Azitro sandoz®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZITHROSANDOZ®

Composition:

Active substance: azithromycin;

5 ml of suspension contain 100 mg or 200 mg of azithromycin in the form of azithromycin dihydrate;

Excipients: refined fine crystalline sucrose, powdered sucrose, xanthan gum, hydroxypropyl cellulose, anhydrous trisodium phosphate, colloidal anhydrous silica, aspartame (E 951), banana flavor, vanilla cream flavor, cherry flavor.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or almost white powder.

Pharmacotherapeutic group.

Antibacterials for systemic use. Macrolides. 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 50S ribosomal subunit and suppression of peptide translocation. This typically results in a bacteriostatic effect.

Pharmacokinetic/pharmacodynamic (PK/PD) interactions

Efficacy is strongly dependent on the ratio of the area under the concentration-time curve (AUC) to the minimum inhibitory concentration (MIC) of the pathogen.

Mechanism of resistance

Resistance to azithromycin may be intrinsic or acquired and is associated with three main mechanisms: alteration of the target site, alteration of antibiotic transport, and modification of the antibiotic.

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

Susceptibility testing breakpoints

The scale of microbial susceptibility to azithromycin (MIC, mg/L), established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (Clinical breakpoints v.8.0, 01.01.2018), is as follows:

Pathogen	Susceptible	Resistant
Staphylococcus spp.	≤ 1a mg/L	> 2a mg/L
Streptococcus spp. (groups A, B, C, G)	≤ 0.25a mg/L	> 0.5a mg/L
Streptococcus pneumoniae	≤ 0.25a mg/L	> 0.5a mg/L
Haemophilus influenzae	≤ 0.12b mg/L	> 4b mg/L
Moraxella catarrhalis	≤ 0.25a mg/L	> 0.5a mg/L
Neisseria gonorrhoeae	≤ 0.25 mg/L	> 0.5 mg/L
Campylobacter jejuni and coli	Notec	Notec
Kingella kingae	0.25d	0.25d
Viridans group streptococci	IE	IE
PK-PD (non-species-related MIC breakpoints)	IE	IE

a Erythromycin can be used to predict susceptibility to azithromycin, clarithromycin, and roxithromycin.

b Clinical data on macrolide efficacy in respiratory tract infections caused by H. influenzae are conflicting due to a high rate of spontaneous recovery. If testing macrolide efficacy against these infections is necessary, epidemiological cut-off values (ECOFFs) should be used to identify strains with acquired resistance. ECOFF data for each agent are as follows: azithromycin – 4 mg/L, clarithromycin – 32 mg/L, erythromycin – 16 mg/L, and telithromycin – 8 mg/L. Insufficient data are available to establish an ECOFF for roxithromycin.

c Erythromycin can be used to predict susceptibility to azithromycin and clarithromycin.

d Susceptibility may be inferred from erythromycin susceptibility data.

IE indicates insufficient data to determine whether an organism or group of organisms is susceptible to azithromycin. An MIC is reported, but without a corresponding susceptibility category – S (susceptible), I (intermediate), or R (resistant).

Resistance

The prevalence of acquired resistance may vary geographically and over time for specific species; therefore, local resistance data are essential, particularly when treating severe infections. Expert advice should be sought if local resistance prevalence renders the benefit of azithromycin questionable. In cases of severe infection or treatment failure, microbiological diagnosis with identification of the pathogen and determination of its susceptibility to azithromycin is required.

Antimicrobial spectrum of azithromycin:

Organisms usually susceptible to azithromycin:

Aerobic Gram-negative bacteria: Haemophilus influenzae ⃰, Haemophilus parainfluenzae, Moraxella catarrhalis ⃰;

Other bacteria: Chlamydia trachomatis, Chlamydophila pneumoniae, Legionella pneumophila, Mycobacterium avium, Mycoplasma pneumoniae.

Species for which acquired resistance may be a problem:

Aerobic Gram-positive bacteria: Staphylococcus aureus ⃰, Streptococcus agalactiae, Streptococcus pneumoniae ⃰, Streptococcus pyogenes ⃰;

Other bacteria: Ureaplasma urealyticum.

