Azitro Sandoz film-coated tablets 500 mg blister No. 3

Instructions for use Azitro Sandoz film-coated tablets 500 mg blister No. 3

Composition

active ingredient: azithromycin;

1 tablet contains 250 mg or 500 mg of azithromycin in the form of azithromycin dihydrate;

excipients: microcrystalline cellulose, corn starch, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate, sodium lauryl sulfate;

shell: lactose monohydrate, hypromellose, titanium dioxide (E 171), macrogol 4000.

Dosage form

Film-coated tablets.

Main physicochemical properties:

250 mg tablets: oval, film-coated tablets, white or almost white in color, scored on both sides and embossed with “A250” on one side;

500 mg tablets: oval, film-coated tablets, white or almost white in color, scored on one side and embossed with “A500” on one side.

Pharmacotherapeutic group

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

ATX code J01F A10.

Pharmacological properties

Pharmacodynamics

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the introduction of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin is to inhibit bacterial protein synthesis by binding to the 50 S subunit of ribosomes and inhibiting peptide translocation.

Mechanism of resistance.

Complete cross-resistance exists among Streptococcus pneumoniae, group A beta-hemolytic streptococcus, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.

The prevalence of acquired resistance may vary with location and time for the species concerned, so local information on resistance is necessary, especially in the treatment of severe infections. Qualified advice may be sought if the local prevalence of resistance is such that the efficacy of the drug in the treatment of at least some types of infections is questionable.

Spectrum of antimicrobial activity of azithromycin

*Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and has been listed here because of its rare susceptibility to azithromycin.

Pharmacokinetics

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached 2-3 hours after administration.

When taken orally, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that the concentration of azithromycin in tissues is significantly higher (50 times) than in blood plasma, which indicates strong binding of the drug to tissues.

Serum protein binding varies with plasma concentrations and ranges from 12% at 0.5 μg/mL to 52% at 0.05 μg/mL in serum. The apparent volume of distribution at steady state (VVss) was 31.1 L/kg.

The terminal plasma half-life fully reflects the tissue half-life of 2-4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in the urine over the next 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Also found in bile are 10 metabolites formed by N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of the results of liquid chromatography and microbiological analyses showed that the metabolites of azithromycin are not microbiologically active.

Indication

Infections caused by microorganisms sensitive to azithromycin:

ENT infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);

respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);

Skin and soft tissue infections: erythema migrans (initial stage of Lyme disease), erysipelas, impetigo, secondary pyodermatosis, acne vulgaris (common acne) of moderate severity;

sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindication

The use of the drug is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, macrolide/ketolide antibiotics, or to any excipient.

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

Interaction with other medicinal products and other types of interactions

Antacids: In a study of the effect of concomitant administration of antacids on the pharmacokinetics of azithromycin, there was generally no change in bioavailability, although peak plasma concentrations of azithromycin were decreased by approximately 24%. Azithromycin should be taken approximately 2 hours after taking an antacid. Azithromycin and antacids should not be taken simultaneously.

Cetirizine: In healthy volunteers, coadministration of azithromycin with cetirizine 20 mg for 5 days at steady state did not result in any pharmacokinetic interaction or significant changes in the QT interval. Azithromycin should be used with caution in patients receiving other drugs that may prolong the QT interval.

Didanosine: Coadministration of 1200 mg/day of azithromycin with 400 mg/day of didanosine in six HIV-positive patients had no effect on the steady-state pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine (P-glycoprotein substrates). Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, the possibility of increased serum digoxin concentrations should be considered when azithromycin is coadministered with P-glycoprotein substrates such as digoxin. It is important to conduct clinical monitoring during treatment with azithromycin and possibly measure serum digoxin levels.

Zidovudine. Coadministration of azithromycin (single 1000 mg and multiple 1200 mg or 600 mg doses) had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolite. However, azithromycin administration increased the concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of this finding is unclear, but it may be of benefit to patients.

