throat, respiratory tract, and skin and soft tissue infections: on day 1, administer 500 mg as a single dose, and from day 2 to day 5, 250 mg once daily; or 500 mg once daily for 3 days (total course dose – 1.5 g).

For acute urogenital tract infections: administer a single dose of 1 g (4 capsules).

For treatment of early-stage Lyme disease (chronic migrating erythema): administer a single dose of 1 g (4 capsules) on day 1 and 500 mg daily from day 2 to day 5 (total course dose – 3 g).

Elderly patients.

Dosage adjustment is not required in elderly patients.

Since elderly patients may have cardiac conduction disorders, caution is recommended when using azithromycin due to the risk of cardiac arrhythmia and torsade de pointes-type arrhythmia.

Hepatic impairment. The drug should not be administered to patients with severe liver disease, as azithromycin is metabolized in the liver and excreted via bile.

Renal impairment. Patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min) can receive the same dosage as patients with normal renal function. Azithromycin should be administered with caution in patients with severe renal impairment (glomerular filtration rate < 10 mL/min).

If a dose is missed, it should be taken as soon as possible, and subsequent doses should be administered at 24-hour intervals.

Children.

The use of this medicinal product is not recommended in children with body weight less than 45 kg in this dosage form.

Overdose.

Symptoms: adverse reactions occurring after ingestion of doses higher than recommended are similar to those observed with normal therapeutic doses, namely: reversible hearing loss, abdominal pain, pronounced nausea, vomiting, anorexia, diarrhea, constipation, increased liver transaminase activity, weakness.

Treatment: gastric lavage, administration of activated charcoal. Symptomatic therapy to support vital organ and system functions. In severe cases: measures to restore water-electrolyte balance, extracorporeal hemoadsorption. There is no specific antidote.

Adverse Reactions.

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

Blood and lymphatic system disorders: leukopenia, neutropenia, eosinophilia, lymphopenia, thrombocytopenia, hemolytic anemia.

Immune system disorders: hypersensitivity reactions, including anaphylactic reactions and angioedema.

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: aggression, nervousness, insomnia, agitation, restlessness, delirium, hallucinations.

Nervous system disorders: headache, dizziness, somnolence, paresthesia/hypoesthesia, dysgeusia/ageusia, syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia.

Eye disorders: visual disturbances, blurred vision.

Ear and labyrinth disorders: hearing impairment, worsening of hearing, including deafness and/or tinnitus, vertigo. These disorders are usually reversible and associated with prolonged use of high-dose azithromycin.

Cardiac disorders: palpitations, ventricular fibrillation (torsade de pointes), arrhythmias, including ventricular tachycardia, particularly in patients at risk of prolonged cardiac repolarization; QT interval prolongation on ECG; flushing, hypotension.

Respiratory system disorders: breathing difficulty, dyspnea, epistaxis.

Gastrointestinal disorders: gastrointestinal discomfort, dyspepsia (indigestion), nausea, vomiting, dry mouth, belching, oral ulcers, hypersalivation, dysphagia, tongue discoloration, frequent loose stools/diarrhea (in some cases leading to dehydration), abdominal pain/spasms, gastritis, constipation, flatulence, pancreatitis.

Hepatobiliary disorders: liver function abnormalities, cholestatic jaundice, hepatic failure (rarely resulting in fatal outcome), hepatitis (including fulminant hepatitis and necrotic hepatitis).

Skin and subcutaneous tissue disorders: rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis, photosensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, DRESS syndrome, cases of generalized exanthematous pustulosis have been reported.

Musculoskeletal and connective tissue disorders: osteoarthritis, myalgia, back pain, neck pain, arthralgia, myasthenia gravis.

Renal and urinary 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, increased fatigue, hyperthermia, peripheral pain, edema, including facial edema and peripheral edema.

Laboratory findings: decreased leukocyte count, increased eosinophils, basophils, monocytes, neutrophils, platelets, decreased hematocrit level, increased blood levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, urea, creatinine, changes in blood potassium and sodium levels, increased blood chloride and glucose levels, decreased blood bicarbonate level. These laboratory abnormalities usually return to normal within 2–3 weeks after completion of treatment.

Information on adverse reactions possibly associated with prophylaxis and treatment of Mycobacterium Avium Complex is based on clinical trial data of azithromycin and post-marketing observations. These adverse reactions differ in type or frequency from those reported during use of immediate-release and extended-release dosage forms:

Metabolism and nutrition disorders: anorexia.

Psychiatric disorders: dizziness, headache, paresthesia, hypoesthesia, dysgeusia.

Eye disorders: blurred vision.

Ear and labyrinth disorders: deafness, hearing impairment, tinnitus.

Cardiac disorders: palpitations.

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

Hepatobiliary disorders: hepatitis.

Skin and subcutaneous tissue disorders: rash, pruritus, Stevens-Johnson syndrome, photosensitivity.

Musculoskeletal and connective tissue disorders: arthralgia.

General disorders and administration site conditions: increased fatigue, asthenia, malaise.

The product contains the dye sunset yellow FCF (E 110), which may cause allergic reactions, including bronchial asthma. The risk of allergy is higher in patients with hypersensitivity to acetylsalicylic acid.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Packaging. 6 or 10 capsules in a blister, 1 blister per carton.

Prescription category. Prescription only.

Manufacturer. Public joint-stock company "Scientific and Production Center "Borshchagovskiy Chemical and Pharmaceutical Plant".

Manufacturer's address.

17 Miru Street, Kyiv, 03134, Ukraine.