Azithromycin-vista

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Azithromycin-Vista (Azithromycin-Vista)

Composition:

Active substance: azithromycin;

1 vial contains azithromycin dihydrate equivalent to 500 mg of azithromycin;

Excipients: citric acid, sodium hydroxide.

Pharmaceutical form. Powder for solution for infusion.

Main physicochemical properties: lyophilized powder ranging from white to almost white.

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

ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by the insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis through binding to the 50S ribosomal subunit and suppression of peptide translocation. Mechanism of resistance.

Resistance to azithromycin may be inherited or acquired. Complete cross-resistance between erythromycin, azithromycin, other macrolides, and lincosamides exists in Streptococcus pneumoniae, beta-hemolytic group A streptococci, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA).

Macrolides administered intravenously are active against Legionella pneumophila. Macrolides are used in the treatment of infections caused by Campylobacter jejuni. Azithromycin is indicated for the treatment of infections caused by S. typhi and Shigella spp. The prevalence of acquired resistance among these organisms may vary depending on geographical location and time; therefore, local information on resistance patterns is necessary, especially when treating severe infections. Expert advice should be sought if local resistance prevalence renders the efficacy of the medicinal product questionable for at least some types of infections.

Antimicrobial spectrum 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.

Absorption.

The bioavailability of azithromycin after oral administration is approximately 37%. Peak plasma concentration is reached within 2–3 hours after drug intake.

Distribution.

Orally administered azithromycin is well distributed throughout the body. Pharmacokinetic studies have demonstrated that tissue concentrations of azithromycin are significantly higher (up to 50 times) than those in plasma, indicating strong tissue binding of azithromycin.

In animal studies, high concentrations of azithromycin have been detected in phagocytes. It has also been established that during active phagocytosis, azithromycin is released from inactive phagocytes in high concentrations. In animal models, this results in high concentrations of azithromycin accumulating at the site of infection. Pharmacokinetic studies have shown that azithromycin concentrations in target tissues such as lungs, tonsils, and prostate exceed the MIC90 (minimum inhibitory concentration) for potential pathogens after a single 500 mg dose of azithromycin. High concentrations of azithromycin have been detected in female genital tract tissues 96 hours after a single oral dose of 500 mg.

Elimination.

The elimination half-life from plasma is similar to the half-life from tissues and ranges from 2 to 4 days. Approximately 12% of an intravenously administered dose of azithromycin is excreted unchanged in urine over the following 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites have also been detected in bile, formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Comparison of results from liquid chromatography and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Pharmacokinetics in special patient groups.

Elderly individuals.

In elderly volunteers (age > 65 years), a slight increase in AUC values was observed after 5 days of treatment compared to younger volunteers (age < 40 years). This increase is not considered clinically significant; therefore, dose adjustment of azithromycin is not required.

Patients with renal impairment.

After administration of a single 1 g dose, the pharmacokinetics of azithromycin in patients with mild to moderate renal impairment (creatinine clearance 10–80 mL/min) are not altered. Statistically significant differences were observed in patients with severe renal impairment (creatinine clearance < 10 mL/min) compared to patients with normal renal function: AUC0–120 8.8 μg × h/mL vs. 11.7 μg × h/mL, Cmax 1.0 μg/mL vs. 1.6 μg/mL, and renal clearance (CLr) 2.3 mL/min/kg vs. 0.2 mL/min/kg.

Hepatic impairment.

There are no data indicating significant changes in the pharmacokinetics of azithromycin in serum of patients with mild (Class A) or moderate (Class B) hepatic dysfunction compared to patients with normal liver function. In these patients, renal clearance of azithromycin is increased, likely to compensate for reduced hepatic clearance.

Clinical characteristics.

Indications.

Infections requiring initial intravenous therapy caused by microorganisms sensitive to azithromycin:

− Community-acquired pneumonia;

− Pelvic inflammatory disease.

