Zytrox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZITROX (ZITHROX)

Composition:

Active substance: azithromycin;

1 vial contains azithromycin dihydrate equivalent to azithromycin 500 mg;

Excipients: citric acid monohydrate; sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical properties: lyophilized mass or powder, 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 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 50 S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance.

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

Intravenously administered macrolides are active against Legionella pneumophila. Macrolides are used for 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 isolated strains 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 is such that the efficacy of the drug in treating at least some types of infections is questionable.

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 susceptibility to azithromycin.

Pharmacokinetics.

In patients with community-acquired pneumonia who received daily 1-hour intravenous infusions of 500 mg azithromycin at a concentration of 2 mg/mL, the mean peak concentration Cmax ± SD (standard deviation) was 3.63 ± 1.60 µg/mL, while the trough concentration (at 24 hours) was 0.2 ± 0.15 µg/mL, and AUC24 was 9.6 ± 4.80 µg·h/mL.

In healthy volunteers who received a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL, the mean Cmax ± SD, trough concentration (at 24 hours), and AUC24 were 1.14 ± 0.14 µg/mL, 0.18 ± 0.02 µg/mL, and 8.03 µg·h/mL, respectively.

After oral administration, significantly higher levels of azithromycin were found in various tissues such as lungs, tonsils, or prostate, where azithromycin concentrations were up to 50 times higher than in blood plasma. High concentrations of azithromycin were detected in genital tissues 96 hours after administration of a single 500 mg oral dose of azithromycin.

The mean volume of distribution is approximately 30 L/kg. The elimination half-life is 2–4 days both in blood plasma and tissues.

Metabolism occurs via demethylation, hydroxylation, and hydrolysis.

Plasma clearance is approximately 600 mL/min. The primary route of azithromycin elimination is hepatic. High concentrations of unchanged drug have been found in bile, together with numerous microbiologically inactive metabolites. Approximately 12% of an intravenously administered dose was excreted unchanged in urine within 3 days after administration, with the majority excreted within the first 24 hours.

In patients with severe renal dysfunction (glomerular filtration rate < 10 mL/min), a 33% increase in systemic exposure to azithromycin was observed. No differences in pharmacokinetics were observed in mild to moderate hepatic dysfunction.

Clinical characteristics.

Indications.

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

− community-acquired pneumonia;

− inflammatory pelvic disease.

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

Contraindications.

Azithromycin is contraindicated in patients with hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic, or to any other component of the drug.

Patients with a history of cholestatic jaundice/liver dysfunction associated with prior use of azithromycin.

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

Interaction with other medicinal products and other forms of interactions.

Azithromycin should be administered cautiously in patients receiving other medicinal products that may prolong the QT interval.

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%. 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, co-administration of azithromycin for 5 days with 20 mg cetirizine at steady state showed no evidence of pharmacokinetic interaction or significant changes in QT interval.

Didanosine. Concomitant administration of daily doses of 1200 mg azithromycin with didanosine showed no effect on the pharmacokinetics of didanosine compared to placebo.

Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, with P-glycoprotein substrates such as digoxin and colchicine, has been reported to increase serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with digoxin or colchicine, increased serum concentrations of digoxin should be considered as a possibility.

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, azithromycin increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these findings is unclear.

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. It 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 co-administration of azithromycin with the following drugs, 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 analysis of HMG-CoA reductase inhibition).

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 before azithromycin showed no 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 administered to healthy volunteers. During the post-marketing period, reports have been received regarding 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 prescribing azithromycin to patients receiving oral anticoagulants of the coumarin type.

Cyclosporine. Some related macrolide antibiotics affect the metabolism of cyclosporine. Since no pharmacokinetic or clinical studies on possible interaction between azithromycin and cyclosporine have 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 necessary.

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 not changed when fluconazole was co-administered; however, a clinically insignificant reduction 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 500 mg azithromycin 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. No clinically significant adverse events were observed; therefore, dose adjustment is not necessary.

Rifabutin. Concomitant administration of azithromycin and rifabutin did not affect serum concentrations of either drug. Neutropenia was 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.

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

Terfenadine. Pharmacokinetic studies have not reported interactions between azithromycin and terfenadine. In some cases, the possibility of such an interaction cannot be completely excluded; however, there are no specific data confirming such an interaction.

Theophylline. There are no data on clinically significant pharmacokinetic interactions with concomitant administration of azithromycin and theophylline.

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 trimethoprim/sulfamethoxazole double strength (160 mg/800 mg) for 7 days with azithromycin 1200 mg daily for 7 days showed no significant effect on peak concentrations, overall exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum concentrations of azithromycin were consistent with those observed in other studies.

Special precautions for use.

Allergic reactions. Serious allergic reactions have been reported, including angioedema, anaphylaxis, and dermatological reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens–Johnson syndrome, and toxic epidermal necrolysis in patients treated with azithromycin (see section "Contraindications").

