Azizin®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZICIN® (AZICIN)

Composition:

Active substance: azithromycin;

1 capsule contains azithromycin dihydrate equivalent to azithromycin 250 mg;

Excipients: lactose monohydrate, sodium lauryl sulfate, povidone, magnesium stearate.

Pharmaceutical form. Capsules.

Main physicochemical properties: hard capsules with white cap and body. The capsule contents are white powder or granules.

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 through binding to the 50S ribosomal subunit and prevention of peptide translocation, without affecting polynucleotide synthesis. Resistance to azithromycin may be either primary or secondary. 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.

Antimicrobial spectrum of azithromycin:

*Staphylococcus aureus resistant to methicillin has a very high prevalence of acquired resistance to macrolides and is mentioned here due to rare sensitivity to azithromycin.

Pharmacokinetics.

The bioavailability of azithromycin after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after drug intake. After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that the concentration of azithromycin in tissues is significantly higher (up to 50 times) than in plasma, indicating strong binding of the drug to tissues.

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 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 next 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:

• 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, to other components of the medicinal product, or to any other macrolide or ketolide antibiotic.
• Severe hepatic or renal impairment.
• Concomitant use 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 co-administered with other medicinal products that may prolong the QT interval (see section "Special precautions for use").

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

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

Didanosine. Concomitant administration of 1200 mg/day azithromycin with 400 mg/day didanosine in 6 HIV-positive patients did not affect 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. Concomitant administration of azithromycin (single doses of 1000 mg and multiple doses of 1200 mg or 600 mg) has minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, administration of azithromycin resulted in increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this phenomenon is unknown, but it may be beneficial for patients.

Azithromycin has no significant interaction with the cytochrome P450 hepatic enzyme 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.

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

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin and the following medicinal products, whose metabolism involves the cytochrome P450 system.

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

Cimetidine. In pharmacokinetic studies, no changes in azithromycin pharmacokinetics were observed when a single dose of cimetidine was administered 2 hours prior to 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 coumarin-type anticoagulants. Although a causal relationship has not been established, monitoring of prothrombin time is recommended when azithromycin is prescribed to patients receiving oral coumarin-type anticoagulants.

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 significant increase in Cmax and AUC0-5 of cyclosporine was observed. Therefore, concomitant administration of these medicinal products should be done with caution. If such concomitant use is necessary, cyclosporine levels should be monitored and dosage 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. The overall exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a decrease in azithromycin Cmax (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 has no 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 or pharmacodynamics of a single 15 mg dose of midazolam.

Nelfinavir. Administration of nelfinavir results in increased 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 warranted.

Rifabutin. Concomitant administration of azithromycin and rifabutin does not affect serum concentrations of either medicinal product. 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 or Cmax of sildenafil or its main circulating metabolite.

Terfenadine. During pharmacokinetic studies, no evidence of interaction between azithromycin and terfenadine was reported. Isolated cases were reported where such interaction could not be completely ruled out; however, there was no definitive evidence of such interaction.

Theophylline. No evidence of clinically significant pharmacokinetic interaction was obtained when azithromycin and theophylline were administered concomitantly to healthy volunteers.

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

Trimethoprim/sulfamethoxazole. Concomitant administration of trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with 1200 mg azithromycin on day 7 did not significantly affect the maximum concentrations, overall exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations 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 preclinical findings is unknown.

Special precautions for use.

Allergic reactions. Rare cases of serious allergic reactions, such as angioedema and anaphylaxis, have been reported with azithromycin. Some of these reactions led to recurrent symptoms and required prolonged observation and treatment.

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

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

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 arrhythmia and ventricular fibrillation/torsades 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, treatment should be administered with caution in patients:

• with congenital or documented QT prolongation;
• currently receiving treatment with other medicinal products that prolong the QT interval, such as class IA and III antiarrhythmics, cisapride, and terfenadine;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically relevant bradycardia, arrhythmias, 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 in treating streptococcal infections of the oropharynx; however, there are no data demonstrating the efficacy of azithromycin in preventing acute rheumatic fever.

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

Cases of C. difficile-associated diarrhea 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.

C. difficile produces toxins A and B, which contribute to the development of 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. C. difficile-associated diarrhea should be considered in all patients who develop diarrhea following antibacterial use. Careful medical history is essential, as C. difficile-associated diarrhea has been reported to occur up to two months after administration of antibacterial agents.

