Sumamed

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

Composition:

Active substance: azithromycin;

1 capsule contains 250 mg of azithromycin as dihydrate;

Excipients: microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate, gelatin, titanium dioxide (E 171), indigo carmine (E 132), sulfur dioxide (E 220).

Pharmaceutical form. Capsules.

Main physicochemical characteristics: hard gelatin capsules size No. 1 with an opaque blue body and an opaque blue cap; the capsule contents: crystalline powder or agglomerate of crystalline powder, white to yellowish in color.

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 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 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 streptococci, 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 species 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 is such that the efficacy of the drug for the treatment of 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 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-fold) than in 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 have also been 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 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 (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;
• Sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.

Contraindications.

Hypersensitivity to azithromycin, erythromycin, or to any macrolide or ketolide antibiotic, as well as 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, no pharmacokinetic interaction or significant changes in the 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, concomitant administration of daily doses of 1200 mg azithromycin with 400 mg didanosine per day showed no effect on 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 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 blood 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 not established, but it 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 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 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 receiving 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 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, post-marketing reports have described 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 C_max and AUC_0-5 of cyclosporine 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 coadministered; however, a clinically insignificant reduction in C_max (18%) of azithromycin was observed.

Indinavir. Concomitant administration of a single 1200 mg dose of azithromycin did not cause any 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 intake has not been established.

Sildenafil. In healthy male volunteers, there was no evidence of an effect of azithromycin (500 mg daily for 3 days) on AUC or C_max of sildenafil or its main circulating metabolite.

Terfenadine. Pharmacokinetic studies did not report any interaction 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 interaction between azithromycin and theophylline in healthy volunteers.

Triazolam. Concomitant administration of azithromycin (500 mg on day 1 and 250 mg on day 2) with 0.125 mg triazolam in healthy volunteers 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 1200 mg azithromycin on day 7 showed no significant effect on maximum 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

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

Since the liver is the primary route of elimination for azithromycin, caution should be exercised when prescribing azithromycin to patients with severe hepatic impairment. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported during azithromycin therapy. Some patients may have had pre-existing liver disease or may have been taking other hepatotoxic medicinal products.

Liver function tests should be performed if signs or symptoms of hepatic dysfunction develop, such as rapidly progressing fatigue associated with jaundice, dark urine, tendency to bleed, 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. There are no data available 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. Strains of C. difficile 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 presenting with diarrhea following antibiotic use. A careful medical history is necessary, as CDAD has been reported to occur up to two months after administration of antibacterial agents.

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/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 significant bradycardia, cardiac arrhythmias, or severe cardiac insufficiency.

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 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 (MAC) in children have not been established.

Use during pregnancy or breastfeeding.

Pregnancy.

There are no adequate data on azithromycin use in pregnant women. Reproductive toxicity studies in animals have not shown any teratogenic or harmful effects of azithromycin 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 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 convulsions, which may affect the ability to drive or operate machinery, should be taken into account.

Method of Administration and Dosage

Sumamed® should be taken 1 hour before or 2 hours after a meal, as concomitant food intake interferes with the absorption of azithromycin. Capsules must be swallowed whole. The drug is taken once daily.

Adults and children with body weight ≥45 kg.

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: on day 1, take 1 g (4 capsules at once), then 500 mg (2 capsules at once) from day 2 to day 5. The duration of treatment is 5 days.

For sexually transmitted infections: the total dose of azithromycin is 1 g (4 capsules at once).

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

Elderly patients.

Dosage adjustment is not required in elderly patients.

However, since elderly patients may belong to risk groups for disturbances in cardiac conduction, caution is recommended when using azithromycin due to the risk of developing cardiac arrhythmias, including torsade de pointes.

Patients with renal impairment.

In patients with mild to moderate renal impairment (glomerular filtration rate 10–80 mL/min), the same dosage regimen as in patients with normal renal function may be used. 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 used in patients with severe hepatic impairment. Clinical studies on the use of azithromycin in such patients have not been conducted.

Children.

Sumamed® capsules are indicated for use in children with body weight ≥45 kg.

Overdose.

Clinical experience with azithromycin indicates that adverse effects observed following overdose are similar to those seen with normal therapeutic doses. These may include diarrhea, nausea, vomiting, and reversible hearing loss. In case of overdose, activated charcoal may be administered if necessary, along with general symptomatic and supportive treatment measures.

Adverse Reactions

The adverse reactions listed below are classified by system organ class and frequency of occurrence, based on data from clinical trials and post-marketing surveillance observed during the use of all azithromycin dosage forms. Adverse reactions identified 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 (≥1/1000 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 grouping, adverse events are listed in order of decreasing severity.

Adverse reactions possibly or probably related to azithromycin based on data from clinical trials 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 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

The product contains sulfur dioxide (E 220), which may rarely cause hypersensitivity reactions and bronchospasm.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 6 capsules per blister, 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

Manufacturer's address and place of business. Prilaz baruna Filipovića 25, 10000 Zagreb, Croatia.