Azithromycin-cr

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMYCIN-KR (AZITHROMYCIN-KR)

Composition:

Active ingredient: azithromycin;

1 capsule contains: azithromycin (calculated as azithromycin dihydrate) 250 mg (0.25 g) or 500 mg (0.5 g);

Excipients: lactose monohydrate, sodium croscarmellose, magnesium stearate;

Capsule shell contains: gelatin, glycerin, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), titanium dioxide (E 171), diamond blue (E 133) – only in Azithromycin-KR 0.5 g, purified water.

Pharmaceutical form. Capsules.

Main physicochemical properties:

0.25 g – hard gelatin capsules of white color;

0.5 g – hard gelatin capsules of blue color.

The contents of the capsules – powder of white or almost white color.

Pharmacotherapeutic group.

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

ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a representative of a new group of macrolide antibiotics – azalides. It has a broad spectrum of antimicrobial activity: effective against a number of both Gram-positive (staphylococci) and Gram-negative (Escherichia coli, Haemophilus influenzae, Shigella, Salmonella) microorganisms, as well as mycoplasmas, Legionella, and Bacteroides.

Compared to erythromycin, the drug is more effective against Gram-negative microorganisms, more stable in the acidic environment of the stomach, is eliminated from the body more slowly, has a longer duration of action, and is better tolerated. It predominantly provides a bactericidal effect. It inhibits protein synthesis in microbial ribosomes by suppressing peptidyl transferase at the translation stage. It is an effective agent in infections caused by intracellular pathogens.

Pharmacokinetics.

Azithromycin is stable in an acidic environment, lipophilic, and rapidly absorbed from the gastrointestinal tract. After a single oral dose, bioavailability is approximately 37%. It maintains bactericidal concentrations at the site of infectious inflammation for 5–7 days after the last dose, allowing for short treatment courses (3–5 days). It does not bind to cytochrome P450 enzyme complex. Maximum concentration (Cmax) of 0.4 mg/L is achieved within 2–3 hours after an oral 500 mg dose. It readily penetrates histohematic barriers and cell membranes. Tissue concentrations of the drug are 10–15 times higher than in blood plasma, and at the site of infection are 24–34% higher than in healthy tissues, correlating with the degree of inflammatory process. Despite high concentrations in phagocytes, azithromycin does not significantly affect their function. Food intake alters its pharmacokinetics. Approximately 35% of the drug is metabolized in the liver. It is eliminated from plasma in two phases: the elimination half-life is 14–24 hours (within 8–24 hours after dosing) and 41 hours (within 24–72 hours). It is excreted from the body unchanged, primarily via bile (approximately 60%) and urine (approximately 5%).

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), 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, azithromycin should not be administered concurrently with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

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

Although available data indicate that azithromycin does not inhibit the CYP3A4 enzyme, caution should be exercised when prescribing the drug to patients receiving quinidine, cyclosporine, cisapride, astemizole, terfenadine, ergot alkaloids, pimozide, or other medicinal products with a narrow therapeutic index that are primarily metabolized by the CYP3A4 enzyme.

Pharmaceutically incompatible with heparin.

Concomitant use with tetracyclines or chloramphenicol results in synergistic enhancement of antibacterial activity. Concurrent use with lincosamides reduces the efficacy of azithromycin.

Azithromycin prolongs the elimination half-life of carbamazepine, valproic acid, hexobarbital, phenytoin, disopyramide, bromocriptine, and oral hypoglycemic agents.

Macrolide antibiotics may potentiate the effects of ergotamine.

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 and antacids should not be taken simultaneously.

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

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

Digoxin. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with digoxin, the possibility of increased digoxin serum concentrations should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg 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 unclear, but it may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is considered that the drug does not 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 alkaloids. Concomitant use of ergot alkaloids and macrolide antibiotics accelerates the development of ergotism. Data on interaction between ergot alkaloids and azithromycin are lacking. However, due to the risk of ergotism, concomitant administration of azithromycin and ergot derivatives should be avoided.

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 cause changes in plasma concentrations of atorvastatin (based on HMG CoA reductase inhibition analysis). However, during the post-marketing period, cases of rhabdomyolysis were 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, no changes in azithromycin pharmacokinetics were observed after administration of a single dose of cimetidine taken 2 hours before 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 administered to healthy volunteers. During the post-marketing period, reports were received regarding potentiation of the anticoagulant effect after 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 an oral dose of 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 administering these drugs concomitantly. If concomitant use is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz. Concomitant administration of a single dose of azithromycin 600 mg with daily 400 mg efavirenz for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole. Concomitant administration of a single 1200 mg dose of azithromycin does 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 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 show a significant effect on 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 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) leads to 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 administration of azithromycin 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 and Cmax values of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies did not report interactions between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be entirely excluded, although specific data on such interaction are lacking. As with other macrolide antibiotics, azithromycin should be prescribed cautiously in combination with terfenadine.

Theophylline. No data are available on clinically significant pharmacokinetic interactions when azithromycin and theophylline are administered concomitantly to healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers of azithromycin 500 mg on the first day and 250 mg on the second day 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 azithromycin 1200 mg on day 7 showed no significant effect on Cmax, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum concentrations of azithromycin were consistent with those observed in other studies.