Azithromycin does not significantly interact with the hepatic cytochrome P450 system. It is believed that the drug has no pharmacokinetic interaction with erythromycin and other macrolides. Azithromycin does not induce or inactivate cytochrome P450 through the cytochrome-metabolite complex.

Ergot derivatives. Given the theoretical possibility of ergotism, the simultaneous use of azithromycin with ergot derivatives is not recommended.

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin and drugs involved in cytochrome P450-mediated metabolism.

Atorvastatin: Coadministration of atorvastatin (10 mg daily) and azithromycin (500 mg daily) did not alter plasma concentrations of atorvastatin (based on HMG CoA reductase inhibition assay). However, in a postmarketing study, cases of rhabdomyolysis have been reported in patients receiving azithromycin with statins.

Carbamazepine: In a pharmacokinetic interaction study in healthy volunteers who were concomitantly administered with azithromycin, azithromycin had no significant effect on the plasma levels of carbamazepine or its active metabolites.

Cimetidine: In a pharmacokinetic study of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, taken 2 hours before azithromycin, no changes in the pharmacokinetics of azithromycin were observed.

Oral Coumarin Anticoagulants. In a pharmacokinetic interaction study, azithromycin did not alter the anticoagulant effect of a single 15 mg dose of warfarin administered to healthy volunteers. Postmarketing reports of potentiation of the anticoagulant effect following concomitant administration of azithromycin and oral coumarin anticoagulants have been received. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin anticoagulants.

Cyclosporine. Pharmacokinetic studies conducted in healthy volunteers who received 500 mg/day of azithromycin orally for 3 days, followed by a single dose of 10 mg/kg of cyclosporine orally, demonstrated that there was a significant increase in Cmax and AUC0-5 of cyclosporine. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant administration is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz: Coadministration of a single dose of azithromycin 600 mg and efavirenz 400 mg daily for 7 days did not result in any clinically significant pharmacokinetic interactions.

Indinavir: Co-administration of a single dose of 1200 mg azithromycin had no statistically significant effect on the pharmacokinetics of indinavir administered at 800 mg 3 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, coadministration of azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of a single dose of midazolam 15 mg.

Nelfinavir: Coadministration 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, and no dose adjustment is required.

Rifabutin: Concomitant use of azithromycin and rifabutin did not affect the serum concentrations of these drugs.

Neutropenia has been observed in subjects receiving azithromycin and rifabutin concomitantly. Although neutropenia has been associated with rifabutin use, a causal relationship to concomitant azithromycin use has not been established.

Sildenafil: In normal healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on the AUC and Cmax of sildenafil or its major circulating metabolite.

Terfenadine: No pharmacokinetic interaction has been reported between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely excluded; however, there is no specific data on the existence of such an interaction.

Theophylline: There is no evidence of a clinically significant pharmacokinetic interaction with the simultaneous use of azithromycin and theophylline in healthy volunteers.

Triazolam: In 14 healthy volunteers, coadministration of azithromycin 500 mg on day 1 and 250 mg on day 2 with 0.125 mg of triazolam on day 2 had no significant effect on the pharmacokinetics of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole. Concomitant use of trimethoprim/sulfamethoxazole

(160 mg/800 mg) for 7 days with 1200 mg azithromycin on day 7 had no significant effect on the peak concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. Serum azithromycin concentrations were similar to those observed in other studies.

Other antibiotics: The potential for cross-resistance between azithromycin and other macrolide antibiotics (e.g. erythromycin), as well as lincomycin and clindamycin, should be considered when co-administering them. The concomitant use of multiple drugs from this class is not recommended.

Drugs that prolong the QT interval. Azithromycin should not be administered concomitantly with other drugs that prolong the QT interval (e.g. quinidine, cyclophosphamide, ketoconazole, terfenadine, haloperidol, lithium) (see section "Special warnings and precautions for use").

Application features

Hypersensitivity: As with erythromycin and other macrolide antibiotics, rare serious allergic reactions, including angioedema and anaphylaxis (in isolated cases fatal), dermatological reactions, including acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, toxic epidermal necrolysis (in isolated cases fatal), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), have been reported.

