Sumamed

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SUMAMED® (SUMAMED®)

Composition:

Active substance: azithromycin;

1 dose (5 ml) of suspension contains 100 mg of azithromycin as azithromycin dihydrate;

Excipients: sucrose, sodium phosphate, hydroxypropyl cellulose, xanthan gum, colloidal anhydrous silicon dioxide,

flavouring agent(s) and (or) colouring agent:

banana flavour, cherry flavour, vanilla flavour

or

titanium dioxide (E 171), strawberry flavour.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or yellowish-white powder with a characteristic smell of cherry and banana or strawberry.

The reconstituted suspension is a homogeneous yellowish-white suspension with a characteristic smell of cherry and banana or strawberry.

Pharmacotherapeutic group. Antibacterials for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATC code J01FA10.

Pharmacological properties.

Pharmacodynamics.

Azithromycin is a macrolide antibiotic belonging to the azalide group. The molecule is formed by insertion of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin involves inhibition of bacterial protein synthesis by binding to the 50S ribosomal subunit and suppression of peptide translocation.

Mechanism of resistance.

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

The prevalence of acquired resistance among these organisms may vary depending on geographical location and time; therefore, local information on resistance patterns is needed, especially when treating severe infections. Expert advice should be sought when the 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 exhibits a very high prevalence of acquired resistance to macrolides and is listed here due to rare susceptibility to azithromycin.

Pharmacokinetics.

Bioavailability after oral administration is approximately 37%. Maximum serum concentration is achieved within 2–3 hours after drug intake.

After oral administration, azithromycin is distributed throughout the body. Pharmacokinetic studies have demonstrated that azithromycin concentrations in tissues are significantly higher (up to 50-fold) 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 elimination half-life from tissues over 2–4 days.

Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in urine over the following 3 days. Particularly high concentrations of unchanged azithromycin have been found in human bile. Ten metabolites were also detected in bile, formed as a result of 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:

• Otorhinolaryngeal 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), impetigo, secondary pyoderma.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or 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 the pharmacokinetics of azithromycin, no overall changes in bioavailability were observed, although the peak plasma 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 concomitantly with 20 mg cetirizine 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 the 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, and P-glycoprotein substrates such as digox游戏副本

Special precautions for use.

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

Since the liver is the primary route of elimination for azithromycin, caution is advised when prescribing azithromycin to patients with severe hepatic impairment. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported with 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 developing asthenia accompanied by jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy. If hepatic dysfunction is detected, azithromycin should be discontinued.

In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with the rapid onset 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 co-administered with ergot derivatives.

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. Hyperproducing toxin strains of C. difficile 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 presenting with diarrhea following antibiotic use. Careful medical history is essential, as CDAD has been reported to occur up to two months after antibiotic administration.

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 tachycardia/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 pre-existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented acquired prolongation of the QT interval;
• 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 disturbances, particularly hypokalemia and hypomagnesemia;
• with clinically significant bradycardia, cardiac arrhythmia, or severe heart failure.

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

Streptococcal infections. For treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is generally the drug of choice and is also used for prevention of acute rheumatic fever. While azithromycin is generally effective in treating streptococcal pharyngeal infection, there are no data demonstrating the efficacy 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 of azithromycin for prevention or treatment of Mycobacterium avium complex in children have not been established.

Sumamed® oral suspension powder contains sucrose. This medicinal product should not be used in patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Azithromycin oral suspension powder contains 83.7 mg of sodium phosphate per dose. Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin did not show teratogenic effects on the fetus, although it crossed 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 outweighs the potential risk.

breastfeeding.

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

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 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.

Sumamed®, 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.

Dosage measurement

The package contains a graduated oral dosing syringe. The syringe volume is 5 ml.

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, which corresponds to 0.5 ml/kg body weight of the prepared suspension. The treatment duration is 3 days.

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

Preparation and Use of the Suspension

Add distilled or boiled and cooled water to the vial containing the powder.

1. Press down on the cap of the vial and turn it counterclockwise.
2. Using the dosing syringe, measure 12 mL of water from a clean container and add it to the vial with the powder.

1. Shake the contents of the vial thoroughly until a homogeneous suspension is obtained. After dissolving the powder, the vial will contain an additional 5 mL of suspension (to compensate for potential losses during administration), resulting in a total of 25 mL of Sumamed® suspension.
2. Immerse the syringe into the suspension and, by pulling the plunger upwards, draw the required amount of suspension.
3. If there are air bubbles in the syringe, return the preparation to the vial and repeat step 3.
4. Position the child as for feeding.
5. Place the tip of the syringe into the child’s mouth and slowly dispense the contents.
6. Allow the child time to gradually swallow the entire dose.

1. After administering the medication, give the child some tea or juice to drink in order to wash away and swallow any remaining suspension in the oral cavity.
2. Disassemble the used syringe, rinse it thoroughly with running water, dry it, and store in a dry and clean place together with the medication.

1. After the child has taken the last dose of the medication, the syringe and the vial should be disposed of properly.

In the case of migratory erythema, the duration of treatment is 5 days. On day 1, administer 20 mg/kg body weight of azithromycin, corresponding to 1 ml/kg of the ready-to-use suspension. From day 2 to day 5, administer 10 mg/kg body weight, corresponding to 0.5 ml/kg of the ready-to-use suspension.

The total cumulative dose is 60 mg/kg.

Azithromycin has been shown to be effective in the treatment of streptococcal pharyngitis in children as a single daily dose of 10 mg/kg or 20 mg/kg administered for 3 days. When comparing these two doses in clinical studies, similar clinical efficacy was observed, although bacterial eradication was more pronounced with the 20 mg/kg daily dose. 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 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.

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 evaluating azithromycin treatment in such patients have not been conducted.

Children.

For use in children with body weight from 5 to 15 kg. For children with body weight above 15 kg, Sumamed® Forte (200 mg/5 mL) is recommended.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed following ingestion of doses higher than recommended are similar to those seen with standard 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 identified from clinical studies and post-marketing surveillance observed during the use of all dosage forms of azithromycin are listed below by system organ class and frequency of occurrence. Adverse reactions reported during post-marketing surveillance are indicated in italics. Frequency categories are defined as follows: 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 category, adverse reactions are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin, based on data obtained from clinical studies and post-marketing surveillance

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 observations. 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 prepared suspension is 5 days.

Storage conditions.

Store at a temperature not exceeding 25 °C in a place inaccessible to children. Store the prepared suspension at a temperature not exceeding 25 °C.

Packaging.

1 vial containing 20 ml (400 mg) of powder for oral suspension together with a dosing syringe in a carton.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and place of business.

Baruna Filipovića 25, 10000 Zagreb, Croatia.