Azithromycin-astrafarm

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

Composition:

Active substance: azithromycin;

1 capsule contains azithromycin (as azithromycin dihydrate, calculated as 100% substance) 250 mg or 500 mg;

Excipients: microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate;

Capsule shell composition: gelatin, titanium dioxide (E 171), indigocarmine (E 132).

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules of cylindrical shape with hemispherical ends; capsule body and cap are blue. The contents of the capsules are a white or almost white powder.

Pharmacotherapeutic group.

Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. ATC code J01F A10.

Pharmacological Properties.

Pharmacodynamics.

Azithromycin is a member of the macrolide antibiotic group known as azalides, which exhibit a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide translocation, without affecting polynucleotide synthesis.

The prevalence of acquired resistance among specific bacterial species may vary geographically; therefore, local resistance data should be consulted, especially when treating severe infections. Expert consultation is recommended if resistance is so widespread in a given region that the usefulness of the drug for at least several types of infections is questionable.

Azithromycin is active against aerobic gram-positive bacteria: Streptococcus pneumoniae, Streptococcus pyogenes, groups C, F, and G streptococci, 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 may be either intrinsic or acquired: acquired resistance may occur in Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus; intrinsically resistant organisms include Enterobacteriaceae and Pseudomonas spp. Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains.

Pharmacokinetics.

Azithromycin is rapidly absorbed from the gastrointestinal tract. After a single 500 mg oral dose, maximum plasma concentration (Cmax) of azithromycin is reached within 2.5–2.96 hours and amounts to 0.4 mg/L. Bioavailability is approximately 37%. The elimination half-life (T½) is 14–20 hours (within 8–24 hours after dosing) and 41 hours (within 24–72 hours). Food intake significantly alters pharmacokinetics.

Following oral administration, azithromycin is widely distributed throughout the body. The apparent volume of distribution at steady state is 31.1 L/kg. It penetrates well into respiratory tract tissues, genitourinary organs and tissues (including the prostate gland), skin, and soft tissues. Drug concentrations in tissues and cells are 10–100 times higher than in blood. High tissue concentrations and prolonged T½ are due to low plasma protein binding of azithromycin (ranging from 12% to 52%). The drug accumulates extensively in phagocytes, which transport it to sites of infection and inflammation, where it is gradually released during phagocytosis. Azithromycin maintains bactericidal concentrations at sites of inflammation for 5–7 days after the last dose.

Azithromycin is metabolized in the liver (approximately 35%), where it loses activity, via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate.

Over 50% is excreted unchanged in bile, and approximately 4.5% is excreted in urine within 72 hours.

In patients with mild to moderate renal or hepatic impairment, the pharmacokinetics of azithromycin are not significantly altered. In patients with severe renal impairment, statistically significant changes in pharmacokinetic parameters are observed, including area under the concentration-time curve (AUC), Cmax, and plasma clearance. In patients with mild to moderate hepatic impairment, an increase in urinary clearance of azithromycin may occur as a compensatory mechanism for reduced hepatic clearance.

In elderly patients, AUC values are somewhat higher than in individuals under 40 years of age; however, this difference is not clinically significant, and therefore dose adjustment is not required.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Infections of the upper respiratory tract (bacterial pharyngitis, tonsillitis, sinusitis, otitis media);
• Infections of the lower respiratory tract (bacterial bronchitis and acute exacerbations of chronic bronchitis, community-acquired pneumonia);
• Skin and soft tissue infections: chronic migrating erythema (Stage I Lyme disease), pertussis, impetigo, secondary pyoderma;
• Genital infections: uncomplicated and complicated urethritis/cervicitis caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to the components of the medicinal product, to other macrolide/ketolide antibiotics; severe impairment of liver or kidney function, hepatic failure, pronounced bradycardia, arrhythmia, severe heart failure; concomitant use with ergot derivatives (risk of ergotism).

Interaction with other medicinal products and other forms of interaction.

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

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

Cetirizine. In healthy volunteers, concomitant administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not reveal any pharmacokinetic interaction or significant changes in QT interval.

Didanosine. Concomitant administration of daily doses of 1200 mg azithromycin with didanosine showed no effect on the pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with a P-glycoprotein substrate such as digoxin, the possibility of increased serum concentration of the substrate should be considered.

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

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

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered not to have the pharmacokinetic drug interactions commonly observed 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 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).

