Azithromycin-darnitsa

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROMYCIN-DARNYTSIA

Composition:

Active substance: azithromycin;

One tablet contains 500 mg of azithromycin dihydrate calculated as azithromycin;

Excipients: lactose monohydrate, sodium lauryl sulfate, povidone, sodium croscarmellose, microcrystalline cellulose, magnesium stearate, talc, macrogol 4000, sepiofilm 752 white.

Pharmaceutical form. Film-coated tablets.

Main physico-chemical properties: white, elongated, biconvex film-coated tablets.

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

Pharmacological Properties.

Pharmacodynamics.

Azithromycin is a member of the macrolide antibiotic group—azalides—with a broad spectrum of antimicrobial activity. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide translocation, without affecting polynucleotide synthesis. Resistance to azithromycin may be either intrinsic or acquired. Complete cross-resistance exists among Streptococcus pneumoniae, beta-hemolytic streptococci group A, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

Spectrum of antimicrobial activity 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 of azithromycin after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake. Following oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that azithromycin concentrations in tissues are significantly higher (up to 50 times) than in blood plasma, indicating strong tissue binding of the drug.

Protein binding in serum varies depending on plasma concentration, ranging 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 elimination half-life fully reflects the tissue elimination half-life 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 results and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Infections of the ear, nose, and throat (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), erysipelas, impetigo, secondary pyoderma, moderate severity acne vulgaris (common acne);
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

• Hypersensitivity to azithromycin, as well as to any other components of the medicinal product or to any other macrolide or ketolide antibiotic.
• Severe hepatic or renal impairment.
• Should not be used concomitantly with ergot derivatives due to the theoretical possibility of ergotism.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be used with caution when administered concomitantly with other medicinal products that may prolong the QT interval (see section "Special precautions for use").

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

Cetirizine. In healthy volunteers, concomitant administration of azithromycin in a five-day course with 20 mg cetirizine at steady state did not result in pharmacokinetic interaction or significant changes in the QT interval.

Didanosine. Concomitant administration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive patients 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, may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly, the possibility of increased serum concentrations of digoxin and colchicine should be considered.

Zidovudine. Concomitant administration of azithromycin (single doses of 1000 mg and multiple doses of 1200 mg or 600 mg) has a minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unknown, but it may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is considered not to have pharmacokinetic interactions with erythromycin and other macrolides. Azithromycin does not induce or inactivate cytochrome P450 via the cytochrome-metabolite complex.

Ergot derivatives. Due to the theoretical possibility of ergotism, azithromycin should not be administered concomitantly with ergot derivatives.

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin and medicinal products metabolized via the cytochrome P450 system.

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, cases of rhabdomyolysis have been reported in the post-marketing period in patients taking azithromycin with statins.

Carbamazepine. Pharmacokinetic studies in healthy volunteers showed no significant effect on plasma concentrations of carbamazepine and its active metabolite in patients receiving azithromycin concomitantly.

Cimetidine. Pharmacokinetic studies assessing the effect of a single dose of cimetidine on azithromycin pharmacokinetics showed no changes in azithromycin pharmacokinetics when cimetidine was administered 2 hours before azithromycin.

Oral anticoagulants of the coumarin type. Azithromycin did not alter the anticoagulant effect of a single dose (15 mg) of warfarin in healthy volunteers. However, 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, 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 azithromycin 500 mg orally daily for 3 days followed by a single 10 mg/kg dose of cyclosporine, a statistically significant increase in Cmax and AUC0-5 of cyclosporine was observed. Therefore, caution is advised when considering concomitant administration of these medicinal products. If such 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 interactions.

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 unchanged when fluconazole was administered concomitantly, although a decrease in Cmax of azithromycin (by 18%) was observed, which was not clinically significant.

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. Azithromycin does not have a significant effect on the pharmacokinetics of methylprednisolone.

Midazolam. Concomitant administration of 500 mg azithromycin daily for 3 days did not result in clinically significant changes in the pharmacokinetics and pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir. Administration of nelfinavir increases serum concentrations of azithromycin. Although dose adjustment of azithromycin is not recommended when used concomitantly with nelfinavir, careful monitoring for known adverse effects of azithromycin is justified.

Rifabutin. Concomitant administration of azithromycin and rifabutin does not affect serum concentrations of either drug. However, cases of neutropenia have been observed with concomitant use of azithromycin and rifabutin. Although neutropenia has been associated with rifabutin use, a causal relationship with the combination including 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. During pharmacokinetic studies, no evidence of interaction between azithromycin and terfenadine was reported. Isolated cases have been reported where such an interaction could not be completely ruled out; however, there was no definitive evidence that such an interaction occurred.

Theophylline. No evidence of clinically significant pharmacokinetic interaction was obtained in healthy volunteers receiving azithromycin and theophylline concomitantly.

