Zibax

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

Composition:

Active substances: 1 tablet contains azithromycin dihydrate equivalent to azithromycin 250 mg or 500 mg;

Excipients: microcrystalline cellulose, crospovidone, ethylcellulose, isopropyl alcohol, dichloromethane, colloidal anhydrous silicon dioxide, talc, magnesium stearate, Protectab HP-1 (hydroxypropylmethylcellulose, propylene glycol, castor oil, talc, titanium dioxide (E171)), yellow iron oxide (E172).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:
250 mg tablets – light yellow, round, biconvex, film-coated, smooth on both sides;

500 mg tablets – light yellow, biconvex, capsule-shaped, film-coated, with a division line on one side and smooth on the other side.

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

ATC code J01FA10.

Pharmacological Properties.

Pharmacodynamics. Azithromycin is a representative of a new subgroup of macrolide antibiotics – the 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, S. pyogenes, S. agalactiae, viridans group streptococci, Streptococcus 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 reached within 2.5–3 hours and amounts to 0.4 mg/L following a 500 mg oral dose. Azithromycin penetrates well into respiratory tract tissues, organs and tissues of the urogenital system, including the prostate gland, as well as into the skin and soft tissues. Drug concentrations in tissues and cells are 10–100 times higher than in plasma. A steady plasma level is achieved within 5–7 days. 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% bound). Approximately 35% is metabolized in the liver via demethylation, resulting in loss of activity.

More than 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 the 8–24 hour interval after dosing) and 41 hours (within the 24–72 hour interval). Food intake significantly alters pharmacokinetics.

With age, pharmacokinetic parameters do not change 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, moderate acne vulgaris;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any other macrolide or ketolide antibiotics, as well as to excipients of the drug. Due to the theoretical possibility of ergotism, azithromycin should not be administered concomitantly with ergot derivatives.

Interaction with other medicinal products and other interactions.

Azithromycin should be administered cautiously to patients receiving other drugs that may prolong the QT interval.

Antacids: generally, no changes in bioavailability are observed when antacids are co-administered, although plasma peak concentrations of azithromycin are reduced by 30%. Azithromycin should be taken at least 1 hour before or 2 hours after antacid administration. No changes in azithromycin pharmacokinetics are observed when cimetidine is administered 2 hours prior to azithromycin.

Carbamazepine: pharmacokinetic interaction of azithromycin does not show a significant effect on plasma levels of carbamazepine or its active metabolites.

Cyclosporine: in a pharmacokinetic study, after 3 days of oral administration of azithromycin 500 mg/day followed by a single 10 mg/kg dose of cyclosporine, a significant increase in Cmax and AUC0-5 of cyclosporine was observed. Therefore, caution is advised when considering concomitant administration of these drugs. If such co-administration is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Coumarin anticoagulants: increased tendency to bleeding has been reported with concomitant use of azithromycin and warfarin or coumarin-like oral anticoagulants. Prothrombin time monitoring should be carefully maintained.

Digoxin: concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin, may 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.

Methylprednisolone: azithromycin does not significantly affect the pharmacokinetics of methylprednisolone.

Terfenadine: no interaction between azithromycin and terfenadine has been reported. However, as with other macrolide antibiotics, azithromycin should be used with caution in combination with terfenadine.

Theophylline: azithromycin does not affect the pharmacokinetics of theophylline when administered concomitantly. However, combined use of theophylline with other macrolide antibiotics has occasionally led to increased serum levels of theophylline.

Zidovudine: concomitant administration of azithromycin (single doses of 1000 mg and multiple doses of 1200 mg or 600 mg) exerts minimal effect on the plasma pharmacokinetics and urinary excretion of zidovudine or its glucuronide metabolite. However, azithromycin administration increases concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells.

Didanosine: concomitant administration of daily doses of 1200 mg azithromycin with didanosine does not affect the pharmacokinetics of didanosine.

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

Rifabutin: concomitant administration of azithromycin and rifabutin does not affect plasma concentrations of either drug. Neutropenia has been 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.

Cetirizine: concomitant administration of azithromycin in a 5-day course with 20 mg cetirizine at steady state does not result in pharmacokinetic interaction or significant changes in QT interval.

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

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

Atorvastatin: concomitant administration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) does not alter plasma concentrations of atorvastatin (based on HMG-CoA reductase inhibition analysis).

Cimetidine: no changes in azithromycin pharmacokinetics are observed when cimetidine is administered 2 hours prior to azithromycin.

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 are not changed when fluconazole is co-administered; however, a reduction in azithromycin Cmax (by 18%) is observed, which is not clinically significant.

Indinavir: concomitant administration of a single 1200 mg dose of azithromycin does not have a statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg three times daily for 5 days.

Midazolam: concomitant administration of 500 mg azithromycin daily for 3 days does not cause clinically significant changes in the pharmacokinetics or pharmacodynamics of a single 15 mg dose of midazolam.

Triazolam: concomitant administration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg triazolam does not significantly affect the pharmacokinetic parameters of triazolam.

Nelfinavir: administration of nelfinavir increases serum concentrations of azithromycin. Although dose adjustment of azithromycin is not recommended during concomitant use with nelfinavir, careful monitoring for known adverse effects of azithromycin is warranted.

