AZTEC

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

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin dihydrate equivalent to azithromycin 500 mg;

Excipients: microcrystalline cellulose, sodium lauryl sulfate, sodium starch glycolate, polyvinylpyrrolidone, sodium croscarmellose, talc, magnesium stearate, Ponceau 4R (E 124), titanium dioxide (E 171), hydroxypropylmethylcellulose, macrogol 400.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: biconvex, capsule-shaped, pink film-coated tablets, smooth on both sides.

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 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 geographically and over time for specific organisms; therefore, local resistance data are essential, especially when treating severe infections. Expert advice should be sought if local resistance patterns suggest that the efficacy of the drug in treating at least some types of infections may be questionable.

Antimicrobial spectrum of azithromycin:

Typically susceptible organisms

Aerobic Gram-positive bacteria

Staphylococcus aureus methicillin-susceptible

Streptococcus pneumoniae penicillin-susceptible

Streptococcus pyogenes

Aerobic Gram-negative bacteria

Haemophilus influenzae

Haemophilus parainfluenzae

Legionella pneumophila

Moraxella catarrhalis

Pasteurella multocida

Anaerobic bacteria

Clostridium perfringens

Fusobacterium spp.

Prevotella spp.

Porphyriomonas spp.

Other microorganisms

Chlamydia trachomatis

Chlamydia pneumoniae

Mycoplasma pneumoniae

Organisms for which acquired resistance may be a concern

Aerobic Gram-positive bacteria

Streptococcus pneumoniae with intermediate susceptibility to penicillin and penicillin-resistant

Inherently resistant organisms

Aerobic Gram-positive bacteria

Enterococcus faecalis

Staphylococci MRSA, MRSE*

Anaerobic bacteria

Bacteroides fragilis group

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

Pharmacokinetics

Oral bioavailability is approximately 37%. Maximum serum concentration is reached within 2–3 hours after administration.

Following oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, indicating extensive tissue binding.

Protein binding in serum varies depending on plasma concentration, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum. The apparent volume of distribution at steady state (Vss) 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 detected in human bile. Ten metabolites have also been identified 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:

• 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), chancroid, impetigo, secondary pyoderma, moderate acne vulgaris;
• 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.

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

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be used cautiously in patients receiving other medicinal products that may prolong the QT interval (see section "Special warnings and precautions for use").

Antacids. In studies evaluating the effect of concomitant antacid administration on azithromycin pharmacokinetics, no overall changes in bioavailability were observed, although peak plasma concentrations of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously. Azithromycin should be taken at least 1 hour before or 2 hours after antacids.

Cetirizine. In healthy volunteers, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state showed no evidence of 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 steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. There have been reports that concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, may lead to increased 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 or 1200 mg, or multiple doses of 600 mg of azithromycin, had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide 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 fully understood, 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 pharmacokinetic drug interactions commonly associated with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical risk of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended (see section "Contraindications").

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 plasma concentrations of atorvastatin (based on HMG-CoA reductase inhibition analysis). However, post-marketing reports have documented cases of rhabdomyolysis 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 had no effect on 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 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 azithromycin is prescribed to patients receiving oral coumarin-type anticoagulants.

Cyclosporine. Some related macrolide antibiotics affect cyclosporine metabolism. 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 demonstrated. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant use is necessary, 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. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; 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 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 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 that azithromycin (500 mg daily for 3 days) affects 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 completely ruled out; 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 in healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers 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 double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg 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 induce 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 (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Some of these azithromycin-induced reactions have been associated with recurrent symptoms and required prolonged monitoring and treatment.

If an allergic reaction occurs, administration of the drug must be discontinued and appropriate therapy initiated. Allergic symptoms may recur after discontinuation of symptomatic treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for 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 with azithromycin use. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic drugs.

Cases of hepatic dysfunction, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which resulted in fatal outcomes.

Liver function tests should be performed if signs or symptoms suggestive of liver dysfunction develop, such as rapidly progressing fatigue associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin should be discontinued.

Infantile hypertrophic pyloric stenosis (IHPS). Cases of infantile hypertrophic pyloric stenosis (IHPS) have been reported in infants within the first 42 days of life following azithromycin treatment. Parents and caregivers should seek medical advice if the infant develops vomiting or irritability during feeding.

