Chemomycin®

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMOMYCIN® (HEMOMYCIN)

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin 500 mg (in the form of azithromycin dihydrate);

Excipients: microcrystalline cellulose silicate, microcrystalline cellulose, sodium starch glycolate (type A), povidone, magnesium stearate, talc, colloidal anhydrous silicon dioxide, titanium dioxide (E 171), copovidone, ethylcellulose, macrogol 6000, indigocarmine (E 132), quinoline yellow (E 104).

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: round, biconvex, film-coated tablets of light grey-blue color, white to almost white in cross-section.

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

ATC code J01FA10.

Pharmacological Properties

Pharmacodynamics

Azithromycin is a representative of a new subclass of macrolide antibiotics—azalides. It binds to the 50S subunit of the 70S ribosome of susceptible microorganisms, inhibiting RNA-dependent protein synthesis, thereby slowing bacterial growth and reproduction. At high concentrations, a bactericidal effect is possible.

It has a broad spectrum of antimicrobial activity. The drug is active against Gram-positive cocci: Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Groups C, F, and G streptococci, S. viridans; Staphylococcus aureus; Gram-negative bacteria: Haemophilus influenzae, H. parainfluenzae, Moraxella catarrhalis, Bordetella pertussis, B. parapertussis, Legionella pneumophila, H. ducreyi, Campylobacter jejuni, Neisseria gonorrhoeae, Gardnerella vaginalis; certain anaerobic microorganisms: Bacteroides bivius, Clostridium perfringens, Peptostreptococcus species, as well as Chlamydia trachomatis, Mycoplasma pneumoniae, Ureaplasma urealyticum, Treponema pallidum, Borrelia burgdorferi. It has no effect on Gram-positive microorganisms resistant to erythromycin.

Pharmacokinetics

After oral administration, azithromycin is rapidly absorbed from the gastrointestinal tract. Bioavailability is approximately 37% (first-pass effect). Maximum plasma concentration is achieved within 2.5–3 hours and reaches 0.4 mg/L following a 500 mg oral dose. Azithromycin penetrates well into respiratory tissues, organs and tissues of the urogenital tract, including the prostate gland, as well as into skin and soft tissues. Drug concentrations in tissues and cells are 10–100 times higher than in blood serum. A stable plasma level is achieved within 5–7 hours. The drug accumulates extensively in phagocytes, which transport it to sites of infection and inflammation, where it is gradually released during phagocytosis.

Protein binding is inversely proportional to plasma concentration (7–50% of the drug bound). Approximately 35% is metabolized in the liver via demethylation, resulting in loss of activity.

Over 50% of the administered dose is excreted unchanged in bile; about 4.5% is excreted in urine within 72 hours.

The plasma elimination half-life is 14–20 hours (within 8–24 hours after dosing) and 41 hours (within 24–72 hours). Food intake significantly alters pharmacokinetics.

Pharmacokinetic parameters do not change with age in men (65–85 years). In women, maximum concentration (Cmax) increases by 30–50%. In children aged 1–5 years, Cmax, T1/2, and the area under the pharmacokinetic curve are reduced.

Clinical Characteristics

Indications

Infections caused by microorganisms sensitive to azithromycin:

• Ear, nose, and throat (ENT) 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.

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 when co-administered with other medicinal products that may prolong the QT interval.

Antacids. No significant changes in bioavailability were generally observed when antacids were administered concomitantly, although the peak plasma concentration of azithromycin was reduced by approximately 25%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid administration.

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

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

Digoxin. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin, may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is co-administered with digoxin, the potential for increased digoxin serum concentrations should be considered.

Zidovudine. Single doses of 1000 mg and 1200 mg, or multiple doses of 600 mg of azithromycin, did not affect 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 known.

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

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that the drug does not exhibit the pharmacokinetic drug interactions commonly observed with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via a metabolite complex.

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).

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, administration of a single dose of cimetidine 2 hours before azithromycin showed no changes in the pharmacokinetics of azithromycin.

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 in healthy volunteers. However, during the post-marketing period, potentiation of the anticoagulant effect has been reported following concomitant use of azithromycin and oral anticoagulants of the coumarin type. Although a causal relationship has not been established, monitoring of prothrombin time is recommended when azithromycin is prescribed to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. Some related macrolide antibiotics affect the metabolism of cyclosporine. Since no pharmacokinetic or clinical studies have been conducted on the potential interaction between azithromycin and cyclosporine, the therapeutic situation should be carefully evaluated before co-administration. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are required.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg of 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. Total exposure and elimination half-life of azithromycin were not altered 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 cause 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 midazolam.

