Sumamed

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

Composition:

Active substance: azithromycin;

1 tablet contains azithromycin 125 mg or 250 mg, or 500 mg, or 1000 mg as azithromycin dihydrate;

Excipients: sodium saccharin dihydrate, microcrystalline cellulose, crospovidone (type A), povidone, sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate, aspartame (E 951); tablets of 125 mg – banana flavoring, tablets of 250 mg, 500 mg, 1000 mg – orange flavoring.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties:

Tablets of 125 mg: round, flat tablets of white or almost white color, beveled edge, with a score line and imprint «TEVA 125» on one side;

Tablets of 250 mg: round, flat tablets of white or almost white color, beveled edge, with a score line, a single notch on one side and imprint «TEVA 250» on the other side;

Tablets of 500 mg: round, flat tablets of white or almost white color, beveled edge, with a score line, a single notch on one side and imprint «TEVA 500» on the other side;

Tablets of 1000 mg: round, flat tablets of white or almost white color, beveled edge, with a score line, two perpendicular notches on one side and imprint «TEVA 1000» on the other side.

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 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 the treatment of at least some types of infections.

Antimicrobial spectrum of azithromycin

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

Based on studies conducted in children, the use of azithromycin for the treatment of malaria is not recommended, either as monotherapy or in combination with chloroquine-based or artemisinin-based drugs, since no superior efficacy has been demonstrated compared to antimalarial agents recommended for the treatment of uncomplicated malaria.

Pharmacokinetics.

Oral bioavailability is approximately 37%. Maximum serum concentration is reached within 2–3 hours after drug administration.

After oral administration, azithromycin distributes throughout the body. Pharmacokinetic studies have shown that azithromycin concentrations in tissues are significantly higher (up to 50 times) than in blood plasma, indicating strong tissue binding.

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 detected 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 results and microbiological assays showed that azithromycin metabolites are not microbiologically active.

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to azithromycin:

• Otorhinolaryngological 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 any other macrolide or ketolide antibiotic, as well as to any other component of the medicinal product.

Interaction with other medicinal products and other types of interactions.

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, co-administration of azithromycin for 5 days with cetirizine 20 mg at steady state did not show any 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 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 digoxine 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 serum substrate concentration should be considered. Clinical monitoring, and if possible, monitoring of serum digoxin levels, should be performed during and after azithromycin treatment.

Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg azithromycin had negligible effects on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, azithromycin administration increased concentrations of phosphorylated zidovudine, the clinically active metabolite, in peripheral blood mononuclear cells. The clinical significance of these data is not fully understood, 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 induce or inactivate 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 result in any 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, monitoring of prothrombin time should be performed when azithromycin is prescribed 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 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 with concomitant fluconazole administration, 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 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) 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. No evidence was found of the effect of azithromycin (500 mg daily for 3 days) on AUC and Cmax values of sildenafil or its main circulating metabolite in healthy male volunteers.

Terfenadine. Pharmacokinetic studies did not report any interaction between azithromycin and terfenadine. However, such an interaction cannot be completely ruled out, although data on its occurrence are lacking.

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 triazolam (0.125 mg) 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 did not significantly affect peak 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.

Hypersensitivity

As with erythromycin and other macrolide antibiotics, rare but serious allergic reactions have been reported, including angioneurotic edema and anaphylaxis (in isolated cases – with fatal outcome), dermatological reactions including acute generalized exanthematous pustulosis, Stevens–Johnson syndrome, toxic epidermal necrolysis (in isolated cases – with fatal outcome), and drug reaction with eosinophilia and systemic symptoms (DRESS). Some of these reactions caused by azithromycin have been associated with recurrent symptoms.

If an allergic reaction occurs, administration of the medicinal product should be discontinued and appropriate therapy initiated. Physicians should be aware that allergic symptoms may recur after discontinuation of symptomatic treatment.

Hepatotoxicity

Since the liver is the primary route of elimination of azithromycin, azithromycin should be administered with caution in patients with severe hepatic impairment. Cases of fulminant hepatitis leading to life-threatening liver dysfunction have been reported in patients receiving azithromycin. 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 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.

Ergot derivatives

In patients receiving ergot derivatives, concomitant administration of some macrolide antibiotics has been associated with rapid onset of ergotism. There are no data available on the potential interaction between ergot derivatives and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be co-administered with ergot derivatives.

Superinfection

As with other antibiotics, monitoring for signs of superinfection caused by non-susceptible organisms, including fungi, is recommended.

Clostridium difficile-associated diarrhea (CDAD)

Diarrhea associated with Clostridium difficile (CDAD), with severity ranging from mild diarrhea to fatal colitis, has been reported with nearly all antibacterial agents, including azithromycin. 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 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 administration of antibacterial agents.

Renal impairment

In patients with severe renal impairment (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to azithromycin has been observed.

QT interval prolongation

Prolongation of cardiac repolarization and QT interval, which increases 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 administered 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 disturbances, particularly hypokalemia and hypomagnesemia;
• with clinically relevant bradycardia, cardiac arrhythmia, or severe heart failure.

Myasthenia gravis

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

Streptococcal infections

For the 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.

Children

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.

Excipients

Aspartame. The medicinal product contains aspartame, a phenylalanine derivative, which may be harmful for patients with phenylketonuria.

Sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e. essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

There are insufficient data on the use of azithromycin in pregnant women. In animal reproductive toxicity studies, azithromycin showed no 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 conducted in rats showed a decreased pregnancy rate following administration of azithromycin. The relevance of these findings to humans is unknown.

Ability to affect the ability to drive and use machines.

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, syncope, and seizures, which may affect the ability to drive or use machinery, should be taken into account.

Method of Administration and Dosage

Sumamed®, dispersible tablets, should be taken once daily. 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 tablet should be dissolved in a sufficient amount of liquid, such as water, apple juice, or orange juice (half a glass), stirring until a fine suspension is obtained. After the suspension is consumed, any residue should be mixed with a small amount of water, stirred, and consumed as well. The prepared suspension may be taken regardless of food intake. The score line on the tablet is not intended for dividing the tablet.

Adults, including elderly patients and children with body weight >45 kg

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

For erythema migrans, the total dose of azithromycin is 3 g, administered as follows: 1000 mg on the first day, followed by 500 mg once daily from day 2 to day 5.

For uncomplicated sexually transmitted infections caused by Chlamydia trachomatis, the recommended single dose of azithromycin is 1000 mg.

Elderly patients

Dosage adjustment is not required in elderly patients.

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

Patients with renal impairment

The same doses 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. Clinical studies on azithromycin use in such patients have not been conducted.

Children

The medication may be administered to children with body weight >45 kg, for whom adult dosing may be applied.

Overdose

Clinical experience with azithromycin indicates that adverse effects associated with doses higher than recommended are similar to those observed with standard 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 based on clinical studies and post-marketing surveillance for all azithromycin formulations. The adverse reactions identified during the post-marketing period are italicized. The frequencies 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 the 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 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 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 medicinal products.

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

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after the medicinal product has been authorized. This enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report all suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

The medicinal product does not require special storage conditions. Keep out of reach and sight of children.

Packaging.

Tablets 125 mg, 250 mg: 6 tablets in a blister; 1 blister per carton.

Tablets 500 mg: 3 tablets in a blister; 1 or 2 blisters per carton.

Tablets 1000 mg: 1 tablet in a blister; 1 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. PLIVA Hrvatska d.o.o.

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