Ziromin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZIROMIN (ZIROMIN)

Composition:

Active ingredient: azithromycin;

1 tablet contains azithromycin (as azithromycin dihydrate) 500 mg;

Excipients: anhydrous lactose, pregelatinized starch, low-substituted hydroxypropyl cellulose, calcium hydrogen phosphate, sodium lauryl sulfate, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;

Coating composition: "Opadry" White (Y-1-7000): hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form.

Film-coated tablets.

Main physicochemical properties: elongated, white film-coated tablets with a score line on one side.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

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

Antimicrobial spectrum of azithromycin

1Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and is mentioned here due to the rare sensitivity to azithromycin.

Pharmacokinetics.

Absorption

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

Distribution

Plasma protein binding varies depending on plasma concentrations and ranges from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in blood plasma. After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that azithromycin concentrations in tissues are significantly higher (up to 50 times) than in plasma, indicating strong tissue binding of azithromycin. The apparent volume of distribution at steady state (Vss) is 31.1 L/kg.

Elimination

The terminal plasma half-life fully reflects the tissue elimination half-life 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 formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate have also been detected in bile. Comparison of results from liquid chromatography and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical Characteristics.

Indications.

Treatment of infections caused by one or more susceptible microorganisms:

• bronchitis;
• community-acquired pneumonia;
• sinusitis;
• pharyngitis/tonsillitis;
• otitis media;
• skin and soft tissue infections;
• uncomplicated genital infections caused by Chlamydia trachomatis and Neisseria gonorrhoeae.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, to any macrolide or ketolide antibiotic, or to any component of the drug.

Interaction with other medicinal products and other forms of interaction.

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 intake.

Cetirizine. Concomitant administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not show any pharmacokinetic interaction or significant changes in QT interval.

Didanosine. When daily doses of 1200 mg azithromycin were administered concomitantly with didanosine, no effect on the pharmacokinetics of didanosine was observed compared to placebo.

Digoxin. Concomitant use of macrolide antibiotics, including azithromycin, and digoxin may alter the microbial metabolism of macrolide antibiotics in the gut in some patients. Therefore, when azithromycin and digoxin are used concomitantly, the possibility of increased digoxin plasma concentrations 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 glucuronidated metabolites. However, azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not established.

Ergot derivatives. In patients taking ergot derivatives, concomitant use of certain macrolide antibiotics may lead to rapid development of ergotism. There are no data on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be used concomitantly with ergot derivatives.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that azithromycin does not exhibit the pharmacokinetic drug interactions observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex. Pharmacokinetic studies have been conducted on the co-administration of azithromycin with the following agents, 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, a single dose of cimetidine administered 2 hours before azithromycin did not result in any changes in azithromycin pharmacokinetics.

Oral anticoagulants of the coumarin type. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin. However, post-marketing reports have described potentiation of the anticoagulant effect following concomitant use of azithromycin and oral anticoagulants of the coumarin type. Although a causal relationship has not been established, prothrombin time should be monitored when azithromycin is prescribed to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. According to pharmacokinetic study results, concomitant oral administration of azithromycin 500 mg for 3 days followed by a single 10 mg/kg dose of cyclosporine led to a significant increase in cyclosporine Cmax and AUC0-5 (by 24% and 21%, respectively), although AUC0-∞ was not significantly altered. If concomitant use is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are recommended.

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. 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 fluconazole was co-administered; however, a clinically insignificant reduction in azithromycin Cmax (18%) 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. Concomitant administration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics or pharmacodynamics of midazolam 15 mg.

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) resulted 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 plasma concentrations of either agent. Neutropenia was observed in subjects receiving both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

Sildenafil. No evidence was found of the effect of azithromycin (500 mg daily for 3 days) on AUC or Cmax of sildenafil or its main circulating metabolite in healthy male volunteers.

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. Although such an interaction cannot be completely ruled out, there are no data confirming its occurrence.

Theophylline. There are no data on clinically significant pharmacokinetic interactions between azithromycin and theophylline when administered concomitantly.

Triazolam. Concomitant administration of azithromycin 500 mg on the first day and 250 mg on the second day with triazolam 0.125 mg 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 significantly affect Cmax, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin plasma concentrations were consistent with those observed in other studies.

Special precautions for use

Azithromycin is generally effective in the treatment of streptococcal infection of the oropharynx; however, there are no data demonstrating the efficacy of azithromycin for the prevention of rheumatic fever. Penicillin is the drug of choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes and for the prevention of rheumatic fever.

Hypersensitivity reactions

Rare but serious allergic reactions, including angioneurotic edema, anaphylaxis (in isolated cases with fatal outcome), and DRESS syndrome, have been reported during azithromycin use. Some of these reactions have led to recurrent symptoms and required prolonged observation and treatment.

Development of superinfection

Azithromycin may lead to the development of superinfection. Patients should be monitored for signs of superinfection caused by non-susceptible organisms, including fungi.

QT interval prolongation

Prolongation of cardiac repolarization and QT interval, which increases the risk of cardiac arrhythmia and ventricular tachycardia (torsade de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be completely ruled out in patients with an increased risk of prolonged cardiac repolarization. The drug should be used with caution in patients:

• with congenital or documented QT interval prolongation;
• currently receiving treatment with other agents that prolong the QT interval, such as class IA and III antiarrhythmics, cisapride, and terfenadine;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

Clostridium difficile (C. difficile)-associated diarrhea

Diarrhea associated with C. difficile (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hyperproducing toxin strains of C. difficile are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is essential, as CDAD may occur up to two months after antibiotic administration. If pseudomembranous colitis is suspected, the drug should be discontinued immediately and specific therapy initiated.