Fatal cases have been reported. Cases of drug reaction with eosinophilia and systemic symptoms (DRESS) have also been observed. Despite successful symptomatic treatment of allergic manifestations, recurrent symptoms occurred in some patients after discontinuation of therapy, without further exposure to azithromycin. These patients required prolonged observation and symptomatic treatment. Currently, the relationship between these episodes and the long elimination half-life of azithromycin, resulting in prolonged antigen exposure, is unknown.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy initiated. Physicians should be aware that allergic symptoms may recur after stopping 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 leading to life-threatening liver failure have been reported during azithromycin therapy. 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 fatigue accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

Azithromycin should be discontinued if hepatic function impairment is detected.

Ergot derivatives. In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with the rapid development of ergotism. There are no data regarding a potential 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.

Diarrhea associated with Clostridium difficile (CDAD), with severity ranging from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including azithromycin. 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. C. difficile strains producing hyper-toxins are associated with increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients with diarrhea following antibiotic use. Careful medical history is necessary, as CDAD has been reported to 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 arrhythmia and ventricular tachyarrhythmia (torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin. Since conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with risk factors for arrhythmia (particularly women and elderly patients), namely:

• patients with congenital or documented QT prolongation;
• 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 such as moxifloxacin and levofloxacin;
• patients with electrolyte disturbances, particularly hypokalemia and hypomagnesemia;
• patients with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Myasthenia gravis. Worsening 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 oropharyngeal streptococcal infections. 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 the medicinal product 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 time frames described in clinical trials involving patients with community-acquired pneumonia and pelvic inflammatory disease.

Azithromycin for injection must be reconstituted and diluted according to the instructions and administered as an intravenous infusion over at least 60 minutes. The drug must not be administered as an intravenous bolus or by intramuscular injection.

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

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies in pregnant women. Studies on reproductive toxicity in animals have shown that azithromycin can cross the placental barrier, but no teratogenic effects were observed. The safety of azithromycin during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

breastfeeding

It has been reported that azithromycin is excreted into human 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 if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

Fertility studies in rats demonstrated a decreased pregnancy rate after administration of azithromycin. 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.

Method of Administration and Dosage.

Adults.

Community-acquired pneumonia: 500 mg intravenously once daily for at least 2 days, followed by oral therapy with 500 mg azithromycin as a single daily dose. Total duration of treatment is 7–10 days. Transition to oral therapy should be carried out at the physician's discretion and according to clinical response.

Pelvic inflammatory disease, including sexually transmitted infections such as endometritis and salpingitis: 500 mg intravenously once daily for 1–2 days, followed by oral therapy with 250 mg azithromycin once daily as a single daily dose. Total duration of treatment is 7 days. Transition to oral therapy should be carried out at the physician's discretion and according to clinical response.

Elderly patients.

Administration of the drug 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 arrhythmias, including torsade de pointes.

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 may be used. 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 drug should not be administered to patients with severe hepatic impairment. Studies on the treatment of such patients with azithromycin have not been conducted.

Method of administration

This medicinal product should be administered as an 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 at concentrations above 2 mg/mL.

The infusion duration of azithromycin must be at least 60 minutes.

The drug must not be administered as a bolus or by intramuscular injection.

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 Zytrox powder. Shake the vial until the powder is completely dissolved. Each 1 mL of the reconstituted concentrate contains 100 mg of azithromycin. The resulting solution should be clear and colorless.

Step 2

Dilute the obtained 5 mL of concentrate 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 can 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 must be visually inspected for particulate matter. 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 administration of azithromycin for the treatment of infections in children have not been established.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed after administration of doses higher than recommended are similar to those seen with usual therapeutic doses and may include diarrhea, nausea, vomiting, and reversible hearing loss.

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

Adverse Reactions

When azithromycin was administered intravenously or orally 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 infusion site was reported. The frequency and severity of these reactions were similar between infusions of 500 mg azithromycin administered 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 pelvic inflammatory disease, the most commonly 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 dosage forms of azithromycin, organized by system organ class and frequency. Adverse reactions identified during the post-marketing period are indicated in italics. Frequency groups are defined according to the following scale: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

Adverse reactions that may be associated with azithromycin, based on data from 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 studies and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release drug formulations:

Shelf life. 2 years.

Storage conditions.

Store at a temperature not exceeding 25°C in the original packaging.

Keep out of the reach of children.

The reconstituted solution can be stored for 24 hours at a temperature not exceeding 25°C.

Incompatibility.

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

Packaging.

1 or 10 vials per cardboard pack.

Prescription status.

Prescription only.

Manufacturer.

Immacul Life Sciences Private Limited.

Manufacturer's address and place of business.

Village Tantewal, Ropar Road, Nalagarh, District Solan, 174101, India.