Microorganisms with intrinsic resistance:

Aerobic Gram-positive bacteria: Enterococcus faecalis, MRSA, MRSE (methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis), Streptococcus pneumoniae ⃰ (penicillin-resistant);

Aerobic Gram-negative bacteria: Escherichia coli, Klebsiella spp., Pseudomonas aeruginosa;

Anaerobic Gram-negative bacteria: Bacteroides fragilis-group.

⃰ Clinical efficacy is demonstrated against susceptible microorganisms when used according to approved clinical indications.

Pharmacokinetics.

Absorption

Maximum serum concentration (Cmax) of the drug is achieved within 2–3 hours after administration. The terminal plasma elimination half-life fully reflects tissue elimination half-life over 2–4 days. In elderly patients (>65 years), slightly higher AUC values were observed after five days of treatment compared to individuals under 40 years of age. The clinical significance is minimal, and no dose adjustment is necessary.

Animal studies have shown high concentrations of azithromycin in phagocytes, with even higher concentrations released during active phagocytosis compared to non-stimulated phagocytes. In animal models, this led to increased azithromycin concentrations at the site of infection.

Non-linearity

Study data indicate non-linear pharmacokinetics of azithromycin within the therapeutic dose range.

Distribution

Tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, indicating extensive tissue binding. In target tissues such as lungs, tonsils, and prostate gland, concentrations exceed the MIC90 of expected pathogens after a single 500 mg dose.

Protein binding in serum varies with plasma concentration, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum. The mean steady-state volume of distribution (Vss) is 31.1 L/kg.

Elimination

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following 3 days, mostly within the first 24 hours. After oral administration, azithromycin is primarily excreted unchanged via bile. Particularly high concentrations of unchanged azithromycin have been detected in human bile, along with 10 metabolites formed via N- and O-demethylation, hydroxylation of the desosamine and aglycone rings, and cleavage of the cladinose conjugate. Relevant studies indicate that azithromycin metabolites are not microbiologically active.

Pharmacokinetic/pharmacodynamic relationship

Renal impairment

In patients with glomerular filtration rates between 10 and 80 mL/min, pharmacokinetic parameters after a single oral 1 g dose of azithromycin were unchanged. In patients with glomerular filtration rates <10 mL/min, statistically significant differences were observed in AUC0–120 (8.8 µg·h/mL vs. 11.7 µg·h/mL), Cmax (1.0 µg/mL vs. 1.6 µg/mL), and CLr (renal clearance) (2.3 mL/min/kg vs. 0.2 mL/min/kg) compared to patients with normal renal function.

Hepatic impairment

In patients with mild to moderate hepatic impairment, no data indicate altered azithromycin pharmacokinetics in serum compared to patients with normal liver function. In these patients, urinary excretion of azithromycin increases, possibly to compensate for reduced hepatic clearance.

Clinical characteristics.

Indications.

For 100 mg/5 ml and 200 mg/5 ml dosage forms

Infections caused by microorganisms sensitive to azithromycin:

• Otorhinolaryngological infections (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• Respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• Skin and soft tissue infections: erythema migrans (early stage of Lyme disease), erysipelas, impetigo, secondary pyoderma.

For 200 mg/5 ml dosage form

• Sexually transmitted infections: uncomplicated urethritis/cervicitis caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or any other macrolide or ketolide antibiotic, as well as to any other component of the drug. Severe hepatic impairment. Due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

Interaction with other medicinal products and other forms of interaction.

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

Cetirizine. Concomitant administration of azithromycin and 20 mg cetirizine for 5 days did not result in pharmacokinetic interaction at steady state, but significantly altered the QT interval.

Didanosine. Concurrent administration of 1200 mg daily azithromycin and 400 mg daily didanosine in 6 HIV-positive patients did not affect steady-state pharmacokinetics of didanosine.

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

Zidovudine. 1000 mg azithromycin as a single dose and 600 mg or 1200 mg azithromycin as multiple doses did not affect the pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin administration caused an increase in the concentration of phosphorylated zidovudine in peripheral blood mononuclear cells. The clinical significance of these findings is unclear, but may be beneficial for patients.

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

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

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

Ergotamine derivatives. Due to the theoretical possibility of ergotism, concomitant use of azithromycin with ergotamine derivatives should be avoided.

Astemizole, alfentanil. There are no available data on their interaction with azithromycin. However, caution is required when co-administering them with azithromycin due to known interactions: enhanced effects of astemizole and alfentanil when co-administered with the macrolide antibiotic erythromycin.