Doxorubicin. Clinical studies on drug interaction between azithromycin and doxorubicin have not been conducted. The clinical significance of these preclinical findings is unknown.

Cisapride. Cisapride is metabolized in the liver by the CYP3A4 enzyme. Since macrolides inhibit this enzyme, concomitant use of cisapride may lead to QT interval prolongation, ventricular arrhythmias, and bidirectional ventricular tachycardia.

Astemizole, alfentanil. Data on interaction with astemizole and alfentanil are lacking. Caution should be exercised when administering azithromycin concomitantly with these drugs, due to enhanced effects observed when these drugs are used concomitantly with the macrolide antibiotic erythromycin.

Special precautions for use.

Azithromycin should be used with caution in patients with impaired liver or kidney function, or heart failure. After discontinuation of treatment, hypersensitivity reactions may persist in some cases, requiring specific therapy under medical supervision.

Caution is necessary when administering the drug to patients with severe impairment of renal or hepatic function, clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

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, such as acute generalized exanthematous pustulosis. Some of these azithromycin-induced reactions have been associated with recurrent symptoms and required prolonged monitoring and treatment.

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

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

Hepatic function impairment. Since the liver is the primary route of elimination for azithromycin, caution is advised when administering 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.

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

If hepatic dysfunction is detected, the drug should be discontinued.

In patients taking ergot derivatives, concomitant use of certain macrolide antibiotics has been associated with 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.

Myasthenia gravis. Exacerbation of symptoms of myasthenia gravis or new-onset myasthenic syndrome has been reported in patients receiving azithromycin therapy.

Diarrhea. Cases of Clostridium difficile-associated diarrhea (CDAD) have 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 antibacterial therapy and require colectomy. CDAD should be considered in all patients with diarrhea following antibiotic use. Careful medical history is essential, as CDAD may 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.

Prolonged cardiac repolarization and QT interval. Prolongation of cardiac repolarization and QT interval, increasing the risk of ventricular arrhythmias and torsade de pointes, has been observed with other macrolide antibiotics, including azithromycin.

Since conditions associated with increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with existing proarrhythmic conditions (particularly women and elderly patients), especially those:

• with congenital or documented 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 arrhythmia, or severe heart failure.

The product contains lactose monohydrate. When used at recommended doses, up to 8.7 mg of lactose is delivered into the body daily. The drug should be used with caution in patients with lactose intolerance, galactosemia, or glucose-galactose malabsorption syndrome. Dose adjustment is not required for elderly patients.

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 insufficient adequate data on the use of azithromycin in pregnant women. Reproductive toxicity studies in animals have not shown teratogenic harmful effects of azithromycin on the fetus; however, the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Period of breastfeeding.

Azithromycin has been shown to pass into human milk; however, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Azithromycin may be used during breastfeeding 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 are no data on the effect of azithromycin on the ability to drive vehicles or operate machinery. The possibility of adverse reactions such as dizziness, somnolence, confusion, and disorientation should be taken into account.

Administration and Dosage.

Azithromycin should be taken once daily, 1 hour before or 2 hours after a meal, as concomitant food intake interferes with azithromycin absorption. Capsules must be swallowed whole.

Adults, including 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): 500 mg (2 capsules of 250 mg or 1 capsule of 500 mg as a single dose) once daily for 3 days.

For migratory erythema, the total dose of azithromycin is 3 g: 1 g once daily (4 capsules of 250 mg or 2 capsules of 500 mg) on Day 1, followed by 500 mg (2 capsules of 250 mg or 1 capsule of 500 mg) once daily from Day 2 to Day 5.

For sexually transmitted infections: a single dose of 1 g (4 capsules of 250 mg or 2 capsules of 500 mg).

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

Dosage adjustment is not required in 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 arrhythmia, including torsade de pointes.

Patients with renal impairment.

The same dosage regimen as in patients with normal renal function may be used in patients with mild renal impairment (glomerular filtration rate 10–80 mL/min). 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 azithromycin use in such patients have not been conducted.

Children.

Azithromycin in capsule form is not recommended for children with body weight less than 45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed after ingestion of doses higher than recommended are similar to those seen with standard therapeutic doses. These 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 identified from clinical trials and post-marketing surveillance for all dosage forms of azithromycin, organized by system organ class and frequency. Adverse reactions reported during the post-marketing period are indicated in italics. Frequency groups were defined according to the following scale: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the 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 obtained from clinical trials and post-marketing surveillance

In addition, children may experience hyperkinesis, nervousness, insomnia, conjunctivitis, and agitation. Altered parameters return to normal within 2–3 weeks after discontinuation of treatment.

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical studies 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:

Shelf life.

3 years.

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

Storage conditions.

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

Keep out of reach of children.

Incompatibility.

Pharmaceutically incompatible with heparin.

Packaging.

0.25 g – 6 capsules in a blister pack. 1 blister pack in a cardboard box.

0.5 g – 3 capsules in a blister pack. 1 blister pack in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and place of business.

1, Gordienkovskaya Street, Kharkiv, Kharkiv region, 61010, Ukraine.