Azimed

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AZIMED® (AZIMED®)

Composition:

Active substance: azithromycin;

5 ml of suspension contain azithromycin dihydrate equivalent to 200 mg of azithromycin;

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 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 streptococci, 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 the isolated species; therefore, local resistance data are essential, 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.

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 the concentration of azithromycin in tissues is 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 (V_ss) is 31.1 L/kg.

The terminal plasma elimination 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 were also 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 results with microbiological assays 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 of 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. In studies evaluating the effect of concomitant antacid administration on azithromycin pharmacokinetics, no overall changes in bioavailability were observed, although the 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 concomitantly for 5 days with cetirizine 20 mg at steady state.

Didanosine. When daily doses of 1200 mg azithromycin were administered concomitantly with 400 mg didanosine daily in six HIV-positive volunteers, no effect on steady-state pharmacokinetics of didanosine was observed compared to placebo.

Digoxin and colchicine. It has been reported that concomitant use of macrolide antibiotics, including azithromycin, with 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 substrate concentration in serum should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg azithromycin had minimal effect on 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 data is unclear but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is believed that the drug does not have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of 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 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). 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.

Cimetidine. In a pharmacokinetic study evaluating the effect of a single dose of cimetidine administered 2 hours before azithromycin on azithromycin pharmacokinetics, no changes in azithromycin pharmacokinetics were observed.

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 of 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/day for 3 days, followed by a single oral dose of cyclosporine 10 mg/kg, a significant increase in Cmax and AUC0-5 of cyclosporine was demonstrated. Therefore, caution should be exercised when these drugs are used concomitantly. If concomitant use of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.

Efavirenz. Concomitant administration of a single 600 mg dose of azithromycin with 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interaction.

Fluconazole. Concomitant administration of a single 1200 mg dose of azithromycin did not alter the pharmacokinetics of a single 800 mg dose of fluconazole. The overall exposure and elimination half-life of azithromycin were unchanged when fluconazole was coadministered; however, a clinically insignificant 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 azithromycin 500 mg daily for 3 days did not cause clinically significant changes in the pharmacokinetics and 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 of the effect of azithromycin (500 mg daily for 3 days) on AUC and Cmax values of sildenafil or its major circulating metabolite.

Terfenadine. Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. However, 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 interaction 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 healthy volunteers 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 with 1200 mg azithromycin on day 7 did not reveal any significant effect on peak concentrations, overall exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Azithromycin serum concentration values 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 arrhythmia, 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 angioedema and anaphylaxis (in isolated cases with fatal outcome), as well as dermatological reactions, including acute generalized exanthematous pustulosis. Some of these reactions induced 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 is advised when prescribing azithromycin to patients with severe hepatic disease. Cases of fulminant hepatitis leading to life-threatening liver failure have been reported during azithromycin use. Some patients may have had pre-existing liver disease or concomitant use of other hepatotoxic medicinal products.

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

If hepatic dysfunction is suspected, azithromycin should be discontinued.

Ergot derivatives. In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics may lead to rapid development of ergotism. Data on the potential interaction between ergot derivatives and azithromycin are lacking. However, due to the theoretical risk of ergotism, azithromycin should not be administered concurrently with ergot derivatives.

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

Clostridium difficile-associated diarrhea (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. Strains of C. difficile that hyperproduce toxins are associated with increased morbidity and mortality, as these infections may be refractory to antimicrobial therapy and may require colectomy. CDAD should be considered in all patients presenting with diarrhea following antibiotic use. Careful medical history is essential, 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), a 33% increase in systemic exposure to azithromycin has been observed.

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 increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be used with caution in patients with pre-existing proarrhythmic conditions (particularly women and elderly patients), especially those:

• 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 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 infection of the oropharynx; however, there are no data demonstrating the efficacy of azithromycin in preventing rheumatic fever.

Other.

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

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

Azithromycin oral suspension powder 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 (24.25 mg per 1 mL of suspension). This should be taken into account when prescribing the product to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy

There are inadequate data on the use of azithromycin in pregnant women. Reproductive toxicity studies in animals have not shown teratogenic effects of azithromycin on the fetus, although the drug crosses the placenta. The safety of azithromycin use during pregnancy has not been established. Therefore, azithromycin should be prescribed during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breastfeeding period

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 have been conducted in rats; a decreased pregnancy rate was observed 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.