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

AZICIN® 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.

There are no adequate data on the use of azithromycin in pregnant women. Reproductive toxicity studies in animals have not shown teratogenic effects of azithromycin on the fetus, although the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit outweighs the potential risk.

breastfeeding.

Azithromycin has been reported to be excreted in breast milk; however, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in 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; a decreased pregnancy rate was observed 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 possibility of adverse reactions such as dizziness, somnolence, and visual disturbances, the medicinal product is not recommended for use when driving or operating machinery.

Method of Administration and Dosage.

AZICIN® should be administered to adults and children with a body weight of more than 45 kg.

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

For infections of the upper and lower respiratory tract, skin and soft tissues (except chronic migrating erythema): 500 mg (2 capsules) once daily for 3 days.

For chronic migrating erythema: on Day 1 – 1 g per day (4 capsules as a single dose), from Day 2 to Day 5 – 500 mg (2 capsules) per day.

For sexually transmitted infections: 1 g (4 capsules) as a single dose. Total course dose – 1 g.

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

In renal impairment: no dosage adjustment is required in patients with mild renal dysfunction (creatinine clearance > 40 mL/min). Azithromycin should be administered with caution to 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.

In elderly patients: dose adjustment is not required.

Children.

AZICIN® in this pharmaceutical form should be administered to children with a body weight of more than 45 kg.

Children with a body weight less than 45 kg should receive 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.

Eye disorders: Visual disturbances.

Ear and labyrinthine disorders: Hearing impairment. Hearing disturbances, including deafness and tinnitus, have been reported in some patients receiving azithromycin. Most of these cases occurred during experimental studies in which azithromycin was administered in high doses over a prolonged period. According to available post-marketing surveillance reports, most of these events were reversible.

Respiratory, thoracic and mediastinal disorders: Dyspnoea.

Gastrointestinal disorders: Nausea, vomiting, diarrhoea, abdominal discomfort (discomfort, pain, spasms), loose stools, flatulence, dyspepsia, gastritis, anorexia, constipation, tongue discoloration, pancreatitis.

Hepatobiliary disorders: Hepatitis, cholestatic jaundice, including altered liver function test results, severe hepatitis, hepatic dysfunction, liver failure, fulminant hepatitis, necrotic hepatitis.

Renal and urinary disorders: Interstitial nephritis, acute renal failure.

Nervous system disorders: Dizziness/vertigo, hypesthesia, somnolence, syncope, headache, convulsions (have been observed with other macrolide antibiotics as well), distortion or loss of taste and smell, ageusia, parosmia, paraesthesia, asthenia, neurosis, lethargy, insomnia, sleep disturbances, myasthenia gravis.

Psychiatric disorders: Aggressiveness, psychomotor hyperactivity, anxiety, nervousness, agitation.

Cardiac disorders: Palpitations, chest pain, paroxysmal ventricular tachycardia of the "torsades de pointes" type, ventricular arrhythmias, including ventricular tachycardia (have been observed with other macrolide antibiotics as well); QT interval prolongation, ventricular fibrillation, hypotension.

Blood and lymphatic system disorders: Neutropenia, leucopenia, thrombocytopenia, haemolytic anaemia.

Infections and infestations: Oral candidiasis, vaginal infections, pseudomembranous colitis.

Skin and subcutaneous tissue disorders: Allergic reactions, including pruritus, hyperaemia, rash, allergic dermatitis, conjunctivitis, angioneurotic oedema, urticaria, photosensitivity; exanthema, serious skin reactions, namely: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: Arthralgia.

Reproductive system and breast disorders: Vaginitis.

Systemic disorders: Anaphylaxis, oedema, candidiasis, angioedema, anaphylactoid reactions.

General disorders: Increased fatigue, weakness, chills.

Laboratory findings: Lymphopenia, eosinophilia, decreased blood bicarbonate levels, increased plasma levels of aspartate aminotransferase, alanine aminotransferase, bilirubin, urea, creatinine, and changes in plasma potassium levels.

Shelf life.

3 years.

Storage conditions.

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

Incompatibility.

Pharmaceutically incompatible with heparin.

Packaging.

6 capsules in a blister pack; 1 blister pack per carton.

Prescription status.

Prescription only.

Manufacturer.

JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's name and address of the place of business.

13, Boryspylska Street, Kyiv, 02093, Ukraine.