Hepatotoxic reactions

Cases of fulminant hepatitis causing life-threatening liver dysfunction have been reported during azithromycin use. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic drugs. Liver function tests should be performed if symptoms of liver dysfunction develop, such as rapidly progressing fatigue associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy. If liver function abnormalities are detected, the drug should be discontinued.

The drug should be used with caution in patients with severe hepatic disease, as the liver is the primary route of elimination for azithromycin.

Use in patients with 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. The drug should be used with caution in such patients.

Use in patients with myasthenia gravis

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported during azithromycin use.

Use in patients with lactose intolerance

The drug contains lactose and therefore should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding

Pregnancy

There are no adequate and well-controlled studies in pregnant women. The drug should be used during pregnancy only if clearly needed.

Breastfeeding period

It is not known whether azithromycin is excreted in human milk. Therefore, during breastfeeding, the drug should be used only if the expected benefit to the mother outweighs the potential risk to the infant.

Ability to affect reaction speed when driving or operating machinery

There are no data on the effect of azithromycin on the ability to drive or operate machinery.

Dosage and Administration

The medication is intended for oral use. Tablets should be taken 1 hour before or 2 hours after eating. The drug should be administered once daily.

Adults, including elderly patients, and children with body weight over 45 kg

The total dose of azithromycin is 1500 mg (500 mg once daily). Treatment duration – 3 days.

Uncomplicated sexually transmitted infections caused by Chlamydia trachomatis:

The recommended dose is a single 1000 mg dose of azithromycin. Treatment duration – 1 day.

Uncomplicated sexually transmitted infections caused by Neisseria gonorrhoeae:

The recommended dose of azithromycin is 1000–2000 mg in combination with ceftriaxone at a dose of 250–500 mg according to local treatment guidelines.

Patients with renal impairment

For patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same doses as in patients with normal renal function may be used. The drug 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 administered to patients with severe hepatic impairment. Studies on azithromycin use in such patients have not been conducted.

Children

The drug is not recommended for children with body weight less than 45 kg.

Overdose

Clinical experience with azithromycin indicates that adverse reactions occurring after ingestion of doses higher than recommended are similar to those observed with normal therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive treatment are recommended, if necessary.

Side effects.

The frequency of adverse reactions was determined using the following criteria: very common (> 1/10), common (from > 1/100 to < 1/10), uncommon (from > 1/1000 to < 1/100), rare (from > 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; unknown – pseudomembranous colitis.

Blood and lymphatic system disorders:

uncommon – leukopenia, neutropenia; unknown – thrombocytopenia, hemolytic anemia.

Immune system disorders:

uncommon – angioedema, hypersensitivity reactions; unknown – anaphylactic reactions.

Metabolism and nutrition disorders:

common – anorexia.

Psychiatric disorders:

uncommon – nervousness; rare – agitation; unknown – aggression, restlessness.

Nervous system disorders:

common – dizziness, headache, paresthesia, dysgeusia; uncommon – hypoesthesia, somnolence, insomnia; unknown – syncope, convulsions, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis.

Eye disorders:

common – visual disturbances.

Ear and labyrinth disorders:

common – deafness; uncommon – hearing impairment, tinnitus; rare – vertigo. Most of these cases were associated with experimental studies in which azithromycin was administered in high doses over a prolonged period. According to available post-marketing surveillance reports, most of these events were reversible.

Cardiac disorders:

uncommon – palpitations; unknown – ventricular fibrillation (torsade de pointes), arrhythmia, including ventricular tachycardia.

Vascular disorders:

unknown – arterial hypotension.

Gastrointestinal disorders:

very common – diarrhea, abdominal pain, nausea, flatulence; common – vomiting, dyspepsia; uncommon – gastritis, constipation; unknown – pancreatitis, change in tongue color.

Hepatobiliary disorders:

uncommon – hepatitis; rare – hepatic function abnormalities; unknown – hepatic failure (rarely fatal), fulminant hepatitis, necrotic hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders:

common – rash, pruritus; uncommon – Stevens-Johnson syndrome, photosensitivity reactions, urticaria; very rare – DRESS syndrome; unknown – toxic epidermal necrolysis, erythema multiforme.

Musculoskeletal and connective tissue disorders:

common – arthralgia.

Renal and urinary disorders:

unknown – acute renal failure, interstitial nephritis.

General disorders:

common – fatigue; uncommon – chest pain, edema, malaise, asthenia.

Laboratory findings:

common – decreased white blood cell count, increased eosinophil count, decreased plasma bicarbonate level; uncommon – increased aspartate aminotransferase (AST) level, increased alanine aminotransferase (ALT) level, increased plasma bilirubin level, increased plasma urea level, increased plasma creatinine level, changes in plasma potassium levels; unknown – QT interval prolongation on ECG.

Shelf life.

5 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 30 °C, protected from light and out of reach of children.

Packaging.

3 film-coated tablets in a blister; 1 blister in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

WORLD MEDICINE ILLAC SAN. VE TIC. A.S., Turkey.

Manufacturer's address and place of business.

15 Temmuz Mahallesi Jamy Yolu Caddesi No:50 Gunesli Bagcilar/Istanbul, Turkey.

Marketing authorization holder.

LLC "WORLD MEDICINE", Ukraine.