Triazolam. Concomitant administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg triazolam on day 2 did not cause a significant effect on the pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with 1200 mg azithromycin on day 7 did not cause a significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum concentrations of azithromycin were similar to those observed in other studies.

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

Special precautions for use.

Allergic reactions. In rare cases, azithromycin has been reported to cause serious allergic reactions such as angioneurotic edema and anaphylaxis (in isolated cases – with fatal outcome), and dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions have led to recurrent symptoms and required longer-term monitoring and treatment.

Hepatic function impairment. Since the liver is the primary route of azithromycin metabolism, azithromycin should be used with particular caution in patients with hepatic insufficiency.

Liver function should be monitored if symptoms of hepatic dysfunction develop, such as rapidly developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, and hepatic encephalopathy.

If hepatic dysfunction is detected, azithromycin therapy should be discontinued.

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.

Cardiac rhythm disturbances. Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmias and ventricular fibrillation, has been observed during treatment 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 administered with caution to patients with existing proarrhythmic conditions (especially women and elderly patients), particularly those:

• with congenital or documented QT interval prolongation;
• currently receiving treatment with other medicinal substances known to prolong the QT interval, such as class IA and III antiarrhythmic agents, cisapride, and terfenadine;
• with electrolyte imbalances, particularly in cases of hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, arrhythmia, or severe heart failure.

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

Streptococcal infections. Azithromycin is generally effective for the treatment of streptococcal pharyngitis, but there are no data demonstrating the efficacy of azithromycin in preventing acute rheumatic polyarthritis.

Superinfections. As with other antibacterial agents, superinfections (e.g., fungal infections) may occur.

With the use of nearly all antibacterial agents, including azithromycin, cases of C. difficile-associated diarrhea have been reported. Antibacterial treatment 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 C. difficile-associated diarrhea. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity, as these infections may be resistant to antibacterial therapy and may require colectomy. The possibility of C. difficile-associated diarrhea should be considered in all patients who develop diarrhea following antibiotic use. Careful medical history is essential, as C. difficile-associated diarrhea has been reported to occur up to two months after antibiotic administration.

Alcoholic beverages should not be consumed during treatment with this medicinal product.

AZITHROMYCIN-DARNYTSIA contains lactose; therefore, the medicinal product should not be administered to patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Use during pregnancy or breastfeeding.

Pregnancy.

Reproductive toxicity studies in animals were conducted using doses corresponding to moderately toxic levels for the maternal organism. These studies provided no evidence of toxic effects of azithromycin on the fetus. However, adequate and well-controlled studies in pregnant women have not been conducted. Since animal reproductive studies do not always predict effects in humans, azithromycin should be prescribed during pregnancy only if clearly needed.

breastfeeding.

Azithromycin has been reported to pass into human milk; however, appropriate 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 were 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.

Given the potential for adverse reactions such as dizziness, somnolence, and visual disturbances, the use of this medicinal product is not recommended when driving or operating machinery.

Method of Administration and Dosage.

AZITHROMYCIN-DARNYTSIA is intended for use in adults and children with body weight over 45 kg.

Azithromycin should be taken orally once daily, at least 1 hour before or 2 hours after a meal.

For infections of the ear, nose, and throat (ENT organs), respiratory tract, skin and soft tissues (except chronic migrating erythema): 500 mg (1 tablet) once daily 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 week’s dose should be taken 7 days after the first tablet, and the subsequent 8 doses should be taken at 7-day intervals.

For migrating erythema: Day 1 – 1 g per day (2 tablets taken at once); Days 2 to 5 – 500 mg (1 tablet) per day.

For sexually transmitted infections: 1 g (2 tablets) as a single dose. Total course dose – 1 g.

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

In renal impairment with mild to moderate dysfunction (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).

In hepatic impairment, the drug should not be used in patients with severe liver disease, as azithromycin is metabolized in the liver and excreted via bile. There have been no studies conducted on the treatment of such patients using azithromycin.

In elderly patients, dose adjustment is not required.

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.

AZITHROMYCIN-DARNYTSIA in this pharmaceutical form should be administered to children with body weight over 45 kg.

Children with body weight less than 45 kg should be administered azithromycin in another pharmaceutical form.

Overdose.

Symptoms: possible symptoms of general intoxication, hearing disturbances, abdominal pain, severe nausea, vomiting, diarrhea.

Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy aimed at supporting vital functions. There is no specific antidote.

Adverse reactions.

The table below lists adverse reactions identified from clinical trials and during the post-marketing period with 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 are defined according to the following scale: 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 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 during the post-marketing period

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:

Shelf life.

3 years.

Storage conditions.

Keep in the original packaging, out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

3 tablets in a blister pack; 1 blister pack in a carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical company "Darnytsia".

Manufacturer's address and place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.