Some of these reactions caused by azithromycin caused recurrent symptoms and required longer observation and treatment.

If an allergic reaction occurs, azithromycin should be discontinued and appropriate therapy should be instituted. Physicians should be aware that symptoms of an allergic reaction may recur after discontinuation of symptomatic therapy.

Hepatic impairment. Since the liver is the primary route of elimination of azithromycin, azithromycin should be used with caution in patients with significant liver disease. Cases of fulminant hepatitis, potentially leading to life-threatening hepatic failure, have been reported with azithromycin. Some patients may have had a history of liver disease or may have been taking other hepatotoxic drugs.

If signs and symptoms of liver dysfunction occur, such as rapidly progressive asthenia associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy, liver function tests/investigations should be performed immediately. Azithromycin should be discontinued if liver function is impaired.

In patients receiving ergot derivatives, ergotism has been precipitated by the concomitant administration of some macrolide antibiotics. There is no data on the possible interaction between ergot derivatives and azithromycin. However, because of the theoretical possibility of ergotism, azithromycin and ergot derivatives should not be taken concomitantly.

Cross-sensitivity: Due to the presence of cross-resistance with erythromycin-resistant Gram-positive strains and most strains of methicillin-resistant staphylococci, the use of azithromycin is not recommended.

Local epidemiology and susceptibility patterns should be taken into account.

Serious infection. Azithromycin is not indicated for the treatment of severe infections where rapid high blood concentrations of the antibiotic are required.

Clostridium difficile-associated diarrhea (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, and has ranged in severity from mild diarrhea to fatal colitis. Antibacterial therapy 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 CDAD.

Hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and require colectomy. This should be considered in all patients with diarrhea following antibiotic use. Careful history-taking is necessary, as diarrhea has been reported to occur 2 months after antibiotic use.

In patients with severe renal impairment (GFR < 10 mL/min), a 33% increase in systemic exposure to azithromycin was observed.

Prolongation of cardiac repolarization and QT interval, which increased the risk of cardiac arrhythmia and torsade de pointes, has been observed with other macrolide antibiotics, including azithromycin. Since the above circumstances may lead to an increased risk of ventricular arrhythmia (including torsade de pointes), which may lead to cardiac arrest, azithromycin should be used with caution in patients with existing proarrhythmic abnormalities (especially women and elderly patients). This group includes patients:

with congenital or registered prolongation of the QT interval;

who are currently being treated with other active substances known to prolong the QT interval, such as antiarrhythmics of classes IA (quinidine and procainamide) and III (dofetilide, amiodarone and sotalol), cisapride and terfenadine, neuroleptics such as pimozide; antidepressants such as citalopram, and fluoroquinolones such as moxifloxacin and levofloxacin;

with electrolyte imbalance, especially in the case of hypokalemia and hypomagnesemia;

with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy (see Adverse Reactions).

Pediatric Population: The safety and efficacy of Mycobacterium avium complex prophylaxis or treatment in children have not been established.

Long-term use: There is no experience regarding the safety and efficacy of long-term use of azithromycin for the above indications. In rapidly recurring infections, treatment with other antibiotics should be considered.

Neurological and psychiatric disorders: Azithromycin should be used with caution in patients with neurological and psychiatric disorders.

Hearing impairment. Macrolide antibiotics have been described to cause hearing impairment. Hearing impairment, deafness, and tinnitus have been reported in some patients receiving azithromycin. Many of these cases were from experimental studies in which azithromycin was used at high doses for long periods of time. However, most of these problems were reversible according to available follow-up reports.

Streptococcal infections. Penicillin is usually the drug of choice for the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, and is also used for prophylaxis in acute rheumatic fever. Azithromycin is generally effective in the treatment of streptococcal oropharyngeal infections; however, there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever.

Other: Safety and effectiveness for the prevention or treatment of Mycobacterium Avium Complex in children have not been established.