Sildenafil: no evidence has been obtained that azithromycin (500 mg daily for 3 days) affects AUC or Cmax values of sildenafil or its main circulating metabolite in men.

Trimethoprim/sulfamethoxazole: concomitant administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with 1200 mg azithromycin on day 7 does not significantly affect maximum concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole.

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

Special precautions for use.

Allergic reactions. Serious allergic (rarely fatal) reactions, such as angioedema and anaphylaxis, have been rarely reported with azithromycin. Some of these reactions led to recurrence of symptoms and required prolonged observation and treatment.

Prolonged cardiac repolarization and QT interval.

Prolongation of cardiac repolarization and QT interval, associated with a risk of developing cardiac arrhythmias and torsade de pointes-type paroxysmal ventricular tachycardia, has been observed during treatment with other macrolide antibiotics.

Azithromycin should be administered with caution to patients at increased risk of prolonged cardiac repolarization:

• with congenital or documented QT prolongation;
• who are receiving treatment with other medicinal products that prolong the QT interval, e.g. class IA and III antiarrhythmics, cisapride, and terfenadine;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmias, or severe heart failure.

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

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

Since azithromycin is predominantly eliminated via the liver, the drug should not be used in patients with severe hepatic impairment.

Hepatic function disorders. Liver function tests should be performed if signs of impaired liver function develop, such as rapidly developing asthenia in combination with jaundice, darkening of urine, tendency to bleeding, or hepatic encephalopathy. Myasthenia gravis. Cases of myasthenic syndrome and exacerbation of symptoms of myasthenia gravis have been reported in patients receiving azithromycin. Ergotism has occasionally occurred in patients taking ergot derivatives due to concomitant administration of certain macrolide antibiotics. Data on drug interaction between ergot derivatives and azithromycin are lacking; however, because of the theoretical possibility of ergotism, azithromycin should not be administered concomitantly with ergot derivatives.

Diarrhea. Cases of diarrhea associated with Clostridium difficile, ranging from mild diarrhea to fatal colitis, have been reported with nearly all antibacterial agents, including azithromycin. Antibacterial treatment alters the normal flora of the colon, leading to overgrowth of C. difficile.

Strains of C. difficile producing toxins A and B are associated with increased morbidity and mortality, as these infections may be refractory to antibacterial therapy and may require colectomy.

The possibility of Clostridium difficile-associated diarrhea should be considered in all cases of diarrhea occurring after antibiotic use. Patient history should be carefully evaluated, as Clostridium difficile-associated diarrhea has been reported to occur up to 2 months after administration of antibacterial agents.

In patients with severe renal impairment (creatinine clearance < 10 ml/min), a 33% increase in systemic exposure to azithromycin has been observed.

Use during pregnancy or breastfeeding.

Due to insufficient data on the safety of the drug, azithromycin is not recommended during pregnancy or breastfeeding, except when the expected benefit to the mother outweighs the potential risk to the fetus or infant.

Data on passage of the drug into breast milk are lacking. Azithromycin may be used during breastfeeding only if absolutely necessary and when appropriate alternative treatments are unavailable.

Ability to influence reaction speed when driving or operating machinery.

When driving or operating machinery, consider the possibility of adverse reactions affecting the nervous system, such as dizziness, somnolence, and convulsions.

Method of Administration and Dosage.

Tablets 500 mg should be administered as a single daily dose, independent of food intake. Tablets should be swallowed whole, without chewing. If a dose is missed, it should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

Adults and children with body weight ≥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 once daily). The treatment duration is 3 days.

For vulgaris acne, the recommended total dose of azithromycin is 6 g, to be taken according to the following regimen: 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 migratory erythema, the total dose of azithromycin is 3 g, to be taken as follows: 1 g (2 tablets of 500 mg) on the first day, followed by 500 mg once daily for 5 days.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (2 tablets of 500 mg as a single dose).

Elderly patients.

No dosage adjustment is required for elderly patients.

Since elderly patients may be at risk of cardiac conduction disorders, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmia and torsade de pointes arrhythmia.

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as for patients with normal renal function can 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 administered to patients with severe hepatic impairment. Studies on azithromycin treatment in such patients have not been conducted.

Children.

Zibax tablets are recommended for children with body weight over 45 kg.

Overdose.

Typical symptoms of overdose: reversible hearing impairment, pronounced nausea, abdominal pain, vomiting, diarrhea, and exacerbation of other adverse reactions.

Treatment: in case of overdose, activated charcoal should be administered, and symptomatic therapy should be provided to support vital functions.

Adverse reactions.

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 the available data).

Information on adverse reactions that may be associated with the prevention and treatment of Mycobacterium Avium Complex. 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.

Storage conditions.

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

Packaging. 250 mg tablets: 3 tablets in a blister, 1 blister in a cardboard box;

6 tablets in a blister, 1 blister in a cardboard box.

500 mg tablets: 3 tablets in a blister, 1 blister in a cardboard box;

6 tablets in a blister, 1 blister in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Bafna Pharmaceuticals Ltd. / Bafna Pharmaceuticals Ltd.

Address. 147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu, IN 600052, India / 147, Madhavaram Red Hills Road, Grantlyon Village, Vadakarai, Chennai, Tamil Nadu, IN 600052, India.