Azithromycin-astrafarm

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

Composition:

Active ingredient: azithromycin;

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

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

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

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules of cylindrical shape with hemispherical ends; capsule body and cap are blue. The contents of the capsules are 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 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 50S ribosomal subunit and suppressing peptide translocation.

Mechanism of resistance.

Complete cross-resistance exists in Streptococcus pneumoniae, beta-haemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance among isolated species may vary depending on geographical region; therefore, local information on resistance patterns is desirable, especially when treating severe infections. If necessary, expert advice should be sought if resistance is so widespread in the region that the usefulness of the drug for at least several types of infections is questionable.

Antimicrobial spectrum of azithromycin

• Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and is listed here due to rare susceptibility to azithromycin.

Pharmacokinetics.

The bioavailability of azithromycin after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that tissue concentrations of azithromycin are significantly higher (up to 50 times) than plasma concentrations, indicating strong tissue binding of the drug.

Protein binding in serum varies depending on plasma concentrations, ranging from 12% at 0.5 mcg/mL to 52% at 0.05 mcg/mL in blood 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 from tissues and amounts to 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 as a result of N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of liquid chromatography results with microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Otorhinolaryngological infections (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), bacillary angiomatosis, impetigo, secondary pyoderma;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any other component of the medicinal product;

severe impairment of liver or kidney function, hepatic failure;

marked bradycardia, arrhythmia, severe heart failure;

concomitant use with ergot derivatives (risk of ergotism).

Interaction with other medicinal products and other forms of interaction.

Antacids. Studies on the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin have generally shown no changes in bioavailability, 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.

Cetirizine. In healthy volunteers, concomitant administration of azithromycin for 5 days with 20 mg cetirizine at steady state showed no evidence of pharmacokinetic interaction or significant changes in QT interval.

Didanosine. When daily doses of 1200 mg azithromycin were administered concomitantly with 400 mg/day didanosine in six HIV-positive volunteers, no effect on the pharmacokinetics of didanosine was observed 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 increase serum levels of P-glycoprotein substrates. Therefore, when azithromycin is used concomitantly with P-glycoprotein substrates such as digoxin, the possibility of increased serum concentrations of the substrate should be considered.

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

Azithromycin does not significantly interact with the hepatic cytochrome P450 system. It is considered that the drug does not exhibit the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not induce or inactivate 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, post-marketing cases of rhabdomyolysis have been reported in patients taking azithromycin with statins.

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 interaction study, a single dose of cimetidine administered 2 hours prior to azithromycin did not affect the pharmacokinetics of azithromycin.

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, post-marketing reports have described 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. In a pharmacokinetic study involving healthy volunteers who received oral azithromycin 500 mg/day for 3 days followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in Cmax and AUC0–5 of cyclosporine was observed. Therefore, if concomitant use of these drugs is necessary, caution should be exercised and cyclosporine levels monitored, with appropriate dose adjustments.

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. The overall exposure and elimination half-life of azithromycin were not altered 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 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 a single 15 mg dose 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 has been observed in patients receiving both azithromycin and rifabutin. Although neutropenia is 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 AUC or Cmax values 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 on clinically significant pharmacokinetic interactions between azithromycin and theophylline in healthy volunteers.

Triazolam. 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 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, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Hydroxychloroquine. Azithromycin should be used with caution in patients receiving medicinal products that prolong the QT interval and may cause cardiac arrhythmias, such as hydroxychloroquine.

Special precautions for use.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare serious allergic reactions have been reported during azithromycin use, including angioedema and anaphylaxis (in rare cases fatal), and dermatological reactions, such as acute generalized exanthematous pustulosis. Some of these azithromycin-induced reactions caused recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the primary route of azithromycin elimination, azithromycin should be administered with caution in patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver failure have been reported with azithromycin use. In some of these cases, patients may have had a history of liver disease or concomitant use of other hepatotoxic medicinal products.

Monitoring of liver function should be performed if signs or symptoms of hepatic dysfunction occur, such as rapidly developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy. If hepatic dysfunction is detected, azithromycin therapy 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. Prolongation of cardiac repolarization and QT interval has been observed with macrolide antibiotics, including azithromycin, increasing the risk of cardiac arrhythmias and ventricular tachyarrhythmias (torsade de pointes). Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be administered with caution in patients with pre-existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented QT prolongation;
• receiving treatment with other active substances that 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);
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia; with clinically relevant bradycardia, cardiac arrhythmias, or severe heart failure.

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

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

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

The safety and efficacy of the medicinal product for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

Superinfections: As with other antibacterial agents, superinfections caused by non-susceptible organisms, including fungi, may occur during azithromycin therapy.

Ergotism has occasionally been reported in patients taking ergot derivatives concurrently with certain macrolide antibiotics. There are no data on a potential drug interaction between ergot derivatives and azithromycin; however, due to the theoretical possibility 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, contributing to diarrhea development). C. difficile strains that overproduce toxins are associated with increased risk of recurrent infection and mortality, as these infections may be resistant to antimicrobial therapy and 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 completion of antibacterial therapy.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on azithromycin use in pregnant women. Reproductive toxicity studies in animals did not show teratogenic effects of azithromycin on the fetus; however, 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 into human breast milk; however, appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted.

Fertility.

Fertility studies were conducted in rats; pregnancy rates decreased after azithromycin administration. 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 delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be considered.

Method of administration and dosage.

Adults and children with body weight over 45 kg

Azithromycin should be taken once daily, at least 1 hour before or 2 hours after a meal. Capsules should be swallowed whole.

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

For chronic migrating erythema: Day 1: 1 g (2 capsules of 500 mg at once), Days 2 to 5: 500 mg daily (1 capsule of 500 mg).

For sexually transmitted infections: single dose of 1 g (2 capsules of 500 mg). Total course dose: 1 g.

Missed dose.

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

Renal impairment.

No dosage adjustment is 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.

Dosage adjustment is not required for elderly patients.

Elderly patients: No dosage adjustment is necessary.

However, since elderly patients may be at increased risk for cardiac conduction disorders, caution is recommended when using azithromycin due to the risk of cardiac arrhythmias, including torsade de pointes.

Children.

The medicinal product is indicated for use in children with body weight ≥45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed following overdose are similar to those seen with normal therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and general symptomatic and supportive measures are recommended, if necessary.

Adverse reactions

The table below lists adverse reactions identified in clinical trials and during the post-marketing surveillance period, observed with the use of all azithromycin dosage forms. Adverse reactions reported during the post-marketing surveillance period are indicated in italics. Adverse reactions are categorized by system organ class and frequency of occurrence: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (frequency cannot be estimated from the available data). Within each frequency category, adverse events are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin, based on data obtained from clinical trials and post-marketing surveillance.

Below is a list of adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex, based on clinical trial data and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release formulations.

Adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex

Reporting suspected adverse reactions.

Reporting adverse reactions after drug registration is highly important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of drug efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

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

500 mg capsules – 3 capsules per blister; 1 or 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "AstraPharm".

Manufacturer's address and location of business activity.

6, Kyivska Street, city of Vyshneve, Bucha district, Kyiv region, 08132, Ukraine.