Atorvastatin. Concomitant administration of 10 mg/day atorvastatin and 500 mg/day azithromycin did not affect atorvastatin plasma concentration (based on HMG-CoA reductase inhibition analysis). However, cases of rhabdomyolysis have been reported in the post-marketing period in patients taking azithromycin with statins.

Carbamazepine. In a pharmacokinetic interaction study in healthy volunteers, azithromycin did not significantly affect plasma levels of carbamazepine or its active metabolites.

Cisapride. Cisapride is metabolized in the liver by the CYP 3A4 enzyme, and macrolides inhibit this enzyme; therefore, concomitant use of cisapride may potentiate QT interval prolongation.

Cimetidine. In a pharmacokinetic interaction study, a single dose of cimetidine taken 2 hours before azithromycin administration had no effect on azithromycin pharmacokinetics.

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. In a pharmacokinetic study involving healthy volunteers who received oral azithromycin 500 mg daily for 3 days, followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in cyclosporine Cmax and AUC0-5 was demonstrated. Therefore, caution should be exercised when administering these drugs concomitantly. If concomitant use is necessary, cyclosporine levels should be monitored and dosage adjusted accordingly.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin and 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. Overall exposure and elimination half-life of azithromycin were unchanged when co-administered with fluconazole, but a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not cause 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 a single 15 mg dose 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 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 of the effect of azithromycin (500 mg daily for 3 days) on 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 interaction cannot be completely ruled out, but there are no specific data confirming such interaction.

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

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam to 14 healthy volunteers did not significantly affect any 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 1200 mg azithromycin on day 7 did not show significant effects on peak concentrations, overall exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

No clinically significant pharmacokinetic interactions were observed when azithromycin was co-administered with doxorubicin.

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

Special precautions for use.

Hypersensitivity reactions

As with erythromycin and other macrolide antibiotics, rare cases of serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases with fatal outcome), dermatological reactions such as acute generalized exanthematous pustulosis (AGEP), Stevens–Johnson syndrome, toxic epidermal necrolysis (in isolated cases with fatal outcome), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Some of these reactions have recurred and required a longer period of observation and treatment.

If an allergic reaction occurs, administration of the drug should be discontinued and appropriate therapy initiated. Physicians should be aware that allergic symptoms may reappear after discontinuation of symptomatic treatment.

The liver is the main route of metabolism and elimination of azithromycin; therefore, azithromycin should not be administered to patients with severe hepatic impairment. Cases of myasthenic syndrome and exacerbation of symptoms of myasthenia gravis have been reported in patients receiving azithromycin therapy.

Azithromycin should be used with caution in patients with severe renal impairment (creatinine clearance <10 mL/min), as plasma concentrations of azithromycin were found to increase by 33% in such patients. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with azithromycin (see section "Adverse reactions"). Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products.

Liver function tests should be performed if signs or symptoms of liver dysfunction develop, such as rapidly progressive fatigue associated with jaundice, dark urine, bleeding tendency, or hepatic encephalopathy.

If liver dysfunction is detected, azithromycin should be discontinued.

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

As with other antibiotics, monitoring for possible signs of superinfection caused by non-susceptible microorganisms, including fungi, should be performed.

Cases of Clostridium difficile-associated diarrhea (CDAD), ranging from mild diarrhea to fatal colitis, have 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 C. difficile-associated diarrhea.

Hyper-toxin-producing strains of C. difficile are associated with increased morbidity and mortality, as these infections may be refractory to antibacterial therapy and may require colectomy.

The possibility of C. difficile-associated diarrhea should be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is necessary, as C. difficile-associated diarrhea has been reported to occur up to two months after administration of antibacterial agents.

In patients with severe renal dysfunction (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed (see section "Pharmacokinetics").

Cardiovascular disorders

Prolongation of cardiac repolarization and QT interval, increasing the risk of cardiac arrhythmia and ventricular tachycardia (including torsade de pointes), has been observed with other macrolide antibiotics, including azithromycin (see section "Adverse reactions"). 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 existing pro-arrhythmic conditions (particularly elderly patients and younger women), especially in patients:

• with congenital or documented acquired QT prolongation;
• 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;
• with electrolyte imbalances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

Epidemiological data on the risk of adverse cardiovascular outcomes with macrolide use vary. Some studies indicate a rare risk of short-term arrhythmia, myocardial infarction, and increased cardiovascular mortality associated with macrolide use, including azithromycin. Given these data, the benefit-risk balance should be carefully considered when prescribing azithromycin.

Exacerbation of symptoms of myasthenia gravis or new onset of myasthenic syndrome has been reported in patients receiving azithromycin therapy.

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

When prescribing azithromycin, the following information should be considered:

Azithromycin oral suspension powder is not intended for the treatment of severe infections requiring rapid achievement of high antibiotic blood concentrations.

Azithromycin is not a first-line agent for empirical treatment of infections in areas where resistance prevalence is ≥10% (see section "Pharmacological properties").

In areas with high erythromycin A resistance, changes in susceptibility patterns to azithromycin and other antibiotics should be carefully considered.

As with other macrolides, resistance rates for Streptococcus pneumoniae (>30%) have been high in certain European countries (see section "Pharmacological properties"). This should be taken into account when treating infections caused by S. pneumoniae.

Pharyngitis/tonsillitis

Penicillin is the first-line treatment for pharyngitis/tonsillitis caused by Streptococcus pyogenes and for prevention of rheumatic fever.

Sinusitis

Azithromycin is generally not a first-line treatment for sinusitis.

Acute otitis media

Azithromycin is generally not a first-line treatment for acute otitis media.

Skin and soft tissue infections

Staphylococcus aureus, the primary pathogen in soft tissue infections, is often resistant to azithromycin. Therefore, susceptibility testing should be performed before initiating azithromycin therapy for soft tissue infections.

Infected burn wounds

Azithromycin is not indicated for the treatment of infected burn wounds.

Sexually transmitted diseases

In sexually transmitted diseases, concomitant infection with Treponema pallidum should be ruled out.

Neurological or psychiatric disorders

Azithromycin should be used with caution in patients with neurological or psychiatric disorders.

Information on excipients

The medicinal product contains sucrose and therefore should not be administered to patients with rare hereditary fructose intolerance, saccharase-isomaltase deficiency, or glucose-galactose malabsorption syndrome.

Five milliliters of 100 mg/5 mL and 200 mg/5 mL suspensions contain 3.81 g and 3.7 g of sucrose, respectively. This should be considered when prescribing the medicinal product to patients with diabetes mellitus.

Aspartame is a phenylalanine derivative and may be harmful to patients with phenylketonuria.

This medicinal product contains 18.4 mg/5 mL of anhydrous trisodium phosphate. Caution is advised when administering the product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

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

Breastfeeding period

Azithromycin has been reported to pass into human breast milk, but adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion in human breast milk have not been conducted. Therefore, breastfeeding should be discontinued during treatment and for 2 days after completion of therapy.

Fertility

Fertility studies were conducted in rats; pregnancy rates decreased 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 taken into account.

Method of Administration and Dosage

The dosage and duration of treatment are determined by a physician. The suspension should be taken once daily, 1 hour before or 2 hours after a meal, as concomitant food intake may interfere with the absorption of azithromycin.

The taste after taking the suspension can be improved by following it with fruit juice. If a dose has been missed, the next dose should be taken as soon as possible, and subsequent doses should be administered at 24-hour intervals.

Adult Patients (use azithromycin 200 mg/5 mL)

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema), the total dose of azithromycin is 1500 mg: 500 mg once daily. The treatment duration is 3 days.

For sexually transmitted infections caused by Chlamydia trachomatis, the dose is 1000 mg administered orally as a single dose.

For migrating erythema, the total dose of azithromycin is 3 g: 1 g on the first day, followed by 500 mg once daily from day 2 to day 5. The treatment duration is 5 days.

Elderly Patients

Dosage adjustment is not required for elderly patients.

However, since elderly patients may be at increased risk for cardiac conduction disorders, caution is recommended when using azithromycin due to the potential risk of cardiac arrhythmia, including torsade de pointes.

Children

For infections of the ear, nose, throat, respiratory tract, skin, and soft tissues (except chronic migrating erythema), the total dose of azithromycin is 30 mg/kg body weight (10 mg/kg body weight once daily). The treatment duration is 3 days.

For migrating erythema, the total dose of azithromycin is 60 mg/kg: 20 mg/kg body weight on day 1, followed by 10 mg/kg body weight once daily from day 2 to day 5. The treatment duration is 5 days.

Azithromycin has been shown to be effective in the treatment of streptococcal pharyngitis in children either as a single dose of 10 mg/kg or 20 mg/kg daily for 3 days. Clinical studies comparing these two regimens have demonstrated similar clinical efficacy, although bacterial eradication was greater with the 20 mg/kg daily dose. However, penicillin remains the drug of choice for the prevention of pharyngitis caused by Streptococcus pyogenes and for the prevention of secondary rheumatic polyarthritis.

Body Weight from 5 to 15 kg (use azithromycin 100 mg/5 mL)

The recommended dosing schedule based on the child's body weight is provided below.

Body weight	Daily dose of suspension 100 mg/5 ml	Content of azithromycin in the daily dose of suspension
5 kg	2.5 ml	50 mg
6 kg	3 ml	60 mg
7 kg	3.5 ml	70 mg
8 kg	4 ml	80 mg
9 kg	4.5 ml	90 mg
10-14 kg	5 ml	100 mg

Body weight more than 15 kg (administer azithromycin 200 mg/5 ml)

Depending on the child's body weight, the dosing regimen recommended below should be followed.

Body weight	Daily dose of suspension 200 mg/5 ml	Content of azithromycin in daily dose of suspension
15-24 kg	5 ml	200 mg
25-34 kg	7.5 ml	300 mg
35-44 kg	10 ml	400 mg
≥ 45 kg	12.5 ml	500 mg

Renal impairment.

In patients with mild renal function impairment (glomerular filtration rate 10–80 mL/min), the same dosage as in 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).

Hepatic impairment.

Since azithromycin is metabolized in the liver and excreted via bile, the drug should not be administered to patients with severe hepatic disease.

To prepare 20 mL of suspension (100 mg/5 mL or 200 mg/5 mL), proceed as follows:

• Shake the bottle thoroughly to loosen the powder from the walls and bottom;
• Remove the cap and insert the adapter into the neck of the bottle;
• Draw 10.5 mL of drinking water into a syringe (10 mL syringe with 0.25 mL graduations);
• Insert the tip of the syringe into the adapter;
• Add 10.5 mL of water from the syringe into the bottle with powder, shaking until a uniform suspension is obtained.

To prepare 30 mL of suspension (200 mg/5 mL) using the method described above, add 15 mL of drinking water to the bottle.

SHAKE WELL BEFORE EACH DOSE.

To measure the required amount of suspension using the provided syringe, proceed as follows:

• Shake the suspension;
• Insert the tip of the syringe into the adapter;
• Invert the bottle;
• Draw the required amount of suspension into the syringe;
• Return the bottle to upright position, remove the syringe, and close the bottle with the cap.

Children.

The 100 mg/5 mL formulation should be administered to children with body weight from 5 to 15 kg.

The 200 mg/5 mL formulation should be administered to children with body weight over 15 kg and adult patients.

Overdose.

Symptoms: reversible hearing loss, severe nausea, vomiting, diarrhea.

Treatment: gastric lavage, symptomatic and supportive therapy.

Adverse reactions.

The table below lists adverse reactions identified from clinical trials and during the post-marketing surveillance period for all dosage forms of azithromycin, organized by system organ class and frequency of occurrence.

Adverse reactions are classified according to frequency: 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), including isolated cases, and frequency not known (cannot be estimated from available data).

Unwanted reactions possibly or probably related to azithromycin, based on data obtained from clinical trials and post-marketing surveillance.

System Organ Class	Adverse Reactions	Frequency
Infections and infestations	Candidiasis, oral candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis	Uncommon
	Pseudomembranous colitis	Frequency unknown
Blood and lymphatic system disorders	Leukopenia, neutropenia, eosinophilia	Uncommon
	Thrombocytopenia, haemolytic anaemia	Frequency unknown
Immune system disorders	Angioneurotic oedema, hypersensitivity reactions	Uncommon
	Anaphylactic reaction	Frequency unknown
Metabolism and nutrition disorders	Anorexia	Uncommon
Psychiatric disorders	Nervousness, insomnia	Uncommon
	Agitation	Rare
	Aggression, restlessness, delirium, hallucinations	Frequency unknown
Nervous system disorders	Headache	Common
	Dizziness, somnolence, dysgeusia, paraesthesia	Uncommon
	Loss of consciousness, convulsions, hypaesthesia, psychomotor hyperactivity, anosmia, ageusia, parosmia, myasthenia gravis	Frequency unknown
Eye disorders	Visual disturbance	Uncommon
	Blurred vision	Frequency unknown
Ear and labyrinth disorders	Ear disorders, vertigo	Uncommon
	Hearing impairment, including deafness and/or tinnitus	Frequency unknown
Cardiac disorders	Palpitations	Uncommon
	Ventricular flutter and fibrillation (torsade de pointes), arrhythmia including ventricular tachycardia, QT interval prolongation on ECG	Frequency unknown
Vascular disorders	Flushing	Uncommon
	Arterial hypotension	Frequency unknown
Respiratory system disorders	Dyspnoea, epistaxis	Uncommon
Gastrointestinal disorders	Diarrhoea	Very common
	Vomiting, abdominal pain, nausea	Common
	Constipation, flatulence, dyspepsia, gastritis, dysphagia, bloating, dry mouth, burping, mouth ulcers, hypersalivation	Uncommon
	Pancreatitis, change in tongue colour	Frequency unknown
Hepatobiliary disorders	Liver function abnormalities, cholestatic jaundice	Rare
	Liver failure (rarely resulting in fatal outcome), fulminant hepatitis, necrotic hepatitis	Frequency unknown
Skin and subcutaneous tissue disorders	Rash, pruritus, urticaria, dermatitis, dry skin, hyperhidrosis	Uncommon
	Photosensitivity, acute generalized exanthematous pustulosis	Rare
	Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) (frequency assessed by the 'rule of three')	Very rare
	Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme	Frequency unknown
Musculoskeletal and connective tissue disorders	Osteoarthritis, myalgia, back pain, neck pain	Uncommon
	Arthralgia	Frequency unknown
Renal and urinary disorders	Dysuria, kidney pain	Uncommon
	Acute renal failure, interstitial nephritis	Frequency unknown
Reproductive system and breast disorders	Uterine bleeding, testicular disorders	Uncommon
General disorders and administration site conditions	Oedema, asthenia, malaise, fatigue, facial swelling, chest pain, hyperthermia, pain, peripheral oedema	Uncommon
Investigations	Decreased lymphocyte count, increased eosinophil count, decreased blood bicarbonate level, increased basophil count, increased monocyte count, increased neutrophil count	Common
	Increased blood levels of aspartate aminotransferase, alanine aminotransferase, bilirubin, blood urea, creatinine; changes in blood potassium levels, increased alkaline phosphatase, chloride, glucose, platelet count; decreased haematocrit; increased bicarbonate level, abnormal sodium level	Uncommon
Injury, poisoning and procedural complications	Procedural complications	Uncommon

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:

System and organ class	Adverse reactions	Frequency
Metabolism and nutrition disorders	Anorexia	Common
Psychiatric disorders	Dizziness, headache, paraesthesia, dysgeusia	Common
	Hypoaesthesia	Rare
Eye disorders	Visual impairment	Common
Ear and labyrinth disorders	Deafness	Rare
	Hearing impaired, tinnitus	Rare
Cardiac disorders	Palpitations	Uncommon
Gastrointestinal disorders	Diarrhoea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools	Very common
Hepatobiliary disorders	Hepatitis	Rare
Skin and subcutaneous tissue disorders	Rash, pruritus	Common
	Stevens-Johnson syndrome, photosensitivity	Rare
Musculoskeletal and connective tissue disorders	Arthralgia	Common
General disorders and administration site conditions	Increased fatigue	Common
	Asthenia, malaise	Rare

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Keep out of reach of children.

The reconstituted suspension should be stored at a temperature not exceeding 25 °C and used within 5 days.

Packaging.

17.1 g of powder in a vial for 20 mL of suspension or 24.8 g of powder in a vial for 30 mL of suspension; 1 vial with an adapter and an oral dosing syringe in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sandoz S. R. L. / Sandoz S. R. L.

Manufacturer's address and place of business.

Str. Livezeni nr. 7A, 540472, Targu Mures, Jud. Mures, Romania.