To reduce the risk of developing antibiotic resistance and to maintain the effectiveness of azithromycin and other antibacterial agents, the medicinal product Azithromycin-Vista should be used only for the treatment of infections caused by microorganisms susceptible to the drug.

Contraindications.

• Hypersensitivity to azithromycin, erythromycin, to any macrolide or ketolide antibiotic, or to any other component of the medicinal product.
• History of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
• Concomitant administration with cisapride.

Interaction with other medicinal products and other forms of interaction.

Azithromycin should be administered cautiously with other medicinal products that may prolong the QT interval.

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%. Patients should not take azithromycin and antacids simultaneously. Oral administration of antacids does not affect the distribution of intravenously administered azithromycin.

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. When daily doses of 1200 mg azithromycin were administered concomitantly with didanosine, no effect on the pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine. It has been reported that concomitant administration of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, may lead to increased serum levels of P-glycoprotein substrates. Therefore, if azithromycin and P-glycoprotein substrates such as digoxin are administered concomitantly, increased serum concentrations of digoxin may occur. Clinical monitoring of serum digoxin levels is required during and after azithromycin treatment.

Zidovudine. Single doses of 1000 mg and 1200 mg or multiple doses of 600 mg azithromycin did not affect the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, administration of azithromycin increased the concentration of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is not established.

Ergot derivatives. Due to the theoretical possibility of ergotism, concomitant administration of azithromycin with ergot derivatives is not recommended.

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

Pharmacokinetic studies have been conducted on the concomitant use of azithromycin and the following medicinal products, whose metabolism is largely mediated by cytochrome P450.

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. 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, a single dose of cimetidine administered 2 hours prior to azithromycin did not result in any changes in the pharmacokinetics of 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 in healthy volunteers. However, post-marketing reports have described potentiation of the anticoagulant effect 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 azithromycin is prescribed to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. Some related macrolide antibiotics affect cyclosporine metabolism. Since pharmacokinetic and clinical studies on the potential interaction between azithromycin and cyclosporine have not been conducted, the therapeutic situation should be carefully evaluated before prescribing concomitant use of these drugs. If combination therapy is considered justified, careful monitoring of cyclosporine levels and appropriate dose adjustments are required.

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 interaction.

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 coadministered; however, a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

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. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect 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.

Nelfinavir. Concomitant administration of azithromycin (1200 mg) and nelfinavir at steady-state concentrations (750 mg three times daily) results in increased azithromycin concentrations. Careful monitoring for adverse reactions such as hepatic function impairment and hearing disturbances is required.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect serum concentrations of either drug. Neutropenia was observed in patients receiving both azithromycin and rifabutin. Although neutropenia was associated with rifabutin use, a causal relationship with concomitant azithromycin administration has not been established.

Sildenafil. In healthy male volunteers, no evidence was found that azithromycin (500 mg daily for 3 days) affects the AUC or Cmax of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. In some cases, such an interaction cannot be completely excluded, but there are no specific data confirming such an interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interaction between azithromycin and theophylline when administered concomitantly.

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam did not significantly affect the 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 the maximum concentration, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole.

Serum azithromycin concentrations were consistent with those observed in other studies.

Cisapride. Cisapride is metabolized in the liver by the CYP3A4 enzyme. Concomitant administration of cisapride with macrolides may increase the risk of cardiac arrhythmia (QT interval prolongation, torsades de pointes), as macrolides inhibit the CYP3A4 enzyme.

Special precautions for use.

Hypersensitivity

Serious allergic reactions, including angioedema, anaphylaxis, and dermatological reactions such as acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, have been reported in patients receiving azithromycin therapy. Fatal cases have been reported. Cases of drug reactions with eosinophilia and systemic symptoms (DRESS) have also been reported. Despite initial symptomatic treatment of azithromycin allergy, recurrence of symptoms shortly after discontinuation of therapy has been observed in some patients, even without further exposure to azithromycin. Such patients required prolonged monitoring and symptomatic treatment. The relationship of these episodes to the tissue half-life of azithromycin and prolonged antigenic exposure remains unknown.