Azithromycin contains sodium compounds. Caution should be exercised when used in patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy. There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin has been shown to cross the placental barrier, but no teratogenic effects were observed. The safety of azithromycin has not been established for use during pregnancy. Therefore, azithromycin should be used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding: Azithromycin has been reported to pass into human milk, but adequate and well-controlled clinical studies to characterize the pharmacokinetics of azithromycin excretion into breast milk in lactating women have not been conducted.

However, the use of azithromycin during breastfeeding is possible only in cases where the expected benefit to the mother outweighs the potential risk to the child.

Fertility.

Fertility studies have been performed in rats; pregnancy rates were reduced following administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to influence reaction speed when driving vehicles or other mechanisms

There is no evidence that azithromycin can affect the ability to drive or use other mechanisms, but the possibility of developing adverse reactions such as delirium, hallucinations, dizziness, drowsiness, fainting, and seizures, which may affect the ability to drive or use other mechanisms, should be taken into account.

Method of administration and doses

Azithromycin should be taken as a single daily dose, regardless of meals. Swallow the tablets whole. If a dose is missed, take the missed dose as soon as possible, and the next dose should be taken at 24-hour intervals.

Adults and children weighing ≥ 45 kg.

For infections of the ENT organs, respiratory tract, skin and soft tissues (except chronic migratory erythema), the total dose of azithromycin is 1500 mg (500 mg 1 time per day). The duration of treatment is 3 days.

For acne vulgaris, the recommended total dose of azithromycin is 6 g, which should be taken as follows: 500 mg once daily for 3 days, followed by 500 mg once weekly for 9 weeks. The second week's dose should be taken 7 days after the first tablet, and the next 8 doses should be taken at 7-day intervals.

For erythema migrans, the total dose of azithromycin is 3 g, which should be taken according to the following scheme: 1 g (2 tablets of 500 mg once) on the first day, followed by 500 mg once a day from the 2nd to the 5th day.

For sexually transmitted infections, the recommended dose of azithromycin is 1000 mg (single dose).

Elderly patients.

There is no need to change the dosage in elderly people.

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

Patients with renal impairment.

For patients with mild renal impairment (glomerular filtration rate 10-80 ml/min), the same dosage can be used as for patients with normal renal function. Azithromycin should be administered with caution to patients with severe renal impairment (glomerular filtration rate < 10 ml/min).

Patients with impaired liver function.

Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be used in patients with severe hepatic impairment. Studies related to the treatment of such patients with azithromycin have not been conducted.

Children

The drug in this dosage form should be used in children with a body weight ≥ 45 kg.

For children weighing less than 45 kg, it is recommended to use AZITRO SANDOZ®, powder for oral suspension.

Overdose

Symptoms.

Side effects that develop when taking higher than recommended doses of the drug are similar to those observed with the use of usual therapeutic doses, namely: they may include diarrhea, nausea, vomiting, reversible hearing loss.

Treatment.

In case of overdose, if necessary, administration of activated charcoal and general symptomatic and supportive treatment measures are recommended.

Side effects

Adverse reactions were identified from clinical trials and post-marketing surveillance by system organ class and frequency.

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).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Adverse reactions possibly or probably related to azithromycin based on data obtained during clinical trials and during post-marketing surveillance:

Infections and infestations: Uncommon: candidiasis, oral candidiasis, vaginal infection, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis. Not known: pseudomembranous colitis.

Blood and lymphatic system disorders: Uncommon: leukopenia, neutropenia, eosinophilia. Not known: thrombocytopenia, haemolytic anaemia.

Immune system disorders: Uncommon: angioedema, hypersensitivity reactions. Not known: anaphylactic reaction.

Metabolism and nutrition disorders: Uncommon: anorexia.

Psychiatric disorders: Uncommon: nervousness, insomnia. Rare: agitation. Not known: aggression, restlessness, delirium, hallucinations.

