AZIMED

INSTRUCTIONS for medical use of the medicinal product AZIMED® (AZIMED®)

Composition:

Active substance: azithromycin;

1 capsule contains azithromycin equivalent to 100% substance 250 mg;

Excipients: microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate;

capsule shell composition: titanium dioxide (E 171), gelatin.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard gelatin capsules with white cap and body. The capsule contents are white or almost white powder.

Pharmacotherapeutic group. Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin.

ATC code J01FA10.

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 through binding to the 50 S 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 the isolated species; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

Staphylococcus aureus resistant to methicillin has a very high prevalence of acquired resistance to macrolides and is mentioned here due to rare susceptibility to azithromycin.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached 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 levels, indicating strong tissue binding of the drug.

Binding to serum proteins varies depending on plasma concentrations and ranges 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 (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 3 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 showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Ear, nose, and throat 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), 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 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 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 cetirizine 20 mg at steady state did not result in any 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. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxine 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 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, administration of azithromycin increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not fully understood, but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is considered not to have 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 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 did not show a significant effect on plasma levels of carbamazepine or its active metabolites.

Cimetidine. In a pharmacokinetic interaction study, a single dose of cimetidine taken 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 administered to healthy volunteers. 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, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. In a pharmacokinetic study involving healthy volunteers who received 500 mg daily of oral azithromycin for 3 days followed by a single oral dose of 10 mg/kg cyclosporine, a significant increase in Cmax and AUC0-5 of cyclosporine was demonstrated. Therefore, caution should be exercised when using these drugs 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 daily of efavirenz 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 total exposure and elimination half-life of azithromycin were not altered by concomitant fluconazole administration, 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 500 mg daily of azithromycin for 3 days did not result in clinically significant changes in the pharmacokinetics or pharmacodynamics of midazolam administered as a single 15 mg dose.

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 an effect of azithromycin (500 mg daily for 3 days) on AUC or Cmax values of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. In some cases, such an interaction cannot be entirely ruled out; however, there are no specific data confirming such an interaction.

Theophylline. There are no data indicating clinically significant pharmacokinetic interactions between azithromycin and theophylline in healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers 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 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. Serum azithromycin 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 angioedema 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, azithromycin should be administered with caution in patients with severe hepatic disease. Cases of life-threatening hepatic dysfunction, including fulminant hepatitis, 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 progressing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If hepatic dysfunction is suspected, azithromycin should be discontinued.

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 risk of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfections. As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Clostridium difficile-associated diarrhea (CDAD), ranging in severity from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including azithromycin. Antibacterial therapy alters the normal flora of the colon, leading to overgrowth of C. difficile.

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 with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after antibiotic administration.

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, increasing the risk of cardiac arrhythmias and ventricular tachyarrhythmias (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with existing pro-arrhythmic conditions (particularly women and elderly patients), especially in patients:

• 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 relevant bradycardia, cardiac arrhythmias, 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 the drug of choice and is also used for prevention of acute rheumatic fever. Azithromycin is generally effective in treating streptococcal pharyngeal infection; however, 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.

Other. 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 azithromycin use in pregnant women. In reproductive toxicity studies in animals, azithromycin was not teratogenic, but it did cross the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit outweighs the potential risk.

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 in human breast milk have not been conducted.

Fertility.

Fertility studies have been conducted in rats; a decrease in 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 taken into account.

Method of Administration and Dosage.

Azimed® should be taken once daily, 1 hour before or 2 hours after a meal, as concomitant intake with food interferes with the absorption of azithromycin.

Do not open or divide the capsules!

For adults, elderly patients, and children with body weight over 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 (2 capsules at once) once daily for 3 days;
• for migratory erythema, the total dose of azithromycin is 3 g: on day 1, take 1 g (4 capsules of 250 mg at once), from day 2 to day 5 – 500 mg (2 capsules of 250 mg at once). The duration of treatment is 5 days.
• for sexually transmitted infections, the total dose of azithromycin is 1 g as a single dose (4 capsules of 250 mg at once).

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

Elderly Patients

Elderly patients do not require dose adjustment. However, since elderly patients may belong to risk groups for disturbances in cardiac electrical conduction, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmia and torsade de pointes.

Patients with Renal Impairment

In patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as in 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 disease. Studies on the treatment of such patients using azithromycin have not been conducted.

Children

Azimed® capsules are indicated for use in children with body weight ≥45 kg.

Overdose

In case of azithromycin overdose, the same adverse reactions may occur as with usual therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss.

Treatment: administration of activated charcoal and symptomatic therapy aimed at supporting vital functions.

Adverse Reactions

The table below lists adverse reactions observed during clinical trials and the post-marketing period with all dosage forms of azithromycin, classified by system organ class and frequency of occurrence. Adverse reactions reported during the post-marketing period are indicated in italics. Frequencies are defined according to the following scale: 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 (cannot be estimated from available data). Within each frequency category, adverse events are listed in descending order of severity.

Adverse reactions possibly or probably related to azithromycin, based on data obtained from clinical studies 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 dosage forms.

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

Shelf life. 3 years.

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

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

Supply category. Prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and location of its business activities.

139 Saksahanskoho Street, Kyiv, 01032, Ukraine.