If an allergic reaction occurs, the drug should be discontinued immediately and symptomatic therapy initiated. It should be noted that allergic symptoms may recur after discontinuation of symptomatic treatment.

Hepatic function impairment. Since the liver is the primary route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis, cholestatic jaundice, and hepatic necrosis leading to life-threatening liver failure have been reported with azithromycin use. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products. Liver function tests should be performed if symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy. If hepatic dysfunction is detected, azithromycin should be discontinued.

Ergot derivatives. In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with rapid development of ergotism. There are no data on a possible interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

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

Diarrhea associated with Clostridium difficile (CDAD), ranging in severity from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including azithromycin. 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. Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients who develop diarrhea following antibiotic use. A careful medical history is necessary, as CDAD may occur up to two months after administration of antibacterial agents.

Renal function impairment. In patients with severe renal dysfunction (glomerular filtration rate < 10 mL/min), systemic exposure to azithromycin increased by 33%.

Prolongation of cardiac repolarization and QT interval, which increases the risk of cardiac arrhythmias and ventricular tachycardia/ventricular fibrillation (torsade de pointes), has been observed with 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 used with caution in patients with risk factors for arrhythmias (particularly women and elderly patients), including:

• patients with congenital or documented acquired QT prolongation, or history of ventricular tachycardia/ventricular fibrillation (torsade de pointes);
• patients 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 (e.g., moxifloxacin and levofloxacin);
• patients with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• patients with clinically significant bradycardia, cardiac 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 the treatment of streptococcal pharyngitis. However, there are no data demonstrating the efficacy of azithromycin for the prevention of rheumatic fever. An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to contribute to the infection.

The safety and efficacy of azithromycin for the prevention or treatment of Mycobacterium avium complex in children have not been established.

The safety and efficacy of intravenous azithromycin have been evaluated only within the timeframes described in clinical trials, in patients with community-acquired pneumonia and pelvic inflammatory disease. Azithromycin for injection must be reconstituted and diluted according to the instructions and administered by intravenous infusion over at least 60 minutes. The medicinal product must not be administered as an intravenous bolus or by intramuscular injection.

Important information on excipients.

This medicinal product contains approximately 188 mg of sodium (as hydroxide) per vial. This should be taken into account when prescribing the medicinal product to patients on a controlled sodium diet.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate and well-controlled studies in pregnant women. Reproductive toxicity studies in animals have shown that azithromycin crosses the placental barrier, but no teratogenic effects were observed. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding period.

Azithromycin has been reported to pass into human breast milk, but appropriate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Therefore, azithromycin may be used during breastfeeding only if the expected benefit to the mother outweighs the potential risk to the infant. A decision should be made whether to discontinue breastfeeding or to withhold/stop the medicinal product.

Fertility.

Fertility studies in rats demonstrated a reduced pregnancy rate following azithromycin administration. The relevance of these findings to humans is unknown.

Ability to affect reaction speed when driving or operating machinery.

There is no evidence that azithromycin impairs the ability to drive or operate machinery. However, the possibility of adverse reactions such as dizziness, somnolence, and visual disturbances should be considered.

Administration and Dosage

Adults.

Community-acquired pneumonia. 500 mg intravenously once daily for at least 2 days, followed by continuation of therapy orally with 500 mg of azithromycin as a single daily dose for 7–10 days. The switch to oral therapy should be made at the physician's discretion and according to clinical response.

Pelvic inflammatory disease. 500 mg intravenously once daily for 1–2 days, followed by continuation of therapy orally with 250 mg of azithromycin once daily as a single daily dose for 7 days. The switch to oral therapy should be made at the physician's discretion and according to clinical response.

Elderly patients.

Administration of the medicinal product to elderly patients does not require dose adjustment. Since elderly patients may have 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 may 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 hepatic impairment.

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

Administration method.

This medicinal product should be administered by intravenous infusion over 3 hours at a concentration of 1 mg/mL or over 1 hour at a concentration of 2 mg/mL. Higher concentrations should be avoided, as local infusion site reactions were observed in all subjects in clinical trials who received infusions of the drug at concentrations exceeding 2 mg/mL.