Nervous system disorders: Common: headache. Uncommon: dizziness, drowsiness, paresthesia, dysgeusia. Not known: syncope, convulsions, hypoesthesia, psychomotor hyperactivity, anosmia, parosmia, ageusia, myasthenia gravis.

Hearing and labyrinth disorders: Uncommon: hearing impairment, vertigo. Not known: hearing impairment, including deafness and/or tinnitus.

Cardiac disorders: Uncommon: Palpitations. Not known: Torsade de pointes, arrhythmia including ventricular tachycardia, QT prolongation on ECG.

Vascular disorders: Uncommon: hot flushes. Not known: hypotension.

Respiratory, thoracic and mediastinal disorders: Uncommon: dyspnoea, epistaxis.

Gastrointestinal disorders: Very common: diarrhoea. Common: vomiting, abdominal pain, nausea.

Uncommon: constipation, flatulence, dyspepsia, gastritis, dysphagia, abdominal distension, dry mouth, eructation, mouth ulcers, salivary hypersecretion. Not known: pancreatitis, tongue discolouration.

Hepatobiliary disorders: Uncommon: hepatic dysfunction, cholestatic jaundice. Not known: hepatic failure (rarely fatal), fulminant hepatitis, necrotizing hepatitis, hepatic necrosis.

Skin and subcutaneous tissue disorders: Uncommon: rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis. Rare: photosensitivity, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)*. Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.

* Frequency is estimated by the "rule of three"

Musculoskeletal and connective tissue disorders: Uncommon: osteoarthritis, myalgia, back pain, neck pain. Not known: arthralgia.

Renal and urinary disorders: Uncommon: dysuria, renal pain. Not known: acute renal failure, interstitial nephritis.

Reproductive system and breast disorders: Uncommon: uterine bleeding, testicular disorders.

General disorders and administration site conditions: Uncommon: edema, asthenia, anxiety, fatigue, facial edema, chest pain, malaise, pain, peripheral edema, hyperthermia, post-procedural complications.

Laboratory parameters. Common: decreased white blood cell count, increased eosinophil count, decreased blood bicarbonate, increased basophil count, increased monocyte count, increased neutrophil count. Uncommon: increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood bilirubin, blood urea, blood creatinine; changes in blood potassium, increased alkaline phosphatase, chloride, glucose, platelets; decreased hematocrit; increased bicarbonate, abnormal sodium levels.

Injury and poisoning: Uncommon: Post-procedural complications.

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 surveillance. These adverse reactions differ in type or frequency from those reported with the immediate-release and extended-release formulations:

Metabolism and nutrition disorders: Common: anorexia.

Nervous system disorders: Common: dizziness, headache, paresthesia, dysgeusia.

Rare: hypoesthesia.

On the part of the organs of vision. Often: visual impairment.

Hearing and labyrinth disorders: Common: deafness. Rare: hearing impairment, tinnitus.

Cardiac system: Rare: palpitations.

Gastrointestinal: Very common: diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools.

Hepatobiliary system disorders: Rare: hepatitis.

Skin and subcutaneous tissue disorders: Common: rash, pruritus. Rare: erythema multiforme syndrome.

Stevens-Johnson syndrome, photosensitivity.

Musculoskeletal and connective tissue disorders: Common: arthralgia.

General disorders and administration site conditions: Common: fatigue. Rare: asthenia, malaise.

Expiration date

3 years.

Storage conditions

Store at a temperature not exceeding 25 °C out of the reach of children.

Packaging

250 mg tablets: 6 tablets in a blister; 1 blister in a box.

500 mg tablets: 3 or 6 tablets in a blister; 1 blister in a box.

Vacation category

According to the recipe.

Producer

1. Salutas Pharma GmbH (primary and secondary packaging, batch control, batch release authorization).

2. Sandoz S. R. L. (full-cycle production).

Address

1. Otto-von-Güricke-Allee 1, 39179, Barleben, Germany.

2. 7A Livezeni Street, 540472, Targu Mures, Mures County, Romania.