Ergot derivatives. In patients receiving ergot derivatives, concomitant use of certain macrolide antibiotics has been associated with rapid development 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 (see section "Contraindications").

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

Diarrhea associated with Clostridium difficile (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. C. difficile strains that hyperproduce toxins are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and require colectomy. CDAD should be considered in all patients who develop 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, which increases the risk of cardiac arrhythmia and ventricular tachycardia (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 pre-existing proarrhythmic 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 significant bradycardia, cardiac arrhythmia, or severe heart failure;
• of advanced age, as they may be more susceptible to QT interval prolongation.

Myasthenia gravis. Exacerbation of symptoms of myasthenia gravis 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 the efficacy of azithromycin in preventing rheumatic fever.

Other.

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

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

The medicinal product contains the excipient Ponceau 4R (E 124), which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on azithromycin use in pregnant women. Reproductive toxicity studies in animals have not shown teratogenic effects of azithromycin on the fetus; however, the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Numerous observational studies conducted in several countries have evaluated the effects of azithromycin during pregnancy, with results compared to no antibiotic use or use of other antibiotics during the same period. While most studies do not indicate an association with adverse fetal outcomes such as major congenital malformations or cardiovascular defects, limited epidemiological data suggest a potential increased risk of miscarriage following azithromycin use in early pregnancy. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding.

Limited study data indicate that azithromycin is excreted in breast milk; the calculated maximum daily dose to the infant is 0.1–0.7 mg/kg/day. No serious adverse reactions in breastfed infants have been observed. The decision to discontinue breastfeeding or to discontinue azithromycin therapy should take into account the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Fertility.

Fertility studies conducted in rats showed a decreased pregnancy rate following azithromycin administration. The relevance of these findings to humans is unknown.

Ability to influence the ability to drive and use machines.

There is no evidence that azithromycin impairs the ability to drive or operate machinery.

Method of Administration and Dosage.

Azithromycin should be taken orally once daily, regardless of food intake. Tablets should be swallowed whole, without chewing. If a dose is missed, the missed dose should be taken as soon as possible, and subsequent doses should be administered at 24-hour intervals.

For adults and children with body weight over 45 kg: in infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema): 500 mg for 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 dose, and the next 8 doses should be taken at 7-day intervals.

For chronic migrating erythema: 1 g on day 1, then 500 mg from day 2 to day 5 of treatment. The treatment course is 5 days.

For sexually transmitted infections: single dose of 1 g (2 tablets of 500 mg or 4 tablets of 250 mg). Total course dose – 1 g.

For patients with mild 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 prescribed with caution to patients with severe renal impairment (glomerular filtration rate <10 mL/min).

In hepatic insufficiency, the drug should not be administered to patients with severe liver disease, as azithromycin is metabolized in the liver and excreted via bile. Clinical studies on azithromycin treatment in such patients have not been conducted.

Dose adjustment is not required for elderly patients.

However, since elderly patients may belong to high-risk groups for disturbances in cardiac conduction, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmias, including torsade de pointes.

Children.

This medicinal product in the given pharmaceutical form can be administered to children with body weight exceeding 45 kg. For this pediatric group, the adult dosage is recommended.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed with doses higher than recommended are similar to those seen with standard therapeutic doses and 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 measures are recommended, if necessary.

Adverse reactions.

The table below lists adverse reactions identified through clinical trials and during the post-marketing surveillance period with all dosage forms of azithromycin, organized by system organ class and frequency. Adverse reactions identified during the post-marketing surveillance period are indicated in italics. Frequency groups were defined using 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 group, adverse events are listed in order of decreasing severity.

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

* Adverse reactions identified during the post-marketing period.

§ The frequency of adverse reactions is represented by the calculated upper limit of the 95% confidence interval, calculated according to the "Rule of 3".

Information on adverse reactions that may be 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 at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 3 tablets in a blister; 1 blister in a cardboard package.

Prescription status. Prescription only.

Manufacturer. FDS Limited.

Manufacturer's address and place of business.
L-56/57, Phase II-D, Verna Industrial Estate, Verna, Salcette, Goa - 403 722, India.