The infusion duration of azithromycin should be no less than 60 minutes.

Azithromycin-Vista must not be administered as a bolus injection or intramuscularly.

Preparation of infusion solution.

Step 1.

Prepare the primary concentrate for infusion solution by adding 4.8 mL of sterile water for injection to the vial containing the Azithromycin-Vista powder. Shake the vial until the powder is completely dissolved. 1 mL of the reconstituted concentrate for infusion solution contains 100 mg of azithromycin. The resulting solution should be clear and colorless.

Step 2.

Dilute the obtained 5 mL of concentrate for infusion with a compatible infusion solution to obtain the final infusion solution containing azithromycin at a concentration of 1 mg/mL or 2 mg/mL (see Table 1 below).

Table 1

Preparation of the final infusion solution

The concentrate for infusion solution may be diluted with:

0.9 % sodium chloride solution;

0.45 % sodium chloride solution;

5 % aqueous solution of d-glucose;

Ringer's solution;

5 % d-glucose solution in 0.3 % sodium chloride solution;

5 % d-glucose solution in 0.45 % sodium chloride solution.

Before administration, the reconstituted and diluted solutions should be visually inspected for the presence of particles. Only clear, particle-free solutions should be used.

If the solution contains particles, it must be discarded. Unused medicinal product or waste material must be disposed of in accordance with local requirements.

Children.

The safety and efficacy of intravenous azithromycin for the treatment of infections in children have not been established.

Overdose.

Symptoms. Clinical experience with azithromycin indicates that adverse effects observed following ingestion of doses higher than recommended are similar to those seen with usual therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss.
Treatment. In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive measures are recommended.

Adverse reactions.

When intravenous or oral azithromycin was used in the treatment of community-acquired pneumonia, the most commonly reported adverse events were diarrhea/loose stools, nausea, stomach pain, and vomiting. With intravenous administration of azithromycin, local inflammation/pain at the injection site was reported. The frequency and severity of these reactions were similar to those observed during infusion of 500 mg azithromycin over 1 hour (2 mg/mL as a 250 mL infusion) or over 3 hours (1 mg/mL as a 500 mL infusion).

In adult women receiving intravenous or oral azithromycin for the treatment of pelvic inflammatory disease, the most frequently reported adverse events were diarrhea, nausea, vaginitis, stomach pain, anorexia, rash, and pruritus. When azithromycin was administered concomitantly with metronidazole, the majority of women experienced adverse events such as nausea, stomach pain, vomiting, infusion site irritation, stomatitis, dizziness, or dyspnea.

The table below lists adverse reactions identified from clinical trials and post-marketing surveillance for all azithromycin dosage forms, organized by system organ class and frequency. Adverse reactions identified during the post-marketing period are indicated in italics. Frequency groups were defined using 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 available data). Within each frequency category, adverse events are listed in order of decreasing severity.

Table 2

Adverse reactions that may be associated with the use of azithromycin, identified from data obtained during clinical trials and post-marketing surveillance.

Information on adverse reactions that may be 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 use of immediate-release and extended-release dosage forms (see Table 3).

Table 3

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of a medicinal product is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Storage conditions.

No special storage conditions are required for this medicinal product. Keep out of reach and sight of children.

The reconstituted solution can be stored for 24 hours at a temperature not exceeding 30 °C or for 72 hours at 2–8 °C.

Incompatibilities.

Use only the solvents specified in the section "Directions for use and dosage".

Packaging.

500 mg in a vial, 1 vial in a carton.

Prescription status.

Prescription only.

Manufacturer.

ANFARM HELLAS S.A / ANFARM HELLAS S.A

Address of the manufacturer and location of the site of operation.

61st km Nat. Rd. Athens-Lamia, Schimatari Viotias 32009, Greece /
61st km Nat. Rd. Athens-Lamia, Schimatari Viotias 32009, Greece