Sumamed®

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

Composition:

Active substance: azithromycin;

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

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

flavoring agent(s) and (or) colorant:

banana flavoring, cherry flavoring, vanilla flavoring

or

titanium dioxide (E 171), strawberry flavoring.

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. 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 in 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 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 if local resistance rates are such that the efficacy of the drug in treating at least some types of infections is questionable.

Antimicrobial spectrum of azithromycin

*Methicillin-resistant Staphylococcus aureus exhibits a very high prevalence of acquired resistance to macrolides and is listed here due to its rare susceptibility to azithromycin.

Pharmacokinetics.

The 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 tissue concentrations of azithromycin are significantly higher (up to 50-fold) than plasma concentrations, 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 have also been identified 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:

• Ear, nose, and throat (ENT) 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 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 peak plasma concentration of azithromycin decreased by approximately 25%. Azithromycin and antacids should not be taken simultaneously.

Cetirizine. In healthy volunteers, co-administration of azithromycin for 5 days with 20 mg cetirizine at steady state did not result in pharmacokinetic interaction or significant changes in QT interval.

Didanosine. In six HIV-positive volunteers, concomitant administration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day showed no effect on steady-state didanosine pharmacokinetics compared to placebo.

Digoxin and colchicine. There have been reports 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 findings is unclear but may be beneficial for patients.

Azithromycin has no significant interaction with the hepatic cytochrome P450 system. The drug is not considered to have the pharmacokinetic drug interactions typical of erythromycin and other macrolides. Azithromycin does not cause induction or inactivation of hepatic cytochrome P450 via a 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, post-marketing reports have documented cases of rhabdomyolysis 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 interaction study, a single dose of cimetidine administered 2 hours before azithromycin showed no changes in azithromycin pharmacokinetics.

Oral coumarin-type anticoagulants. 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 coumarin-type anticoagulants. Although a causal relationship has not been established, frequent monitoring of prothrombin time should be considered when prescribing azithromycin to patients receiving oral coumarin-type anticoagulants.

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 these drugs are used 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 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. Total exposure and elimination half-life of azithromycin were unchanged when fluconazole was co-administered; however, a clinically insignificant reduction in azithromycin Cmax (18%) 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) affected 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, the possibility of such an interaction cannot be entirely 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 day 1 and 250 mg on day 2) with triazolam 0.125 mg 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 azithromycin 1200 mg on day 7 showed no significant effect on peak concentrations, total exposure, or urinary excretion of either trimethoprim or sulfamethoxazole. Serum azithromycin 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.

As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (some 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 of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic impairment. Cases of fulminant hepatitis leading to life-threatening hepatic dysfunction have been reported during azithromycin therapy. Some of these 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 associated with jaundice, dark urine, tendency to bleeding, or hepatic encephalopathy. If hepatic dysfunction is detected, azithromycin should be discontinued.

In patients receiving ergot derivatives, concomitant administration of certain macrolide antibiotics may lead to rapid onset of ergotism. There are no data on the potential 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 signs of superinfection caused by resistant 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 flora of the colon, 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 must be considered in all patients presenting with diarrhea following antibiotic use. A careful medical history is necessary, as CDAD has been reported to occur up to 2 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 arrhythmias and ventricular tachycardia/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 pre-existing proarrhythmic conditions (particularly women and elderly patients), especially in patients:

• with congenital or documented QT prolongation;
• currently receiving treatment with other medicinal products known to prolong the QT interval, such as class IA antiarrhythmics (quinidine, procainamide) and class III antiarrhythmics (dofetilide, amiodarone, sotalol), cisapride and 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.

Exacerbation 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. While azithromycin is generally effective in treating streptococcal pharyngeal infections, there are no data demonstrating 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 administered to patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Azithromycin oral suspension powder contains 83.7 mg/dose of sodium phosphate. 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 azithromycin use in pregnant women. In animal reproductive toxicity studies, azithromycin did not show teratogenic or harmful effects on the fetus; however, 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 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 have been conducted in rats; a decreased pregnancy rate was observed after azithromycin administration. 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.

Dosage and Administration

Sumamed®, oral suspension powder, 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 administered at 24-hour intervals.

Dose 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 0.5 ml/kg body weight of the prepared suspension, corresponding to 10 mg/kg body weight. The duration of treatment is 3 days.

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

Preparation and Use of the Suspension

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

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

1. Shake the contents of the bottle thoroughly until a uniform suspension is obtained. After dissolving the powder, the bottle 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 suspension to the bottle and repeat step 3.
4. Position the child as if for feeding.
5. Place the tip of the syringe into the child’s mouth and slowly dispense the contents.
6. Allow the child to gradually swallow the entire dose.

1. After administering the medication, give the child some tea or juice to rinse and swallow any remaining suspension in the oral cavity.
2. Disassemble the used syringe, wash it thoroughly with running water, dry it, and store it 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 of azithromycin, corresponding to 1 mL/kg of the ready-to-use suspension. From day 2 to day 5, administer 10 mg/kg, corresponding to 0.5 mL/kg of the ready-to-use suspension.

The total cumulative dose is 60 mg/kg.

It has been shown that azithromycin is 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 daily dose of 20 mg/kg. However, penicillin remains the drug of choice for the prevention of pharyngitis caused by Streptococcus pyogenes and for the prevention of rheumatic polyarthritis as a secondary complication.

Elderly patients.

Dosage adjustment is not required for elderly patients.

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

Patients with renal impairment.

The same dosage as in patients with normal renal function may 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.

For use in children weighing 5 to 15 kg. For children weighing more than 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 listed in the table below are classified by system organ class and frequency of occurrence, and were identified from clinical studies and the post-marketing surveillance period during the use of all azithromycin dosage forms. Adverse reactions reported during post-marketing surveillance are indicated in italics. Frequency groups were 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.

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

Information on adverse reactions possibly associated with the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical studies 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 reconstituted suspension is 5 days.

Storage conditions.

Store at a temperature not exceeding 25 °C, in a place inaccessible to children. The reconstituted suspension should be stored 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 box.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and place of business.

Baruna Filipovića 25, 10000 Zagreb, Croatia.