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic study assessing the effect of a single dose of cimetidine administered 2 hours before azithromycin on azithromycin pharmacokinetics, no changes in azithromycin pharmacokinetics 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. However, there have been reports of potentiation of the anticoagulant effect following concomitant use 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 related macrolide antibiotics affect cyclosporine metabolism. Since pharmacokinetic and clinical studies on possible interaction during concomitant administration of azithromycin and cyclosporine have not been conducted, the therapeutic situation should be carefully evaluated before prescribing these drugs together. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are necessary.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg efavirenz daily 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 elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a clinically insignificant reduction in C_max (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not have a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three 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 or pharmacodynamics of midazolam.

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 required.

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

Sildenafil. In healthy male volunteers, no evidence was found that azithromycin (500 mg daily for 3 days) affects the AUC or C_max of sildenafil or its main circulating metabolite.

Terfenadine. No interaction between azithromycin and terfenadine was reported in clinical studies. In some cases, the possibility of such an interaction cannot be entirely excluded; however, there are no specific data confirming such an interaction.

Theophylline. There are no data indicating a clinically significant pharmacokinetic interaction between azithromycin and theophylline.

Triazolam. Concomitant administration of azithromycin (500 mg on Day 1 and 250 mg on Day 2) with triazolam (0.125 mg) did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam with placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of trimethoprim/sulfamethoxazole (double strength, 160 mg/800 mg) for 7 days with azithromycin 1200 mg daily for 7 days showed no significant effect on peak concentrations, overall exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were consistent with those observed in other studies.

Special precautions for use.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioedema and anaphylaxis (in rare cases with fatal outcome). 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 of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver failure have been reported with azithromycin use. Monitoring of liver function should be performed if signs or symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

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, which increases the risk of cardiac arrhythmia and ventricular tachyarrhythmia (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 prolonged cardiac repolarization; therefore, caution should be exercised when prescribing azithromycin to patients with congenital or documented QT prolongation; patients currently receiving medicinal products known to prolong the QT interval, such as class IA (quinidine, procainamide) and class III (dofetilide, amiodarone, sotalol) antiarrhythmics, cisapride, terfenadine, neuroleptics (pimozide); antidepressants (citalopram), and fluoroquinolones (moxifloxacin, levofloxacin); patients with electrolyte imbalances, particularly hypokalemia and hypomagnesemia; patients with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

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

Streptococcal infections. For treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is generally the drug of choice and is also used for prevention of acute rheumatic fever. While azithromycin is generally effective in treating oropharyngeal streptococcal infection, there are no data demonstrating its efficacy in preventing rheumatic fever.

The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

Superinfections: as with other antibacterial agents, superinfections (e.g., fungal infections) may occur.

Ergotism has occasionally been reported in patients taking ergot derivatives when co-administered with certain macrolide antibiotics. There are no data on a potential drug interaction between ergot derivatives and azithromycin; however, due to the theoretical risk of ergotism, azithromycin should not be co-administered with ergot alkaloids.

With the use of nearly all antibacterial agents, including azithromycin, Clostridium difficile-associated diarrhea, ranging from mild to severe colitis with fatal outcome, may occur. Antibacterial agents alter the normal flora of the colon, leading to overgrowth of C. difficile, which produces toxins A and B that contribute to diarrhea development. Strains of C. difficile that overproduce toxins are associated with higher risk of recurrent infection and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. C. difficile-associated diarrhea should be considered in all patients receiving antibiotics. A detailed medical history should be obtained, as C. difficile-associated diarrhea may occur up to two months after discontinuation of antibacterial agents.

Use during pregnancy or breastfeeding.

Due to insufficient data on the safety of azithromycin use, the drug is not recommended during pregnancy or breastfeeding, except when the expected benefit to the mother outweighs the potential risk to the fetus/infant.

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 delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be taken into account.

Method of administration and dosage.

Adults and children with body weight over 45 kg

Azithromycin should be administered once daily, at least 1 hour before or 2 hours after food intake.

For respiratory tract infections and skin and soft tissue infections (except chronic migrating erythema), the dose is 500 mg once daily for 3 days.

Chronic migrating erythema: Day 1: 1 g (2 capsules of 500 mg taken at once); Days 2 to 5: 500 mg daily (1 capsule of 500 mg).

Uncomplicated and complicated urethritis/cervicitis: single dose of 1 g (2 capsules of 500 mg). Total course dose: 1 g.

Missed dose instructions.

A missed dose should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Renal impairment.

Dose adjustment is not required in patients with mild renal dysfunction (creatinine clearance > 40 mL/min). No studies have been conducted in patients with creatinine clearance < 40 mL/min. Therefore, azithromycin should be used with caution in these patients.

Hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to patients with severe hepatic disease.

Dose adjustment is not required in elderly patients.

Elderly patients: no dosage adjustment is necessary.