Azimed® powder for oral suspension should be taken once daily, at least 1 hour before or 2 hours after a meal.

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

The package contains a dosing syringe and a spoon. The physician may recommend using either the spoon or the syringe. The spoon has markings for 2.5 ml and 5 ml. The syringe has a minimum unit of 0.1 ml.

Children

For infections of the ear, nose, throat, respiratory tract, skin and soft tissues (except chronic migrating erythema), the daily dose of azithromycin is 10 mg/kg body weight, corresponding to 0.25 ml/kg body weight of the prepared suspension. The duration of treatment is 3 days.

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

Preparation and Use of the Suspension

To the bottle containing the powder, add distilled or boiled and cooled water.

1. Press down on the bottle cap and turn it counterclockwise.
2. Using a clean container and the dosing syringe, measure the appropriate amount of water (8.3 or 14.5 mL) and add it to the bottle with the powder:

Bottle with powder for the preparation of 15 mL of oral suspension 200 mg/5 mL: add 8.3 mL of water to the contents of the bottle. Shake the bottle thoroughly until a homogeneous suspension is obtained. The volume of the resulting suspension is approximately 20 mL*.

Bottle with powder for the preparation of 30 mL of oral suspension 200 mg/5 mL: add 14.5 mL of water to the contents of the bottle. Shake the bottle thoroughly until a homogeneous suspension is obtained. The volume of the resulting suspension is approximately 35 mL*.

* After dissolving the powder, the bottle will contain an additional 5 mL of suspension (to compensate for potential losses during administration).

**Information on the vial volume is provided on the carton and the vial label.

1. Insert the syringe into the suspension and draw up the required amount by pulling the plunger upwards.
2. If there are air bubbles in the syringe, return the medication to the vial and repeat step 3.
3. Position the child as for feeding.
4. Place the tip of the syringe into the child's mouth and slowly expel the contents.
5. Allow the child sufficient time to gradually swallow the entire dose.
6. After administration, give the child a small amount of tea or juice to help wash down and swallow any remaining suspension in the mouth.
7. After use, disassemble the syringe, wash it with running water, dry it thoroughly, and store it in a clean, dry place together with the medication.
8. After the child has taken the final dose, dispose of both the syringe and the vial.

In the case of migratory erythema, the treatment duration is 5 days. On day 1, administer
20 mg/kg of azithromycin, corresponding to 0.5 ml/kg of the reconstituted suspension. From day 2 to day 5, administer 10 mg/kg daily, corresponding to 0.25 ml/kg of the reconstituted suspension.

The total cumulative course dose is 60 mg/kg.

It has been shown that azithromycin is effective in the treatment of streptococcal pharyngitis in children as a single dose of 10 mg/kg or 20 mg/kg for 3 days. When comparing these two doses in clinical studies, similar clinical efficacy was observed, 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 rheumatic polyarthritis, which occurs as a secondary disease.

Adults

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

For migratory 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 duration of treatment is 5 days.

Elderly patients.

Dosage adjustment is not required for elderly patients.

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

Patients with renal impairment.

The same dosage as in patients with normal renal function can be used in patients with mild to moderate 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 treatment of such patients with azithromycin have not been conducted.

Children.

To be used in children with body weight above 15 kg. For children with body weight below 15 kg, it is recommended to prescribe Azimed® 100 mg/5 mL.

Overdose.

Clinical experience with azithromycin indicates that adverse effects occurring after ingestion of doses higher than recommended are similar to those observed with usual therapeutic doses, namely: they may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, activated charcoal should be administered if necessary, along with general symptomatic and supportive treatment measures.

Adverse Reactions

The adverse reactions listed in the table below are classified by system organ class and frequency of occurrence, as identified in clinical trials and during the post-marketing period with all dosage forms of azithromycin. Adverse reactions reported 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, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from available data). Within each frequency 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 drug formulations.

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

Shelf life.

2 years.

The shelf life of the suspension is 10 days.

Storage conditions.

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

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

Keep out of reach of children.

Packaging.

600 mg of azithromycin in a vial for preparation of 15 ml of oral suspension or 1200 mg of azithromycin in a vial for preparation of 30 ml of oral suspension. One vial with a calibrated syringe and a measuring spoon in a carton pack.

Prescription category. By prescription only.

Manufacturer. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.

139 Saksahanskoho Street, Kyiv, 01032, Ukraine.