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 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. No evidence was found that azithromycin (500 mg daily for 3 days) affects AUC or Cmax values of sildenafil or its main circulating metabolite in healthy male volunteers.

Terfenadine. Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. However, the possibility of such an interaction cannot be completely ruled out, although data confirming such an interaction are lacking.

Theophylline. There are no data on clinically significant pharmacokinetic interactions with concomitant administration of azithromycin and theophylline.

Triazolam. Concomitant administration 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 did not significantly affect the peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum concentrations of azithromycin were consistent with those observed in other studies.

Special precautions for use.

Allergic reactions. As with the use of erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases – with fatal outcome). Some of these reactions caused by azithromycin led to recurrent symptoms and required prolonged observation and treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for azithromycin, caution is advised 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 may have been taking other hepatotoxic medicinal products.

Liver function tests should be performed if signs of liver dysfunction develop, such as rapidly developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

If liver dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, concomitant use of certain macrolide antibiotics may rapidly lead to ergotism. There are no data on the 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, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Diarrhea associated with Clostridium difficile (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 hyper-produce 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. A careful patient 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 increases the risk of cardiac arrhythmias and ventricular tachyarrhythmias (torsade de pointes), has been observed with other macrolide antibiotics. A similar effect of azithromycin cannot be completely ruled out in patients at increased risk of prolonged cardiac repolarization; therefore, caution is advised when prescribing azithromycin to patients:

• with congenital or acquired prolongation of the QT interval;
• currently 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 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 myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Streptococcal infections. Azithromycin is generally effective in the treatment of oropharyngeal streptococcal infections; however, there are no data demonstrating the effectiveness of azithromycin in the prevention of rheumatic fever. An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to contribute to the infection.

Other.

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

Use during pregnancy or breastfeeding.

Pregnancy.

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

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. Use of azithromycin during breastfeeding is possible only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility.

Fertility studies have been conducted in rats; pregnancy rates decreased 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 dizziness, somnolence, and visual disturbances should be considered.

Method of Administration and Dosage

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

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

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema): 500 mg (1 tablet per dose) once daily for 3 days.

For migratory erythema: once daily for 5 days; on the first day – 1 g (2 tablets of 500 mg), from the second to the fifth day – 500 mg (1 tablet) daily.

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

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

Dosage adjustment is not required for elderly patients.

Renal Impairment

No dosage adjustment is necessary for patients with mild renal dysfunction (creatinine clearance > 40 mL/min). No studies have been conducted in patients with creatinine clearance < 40 mL/min. Therefore, Chemomycin® should be used with caution in such patients.

Hepatic Impairment

Dosage adjustment is not required for patients with mild to moderate hepatic impairment (see section "Special Warnings and Precautions for Use").

The drug is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Elderly Patients

Dosage adjustment is not required for elderly patients.

Since elderly patients may have disturbances in cardiac conduction, caution is recommended when administering azithromycin due to the risk of developing cardiac arrhythmias, including torsade de pointes.

Children

The drug is indicated for children with body weight above 45 kg.

Overdose

Typical symptoms of overdose: reversible hearing impairment, abdominal pain, severe nausea, vomiting, diarrhea.

Treatment: in case of overdose, administration of activated charcoal and symptomatic therapy aimed at supporting vital functions is recommended. There is no specific antidote.

Adverse reactions.

The table below lists adverse reactions identified during clinical trials and in the post-marketing surveillance period with all dosage forms of azithromycin. Adverse reactions are listed by system organ class and frequency. Adverse reactions reported during the post-marketing period are indicated in italics. Frequency is defined as follows: 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 order of decreasing severity.

Table 1

Adverse reactions probably associated with azithromycin based on data from clinical trials and post-marketing surveillance

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 surveillance. These adverse reactions (see Table 2) differ in type or frequency from those reported with the use of immediate-release and extended-release formulations.

Table 2

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 30 °C in the original packaging to protect from light and moisture.

Keep out of reach of children.

Packaging. 3 tablets per blister; 1 blister per cardboard box.

Prescription status. Prescription only.

Manufacturer. "Hemofarm" AD.

Manufacturer's address and location of business operations.

Beogradski put bb, 26300 Vrsac, Serbia.