Since elderly patients may belong to risk groups for disturbances in cardiac conduction, caution is recommended when using azithromycin due to the risk of cardiac arrhythmia and torsade de pointes.

Children.

This medicinal product in the given pharmaceutical form should not be administered to children with body weight below 45 kg.

For children under 6 years of age, azithromycin in other pharmaceutical forms is recommended. The product may be prescribed to children aged 6 years and older who are able to swallow capsules.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with standard therapeutic doses. These may include diarrhea/frequent loose stools, nausea, abdominal pain, or vomiting.

Treatment: gastric lavage, administration of activated charcoal, and symptomatic therapy aimed at supporting vital functions should be performed. There is no specific antidote.

Adverse Reactions

Below is a list of adverse reactions identified during clinical trials and post-marketing surveillance for all dosage forms of azithromycin, categorized by system organ class and frequency: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000), and not known (cannot be estimated from available data).

Infections and infestations:
Uncommon – candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory tract disorder, rhinitis, oral candidiasis;
Not known – pseudomembranous colitis.

Blood and lymphatic system disorders:
Uncommon – leukopenia, neutropenia, eosinophilia;
Not known – thrombocytopenia, hemolytic anemia.

Immune system disorders:
Uncommon – angioneurotic edema, hypersensitivity reactions;
Not known – anaphylactic reaction.

Metabolism and nutrition disorders:
Uncommon – anorexia.

Psychiatric disorders:
Uncommon – nervousness, insomnia;
Rare – agitation;
Not known – aggression, anxiety, delirium, hallucinations.

Nervous system disorders:
Common – headache;
Uncommon – dizziness, somnolence, dysgeusia, paraesthesia;
Not known – loss of consciousness, convulsions (also reported with other macrolide antibiotics), hypoaesthesia, psychomotor hyperactivity, taste disturbances or loss of taste and smell, ageusia, parosmia, myasthenia gravis, syncope, asthenia, neurosis, lethargy.

Eye disorders:
Uncommon – visual disturbances.

Ear and labyrinth disorders:
Uncommon – hearing disorders, vertigo;
Not known – hearing impairment, including deafness and/or tinnitus. Most of these cases were reported in experimental studies where azithromycin was administered in high doses over prolonged periods. According to available follow-up data, most of these events were reversible.

Cardiac disorders:
Uncommon – palpitations, flushing;
Not known – ventricular fibrillation (torsade de pointes), QT interval prolongation, ventricular arrhythmia including ventricular tachycardia (also reported with other macrolide antibiotics), chest pain.

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

Gastrointestinal disorders:
Very common – diarrhea;
Common – vomiting, abdominal discomfort (pain/spasms), nausea;
Uncommon – loose stools, constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, belching, oral ulcers, hypersalivation;
Not known – pancreatitis, tongue discoloration, pseudomembranous colitis, anorexia.

Hepatobiliary disorders:
Rare – hepatic function abnormalities; hepatitis and cholestatic jaundice, including altered liver function tests; severe hepatitis and hepatic dysfunction;
Not known – hepatic failure (rarely leading to fatal outcome), fulminant hepatitis, hepatic necrosis.

Skin and subcutaneous tissue disorders:
Uncommon – rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis;
Rare – photosensitivity, acute generalized exanthematous pustulosis;
Not known – 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;
Not known – arthralgia, weakness.

Renal and urinary disorders:
Uncommon – dysuria, renal pain;
Not known – acute renal failure, interstitial nephritis.

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

General disorders and administration site conditions:
Uncommon – edema, asthenia, malaise, fatigue, facial swelling, chest pain, 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, increased alanine aminotransferase, increased blood bilirubin, increased blood urea, increased blood creatinine, blood potassium level abnormalities, increased alkaline phosphatase, increased chloride level, increased glucose level, increased platelet count, decreased hematocrit, increased bicarbonate level, sodium level abnormalities.

Injury, poisoning and procedural complications:
Uncommon – procedural complications.

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

Adverse reactions possibly associated with prophylaxis and treatment of Mycobacterium Avium Complex

Metabolism and nutrition disorders:
Common – anorexia.

Nervous system disorders:
Common – dizziness, headache, paraesthesia, dysgeusia;
Uncommon – hypoaesthesia.

Eye disorders:
Common – visual disturbances.

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. 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.

250 mg capsules – 6 capsules in a blister; 1 blister per carton.

500 mg capsules – 3 capsules in a blister; 1 blister per carton.

Prescription category. Prescription only.

Manufacturer.

LLC "AstraPharm".

Manufacturer's address and place of business.

6 Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.