Aziaar

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

Composition:

Active substance: azithromycin;

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

Excipients: citric acid monohydrate; sodium hydroxide.

Pharmaceutical form. Lyophilisate for solution for infusion.

Main physicochemical characteristics: lyophilized solid 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 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 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-haemolytic group A streptococci, 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 to treat 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 data on resistance patterns are 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

*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.

In patients with community-acquired pneumonia receiving daily 500 mg intravenous infusions of azithromycin over 1 hour at a concentration of 2 mg/mL, the mean maximum plasma 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 receiving a 500 mg intravenous infusion of azithromycin over 3 hours at a concentration of 1 mg/mL, the mean Cmax ± SD, trough concentration
(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 plasma. High concentrations of azithromycin were detected in genital tissue 96 hours after administration of a single 500 mg oral dose.

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

Metabolism occurs via demethylation, hydroxylation, and hydrolysis.

Plasma clearance is approximately 600 mL/min. The primary route of elimination of azithromycin is via the liver. High concentrations of unchanged drug were found in bile together with numerous microbiologically inactive metabolites. Approximately 12% of the 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;

− pelvic inflammatory disease.

Contraindications.

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

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

Interaction with other medicinal products and other forms of interaction.

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

Antacids. In studies evaluating the effect of concomitant antacid administration on the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although peak plasma 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, no pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days together with 20 mg cetirizine at steady state.

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

Digoxin. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is co-administered with digoxin, the potential for increased serum digoxin concentrations should be considered.

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 the concentration 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. The drug is not considered to have the pharmacokinetic drug interactions commonly associated with erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 via a cytochrome-metabolite complex.

Pharmacokinetic studies have been conducted on the co-administration of azithromycin with 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 showed no 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 had no effect on 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. 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 prescribing azithromycin 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 co-administering these medicinal products. If combination therapy is considered justified, close 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 unchanged when co-administered with fluconazole, although 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 had no significant effect on 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) resulted 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 has been 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 AUC or Cmax values of sildenafil or its main circulating metabolite.

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

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

Triazolam. Concomitant administration of azithromycin (500 mg on Day 1 and 250 mg on Day 2) with triazolam (0.125 mg) 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 the maximum concentrations, total 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. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions, including angioedema and anaphylaxis (in rare cases resulting in death), have been reported. Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged observation and 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 have been reported during azithromycin therapy, leading to life-threatening liver failure. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

Liver function tests should be performed if symptoms of hepatic dysfunction develop, such as rapidly developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy.

Azithromycin therapy should be discontinued if hepatic impairment is detected.

Ergot derivatives. In patients taking ergot derivatives, concomitant use of certain macrolide antibiotics may lead to 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, patients should be monitored for signs of superinfection caused by non-susceptible organisms, including fungi.

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 flora of the colon, leading to overgrowth of C. difficile.

C. difficile produces toxins A and B, which contribute to the development of CDAD. Strains of C. difficile that produce hyper-toxins have been linked to increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use. A 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, increasing 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 who have risk factors for arrhythmia (particularly women and elderly patients), namely:

• patients with congenital or documented acquired prolongation of the QT interval;
• patients currently receiving treatment with other medicinal substances known to prolong the QT interval, such as class IA (quinidine, procainamide) and class III antiarrhythmics (dofetilide, amiodarone, sotalol), cisapride, terfenadine, neuroleptics such as pimozide, antidepressants (such as citalopram), and fluoroquinolones such as 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 oropharyngeal streptococcal infections. However, there are no data demonstrating the efficacy of azithromycin in the prevention of rheumatic fever. An antimicrobial agent with anaerobic activity should be used in combination with azithromycin if anaerobic microorganisms are suspected to be involved in 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 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-controlled 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 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

Azithromycin has been reported to be 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 only if the expected benefit to the mother outweighs the potential risk to the infant.

Fertility

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

Ability to affect the speed of reactions 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 once daily as a single daily dose. Total duration of treatment is 7–10 days. Transition to oral therapy should be performed at the physician's discretion and according to clinical response.

Pelvic inflammatory disease, including genital tract 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 performed at the physician's discretion and according to clinical response.

Elderly patients.

Dosage adjustment is not required for elderly patients.

Since elderly patients may have disturbances in cardiac conduction, caution is recommended when administering azithromycin due to the risk of developing cardiac arrhythmias, including torsade de pointes.

Patients with renal impairment.

For patients with mild to moderate 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 in patients with severe renal impairment (glomerular filtration rate < 10 mL/min).

Patients with hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to patients with severe hepatic impairment. Studies on the use of azithromycin in such patients 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 with concentrations exceeding 2 mg/mL.

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

Azithromycin must not be administered as an intravenous bolus or by intramuscular injection.

PREPARATION OF INFUSION SOLUTION

Step 1

Prepare the initial concentrate for infusion solution by adding 4.8 mL of sterile water for injection to the vial containing Aziaar 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 prepare 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 using:

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 the presence of particles. Only clear solutions free from particles should be used. If the solution contains particles, it must be discarded. Unused medicinal product must be destroyed. Any unused medicinal product or waste material should 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 associated with doses higher than recommended are similar to those observed 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 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 infusion site was reported. The frequency and severity of these reactions were similar to those observed with 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 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 formulations of azithromycin, classified by organ system and frequency. Adverse reactions reported during the post-marketing period are indicated in italic. Frequency categories are defined using the following scale: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency category, adverse events are listed in order of decreasing severity.

Adverse reactions possibly related to 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 trials and post-marketing observations. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release medicinal products:

Shelf life. 2 years.

Storage conditions.

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

Keep out of the reach of children.

The reconstituted solution is chemically and physically stable for 24 hours when stored at a temperature not exceeding 25 °C, or for 7 days if stored at a temperature between 2 °C and 8 °C. From a microbiological standpoint, the reconstituted solution should be used immediately.

Incompatibility.

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

Packaging.

Glass vials stoppered with a rubber plug and sealed with an aluminium crimp cap fitted with a flip-off cap providing a tamper-evident seal.

10 vials per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

IMMACULE LIFESCIENCES PRIVATE LIMITED
IMMACULE LIFESCIENCES PRIVATE LIMITED

Address of the manufacturer and location of its operations.

Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, 174101, India
Village Thanthewal, Ropar Road, Nalagarh, District Solan, Himachal Pradesh, In 174101, India

Marketing Authorisation Holder.

M.BIOTECH LIMITED
M.BIOTECH LIMITED

Address of the Marketing Authorisation Holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom
Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom