Azimed

INSTRUCTIONS for medical use of the medicinal product AZIMED® (AZIMED®)

Composition:

Active substance: azithromycin;

1 vial contains azithromycin dihydrate equivalent to azithromycin 400 mg;

5 ml of suspension contains azithromycin dihydrate equivalent to azithromycin 100 mg;

Excipients: sucrose, sodium phosphate, hydroxypropyl cellulose, xanthan gum, colloidal anhydrous silicon dioxide, cherry flavor, banana flavor, vanilla flavor.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white to yellowish-white powder with a characteristic odor of banana, vanilla, and cherry.

The reconstituted suspension is a homogeneous suspension of white to light yellow color with a characteristic odor of banana, vanilla, and cherry.

Pharmacotherapeutic group.

Antimicrobial agents for systemic use. Antibacterial agents 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.

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.

The prevalence of acquired resistance may vary depending on geographical location and time for isolated species; therefore, local resistance data are necessary, especially when treating severe infections. If necessary, expert advice should be sought when local resistance prevalence renders the efficacy of the drug questionable for the treatment of 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.

The bioavailability after oral administration is approximately 37%. Maximum serum concentration is reached within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have shown that azithromycin concentrations in tissues are significantly higher (up to 50 times) than in blood plasma, indicating strong tissue binding of the drug.

Protein binding in serum varies depending on plasma concentrations, ranging from 12% at 0.5 µg/mL to 52% at 0.05 µg/mL in serum. The apparent volume of distribution at steady state (VVss) is 31.1 L/kg.

The terminal plasma half-life fully reflects the tissue elimination half-life over 2–4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following three 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 liquid chromatography and microbiological assay results showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

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

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, or to any other component of the drug.

Interaction with other medicinal products and other forms of interaction.

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

Cetirizine. In healthy volunteers, no pharmacokinetic interaction or significant changes in QT interval were observed when azithromycin was administered for 5 days together with cetirizine 20 mg at steady state.

Didanosine. In six HIV-positive volunteers, no effect on steady-state pharmacokinetics of didanosine was observed when daily doses of 1200 mg azithromycin were administered together with 400 mg didanosine per day, compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine may lead to increased serum levels of the P-glycoprotein substrate. Therefore, when azithromycin is used concomitantly with a P-glycoprotein substrate such as digoxin, the possibility of increased serum concentration of the substrate should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg azithromycin had minimal effect on plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, administration of azithromycin increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in mononuclear cells of peripheral circulation. The clinical significance of these data is unclear but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is considered not to have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of hepatic cytochrome P450 via 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 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 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 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 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, in the post-marketing period, reports have been received regarding potentiation of the anticoagulant effect after concomitant administration 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/day 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 the dose 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 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 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 midazolam administered as a single 15 mg dose.

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 required.

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 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 interactions between azithromycin and terfenadine. In some cases, the possibility of such 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 when azithromycin and theophylline are administered concomitantly to healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers of azithromycin 500 mg on the first day and 250 mg on the second day together with 0.125 mg triazolam did not significantly affect any pharmacokinetic parameters of triazolam compared to triazolam and placebo.

Trimethoprim/sulfamethoxazole. Concomitant administration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days together with 1200 mg azithromycin on day 7 showed no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentrations were consistent with those observed in other studies.

Hydroxychloroquine. Azithromycin should be used with caution in patients receiving medicinal products that prolong the QT interval and may cause cardiac arrhythmias, such as hydroxychloroquine.

Special precautions for use.

Allergic reactions. As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases with fatal outcome), as well as dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions caused by azithromycin have been associated with recurrent symptoms and required prolonged monitoring and treatment.

Hepatic function impairment. Since the liver is the primary route of elimination for azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening hepatic dysfunction 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 signs or symptoms of hepatic dysfunction develop, such as rapidly progressing asthenia accompanied by jaundice, dark urine, bleeding tendencies, or hepatic encephalopathy.

If hepatic dysfunction is suspected, 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 the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

Superinfections. As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Diarrhea associated with Clostridium difficile (CDAD) has been reported with nearly all antibacterial agents, including azithromycin, with severity ranging from mild diarrhea to fatal colitis. 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. C. difficile strains that hyperproduce 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 who develop diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after antibiotic administration.

Renal function impairment. In patients with severe renal impairment (glomerular filtration rate < 10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed.

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 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 existing proarrhythmic conditions (particularly women and elderly patients), especially in those:

• with congenital or documented QT interval prolongation;
• currently receiving treatment with other medicinal substances 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 arrhythmias, 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. For treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is the drug of choice and is also used for prevention of acute rheumatic fever. Azithromycin is generally effective in treating streptococcal pharyngeal infection; however, there are no data demonstrating the effectiveness of azithromycin in preventing rheumatic fever.

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

The safety and efficacy for prophylaxis or treatment of Mycobacterium Avium Complex in children have not been established.

Azithromycin, powder for oral suspension, contains sucrose. This medicinal product should not be administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

The product contains sodium phosphate (18.2 mg in 1 mL of suspension). This should be taken into account when prescribing the product to patients on a sodium-controlled diet.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In reproductive toxicity studies in animals, azithromycin did not show teratogenic harmful effects on the fetus; however, the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been confirmed. Therefore, azithromycin should be used during pregnancy only if the potential benefit outweighs the potential risk.

Breastfeeding.

Azithromycin has been reported to be excreted into human breast milk; however, adequate and well-controlled clinical studies characterizing the pharmacokinetics of azithromycin excretion into human breast milk have not been conducted.

Fertility.

Fertility studies conducted in rats showed 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 delirium, hallucinations, dizziness, somnolence, loss of consciousness, and seizures, which may affect the ability to drive or operate machinery, should be considered.

Method of Administration and Dosage.

The medication should be taken as a single daily dose at least 1 hour before or 2 hours after a meal. The dose should be measured using the oral dosing syringe or dosing spoon provided in the package.

Immediately after administering the suspension, the child should be given several sips of liquid to rinse and swallow any remaining suspension in the oral cavity.

If one dose is missed, it should be taken as soon as possible, and subsequent doses should be taken at 24-hour intervals.

For infections of the ear, nose and 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 duration of treatment is 3 days.

Depending on the child's body weight, the following dosing schedule for Azimed® suspension is recommended:

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

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

Geriatric patients.

Dosage adjustment is not required for elderly patients.

Since elderly patients may be at increased risk for cardiac conduction disorders, caution is recommended when administering azithromycin due to the potential risk of developing cardiac arrhythmia and torsade de pointes.

Patients with renal impairment.

The same dosage regimen as in patients with normal renal function may be used in patients with mild renal impairment (glomerular filtration rate 10–80 mL/min). 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.

Preparation of suspension.

The vial contains a powder, which is reconstituted with water (distilled or boiled and cooled) to form a suspension. The required volume of water may be measured using the dosing syringe provided.

1. Press down on the vial cap and turn counterclockwise to remove.
2. Measure 11 mL of water in a clean container and add to the vial containing the powder.
3. Shake the vial thoroughly until a uniform suspension is obtained.

After reconstitution, the vial will contain an additional 5 mL of Azimed® suspension.

Use of dosing syringe and spoon.

The package contains a dosing syringe and a spoon. Your doctor will advise you on how to use the spoon or syringe. The spoon is marked at 2.5 mL and 5 mL.

Filling the syringe with medication.

1. Shake the suspension well before administration.
2. Press down on the cap and turn counterclockwise to remove.
3. Insert the syringe into the suspension and draw up the required amount by pulling the plunger upward.
4. If air bubbles are present in the syringe, return the medication to the vial and repeat step 3.

Administering the medication to a child.

1. Position the child as for feeding.
2. Place the tip of the syringe into the child’s mouth and slowly expel the contents.
3. Allow the child time to gradually swallow the entire dose.
4. After administration, give the child a small amount of tea or juice to help wash down and swallow any remaining suspension in the oral cavity.

Cleaning and storage.

1. After use, disassemble the syringe, rinse with tap water, dry thoroughly, and store in a clean, dry place together with the medication.

After the child has taken the final dose, the syringe and vial should be properly discarded.

Children.

For use in children with body weight from 5 to 15 kg. For children with body weight above 15 kg, Azimed®, powder for oral suspension 200 mg/5 mL, is recommended.

Overdose.

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with normal 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 measures are recommended, if necessary.

Adverse reactions.

The adverse reactions listed in the table below are classified by system organ class and frequency of occurrence, and were identified from clinical trials and post-marketing surveillance for all dosage forms of azithromycin. Adverse reactions reported during post-marketing surveillance 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.

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical trials and post-marketing surveillance. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release dosage forms.

Adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex

Shelf life.

2 years.

Shelf life of the prepared suspension – 5 days.

Storage conditions.

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

The prepared suspension should be stored in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

400 mg of azithromycin for the preparation of 20 ml of oral suspension in a bottle. 1 bottle with a calibrated dosing syringe and a measuring spoon in a carton pack.

Prescription status. By prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business. 139 Saksahanskoho Street, Kyiv, 01032, Ukraine.