Sumamed® forte

INSTRUCTION for medical use of the medicinal product SUMAMED® FORTE (SUMAMED® FORTE)

Composition:

Active substance: azithromycin;

1 dose (5 ml) of suspension contains azithromycin 200 mg as azithromycin dihydrate;

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

flavour(s) and/or colour:

banana flavour, cherry flavour, vanilla flavour

or

titanium dioxide (E 171), banana flavour, vanilla flavour,

or

titanium dioxide (E 171), strawberry flavour,

or

titanium dioxide (E 171), raspberry flavour.

Pharmaceutical form. Powder for oral suspension.

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

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

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 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 prevalence renders the efficacy of the drug questionable for 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.

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 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 mcg/mL to 52% at 0.05 mcg/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 three days. Particularly high concentrations of unchanged azithromycin were detected in human bile. Ten metabolites were also 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 results from liquid chromatography and microbiological assays 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, pyoderma, secondary pyodermatoses.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, 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 antacid administration 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, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not result in any pharmacokinetic interaction or significant changes in the QT interval.

Didanosine. In six HIV-positive volunteers, concomitant administration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day did not affect the steady-state pharmacokinetics of didanosine 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 P-glycoprotein substrates. Therefore, when azithromycin is co-administered with a P-glycoprotein substrate such as digoxin, the potential for increased substrate concentration in serum should be considered.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin had minimal effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, administration of azithromycin increased the concentration 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 does not significantly interact 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 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 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 did not affect the pharmacokinetics of azithromycin.

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 Cmax and AUC0-5 of cyclosporine was observed. Therefore, caution should be exercised when co-administering these drugs. If co-administration 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 not altered when co-administered with fluconazole, although a clinically insignificant decrease 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 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) 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 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 azithromycin (500 mg daily for 3 days) affecting 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 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 co-administered to healthy volunteers.

Triazolam. Concomitant administration to healthy volunteers of azithromycin 500 mg on day 1 and 250 mg on day 2 together with 0.125 mg triazolam 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 a single 1200 mg dose of azithromycin on day 7 did not show a 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, there have been reports of rare but serious allergic reactions, including angioedema and anaphylaxis (some cases with fatal outcome), as well as dermatological reactions such as acute generalized exanthematous pustulosis. Some of these azithromycin-induced reactions have been associated with recurrent symptoms and required prolonged observation and treatment.

Since the liver is the main 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 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, bleeding tendency, or hepatic encephalopathy. If hepatic dysfunction is confirmed, azithromycin should be discontinued.

In patients taking ergot derivatives, concomitant administration of certain macrolide antibiotics has been associated with 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 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 existing proarrhythmic conditions (particularly women and elderly patients), 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 relevant 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.

For the 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 the efficacy of azithromycin in preventing rheumatic fever.

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

The safety and efficacy of azithromycin for the 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.

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 insufficient data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, no teratogenic adverse effects of azithromycin on the fetus were observed, 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 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; 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.

Dosage and Administration

Sumamed® Forte, 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 administered at 24-hour intervals.

Dose Measurement

The package contains a graduated oral dosing syringe with a volume of 5 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, which corresponds to 0.25 mL/kg body weight of the prepared suspension. The treatment duration is 3 days.

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

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 a dosing syringe, measure the appropriate amount of water (9.5, 16.5, or 20.0 mL) from a clean container and add it to the vial with the powder:

Vial with powder for oral suspension 200 mg/5 mL, 15 mL: add 9.5 mL of water to the contents of the vial. Shake the vial thoroughly until a homogeneous suspension is obtained. The volume of the resulting suspension is approximately 20 mL*.

Vial with powder for oral suspension 200 mg/5 mL, 30 mL: add 16.5 mL of water to the contents of the vial. Shake the vial thoroughly until a homogeneous suspension is obtained. The volume of the resulting suspension is approximately 35 mL*.

Vial with powder for oral suspension 200 mg/5 mL, 37.5 mL: add 20 mL of water to the contents of the vial. Shake the vial thoroughly until a homogeneous suspension is obtained. The volume of the resulting suspension is approximately 42.5 mL*.

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

**Information regarding the vial volume is located on the carton and vial label.

1. Insert the syringe into the suspension and, by pulling the plunger upward, measure the required amount of suspension.
2. If there are air bubbles in the syringe, return the preparation 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 depress the plunger to administer the contents.
5. 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 from the oral cavity.
2. Disassemble the used syringe, rinse it thoroughly with tap water, dry it, and store it in a clean, dry place together with the medication.

1. After the child has taken the last dose of the medication, the syringe and the bottle 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, which corresponds to 0.5 ml/kg of the ready-to-use suspension. From day 2 to day 5, administer 10 mg/kg daily, which corresponds to 0.25 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 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 more pronounced 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 occurring as a secondary disease.

Adults

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 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 the second to the fifth day. The duration of treatment is 5 days.

Elderly patients

Dosage adjustment is not required for elderly patients.

Since elderly patients may belong to risk groups regarding 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

In patients with mild renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage as in patients with normal renal function can be used. Azithromycin should be administered with caution to 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 using azithromycin have not been conducted.

Children.

For children with body weight less than 15 kg, Sumamed® (100 mg/5 mL) is recommended. Sumamed® Forte is used for children with body weight over 15 kg.

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. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, administration of activated charcoal and implementation of general symptomatic and supportive treatment measures are recommended if necessary.

Adverse Reactions

The adverse reactions listed in the table below are classified according to system organ classes and frequency of occurrence, as identified in clinical trials and during the post-marketing surveillance period, observed with all dosage forms of azithromycin. Adverse reactions reported during the post-marketing surveillance period are indicated in italics. Frequency categories were defined according to the following scale: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10,000 to < 1/1000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency group, adverse events are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin, based on data from clinical trials 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 surveillance. These adverse reactions differ in type or frequency from those reported with the use of immediate-release and extended-release medicinal products.

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

Shelf life. 2 years.

Shelf life of the reconstituted suspension – 5 days (15 mL), 10 days (30 mL, 37.5 mL).

Storage conditions.

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

Store the reconstituted suspension at a temperature not exceeding 25 °C.

Packaging.

One vial containing powder for oral suspension of 15 mL (600 mg), or 30 mL (1200 mg), or 37.5 mL (1500 mg), together with an oral 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.