Azimed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZIMED® (AZIMED®)

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin dihydrate, calculated as azithromycin – 500 mg;

Excipients: calcium hydrogen phosphate anhydrous; hypromellose (hydroxypropyl methylcellulose); maize starch; sodium starch glycolate (type A); microcrystalline cellulose; sodium lauryl sulfate; magnesium stearate; coating mixture "Opadry II BLUE" 33G30700 (polyethylene glycol (macrogol); lactose monohydrate; titanium dioxide (E 171); hypromellose (hydroxypropylmethylcellulose); triacetin; indigo carmine (E 132)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics: film-coated tablets, light blue in color, oval-shaped, biconvex, with a score line on one side of the tablet. The cross-section reveals a white core.

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

Pharmacological properties.

Pharmacodynamics.

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

Mechanism of resistance.

Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic 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 may vary depending on geographical location and time for individual species; therefore, local information on resistance patterns is particularly important, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the efficacy of the medicinal product in treating at least some 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 after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after drug intake.

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

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

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

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following three 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 demonstrated 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), bartonellosis, 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, or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction.

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

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

Didanosine. In six HIV-positive volunteers, concomitant administration of 1200 mg daily doses of azithromycin with 400 mg daily doses of didanosine showed no effect on the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine has been reported to increase 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 substrate concentration in serum 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 unclear but may be beneficial for patients.

Azithromycin has no significant interaction 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 a 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 use 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 showed no significant effect on 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 showed no changes in azithromycin pharmacokinetics.

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 500 mg daily oral azithromycin for 3 days followed by a single 10 mg/kg oral dose of cyclosporine, a significant increase in cyclosporine Cmax and AUC0-5 was demonstrated. Therefore, caution should be exercised when these drugs are used concomitantly. 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 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 unchanged when fluconazole was coadministered; however, 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 500 mg azithromycin 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 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. In healthy male volunteers, 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.

Terfenadine. Pharmacokinetic studies did not report interactions between azithromycin and terfenadine. In some cases, such an interaction cannot be completely ruled out; 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 in healthy volunteers 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 1200 mg azithromycin on day 7 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 but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases with fatal outcome), as well as dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged monitoring 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 dysfunction have been reported during azithromycin therapy. 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 liver dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If liver dysfunction is suspected, azithromycin should be discontinued.

The product contains lactose, which should be taken into account in patients with lactase deficiency, galactosemia, or glucose-galactose malabsorption syndrome.

Ergot derivatives. In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with the rapid onset 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 co-administered with ergot derivatives.

Superinfections. As with other antibiotics, patients should be monitored for signs of superinfection caused by nonsusceptible organisms, including fungi.

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 gut flora, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile that hyperproduce toxins 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. Careful medical history is essential, as CDAD has been reported to occur up to two months after administration of antibacterial agents.

Renal function impairment. In patients with severe renal dysfunction (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 may increase the risk of cardiac arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be administered with caution to patients with proarrhythmic conditions (particularly women and elderly patients), especially those:

• 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 arrhythmia, 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. 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 streptococcal pharyngeal infections, there are no data demonstrating efficacy of azithromycin in preventing rheumatic fever. The safety and efficacy of intravenous azithromycin for treatment of infections in children have not been established.

The safety and efficacy of azithromycin for prevention or treatment of Mycobacterium avium complex in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In reproductive toxicity studies in animals, azithromycin showed no teratogenic effects 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 justifies the potential risk to the fetus.

Breastfeeding.

Azithromycin has been reported to be excreted into human breast milk. However, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted.

Fertility.

Fertility studies have been conducted in rats; a decreased pregnancy rate was observed 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 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

Azimed® 500 mg tablets should be taken as a single daily dose, independent of food intake. Tablets should be swallowed whole, without chewing. If a dose is missed, it should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

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

For migrating erythema: the total course dose of azithromycin is 3 g, administered as follows: 1 g (2 tablets of 500 mg as a single dose) on day 1, followed by 500 mg once daily from day 2 to day 5.

For sexually transmitted infections: the recommended dose of azithromycin is 1000 mg (2 tablets of 500 mg as a single dose).

Elderly patients

No dosage adjustment is required for elderly patients.

Since elderly patients may be at increased risk of cardiac conduction disorders, caution is recommended when using azithromycin due to the potential risk of cardiac arrhythmia, including torsade de pointes.

Patients with renal impairment

For patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as for patients with normal renal function may be used. 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 impairment. Clinical studies on the use of azithromycin in such patients have not been conducted.

Children. Azimed® 500 mg tablets are indicated for children with body weight ≥ 45 kg. For this pediatric group, the adult dosage is recommended.

Overdose. Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with normal therapeutic doses and 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 table below lists adverse reactions observed during clinical trials and the post-marketing period with all dosage forms of azithromycin, organized by system organ class and frequency of occurrence. Adverse reactions identified during the post-marketing period are indicated in italics. Frequencies are defined according to the following categories: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from available data). Within each frequency group, adverse events are listed in decreasing order of severity.

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

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical trials and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release medicinal products.

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

Shelf life. 3 years.

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

Packaging. Film-coated tablets, 500 mg, 3 or 10 tablets per blister, 1 blister per carton.

Prescription status. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Address of the manufacturer and its place of business.

139 Saksaganskogo Street, Kyiv, 01032, Ukraine.