INSTRUCTION
for medical use of the medicinal product
SUMAMED®
(SUMAMED®)
Composition:
active substance: azithromycin;
1 capsule contains azithromycin 250 mg in the form of dihydrate;
excipients: microcrystalline cellulose, sodium lauryl sulfate, magnesium stearate, gelatin, titanium dioxide (E 171), indigo carmine (E 132), sulfur dioxide (E 220).
Medicinal form. Capsules.
The main physical and chemical properties: hard gelatin capsules No. 1 with an opaque blue body and an opaque blue cap; capsule contents: crystalline powder from white to yellowish color or a lump of crystalline powder from white to yellowish color.
Pharmacotherapeutic group. Antibacterial agents for systemic use. Macrolides, lincosamides and streptogramins. Azithromycin. ATX code J01F A10.
Pharmacological properties.
Pharmacodynamics.
Azithromycin is a macrolide antibiotic that belongs to the azalide group. The molecule is formed as a result of the introduction of a nitrogen atom into the lactone ring of erythromycin A. The mechanism of action of azithromycin is inhibition of bacterial protein synthesis by binding to the 50S subunit of ribosomes and inhibition of peptide translocation.
Mechanism of resistance.
Complete cross-resistance exists in Streptococcus pneumoniae, group A beta-hemolytic streptococcus, Enterococcus faecalis, and Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA), to erythromycin, azithromycin, other macrolides, and lincosamides.
The prevalence of acquired resistance for selected species may vary by location and time, so local information on resistance is needed, especially when treating severe infections. If necessary, qualified advice may be sought if the local prevalence of resistance is such that the efficacy of the drug in the treatment of at least some types of infection is questionable.
Spectrum of antimicrobial action of azithromycin
Usually sensitive species
Aerobic gram-positive bacteria
Staphylococcus aureus is methicillin-sensitive
Streptococcus pneumoniae is penicillin sensitive
Streptococcus pyogenes
Aerobic gram-negative bacteria
Haemophilus influenzae
Haemophilus parainfluenzae
Legionella pneumophila
Moraxella catarrhalis
Pasteurella multocida
Anaerobic bacteria
Clostridium perfringens
Fusobacterium spp.
Prevotella spp.
Porphyriomonas spp.
Other microorganisms
Chlamydia trachomatis
Chlamydia pneumoniae
Mycoplasma pneumoniae
Species for which acquired resistance may be a problem
Aerobic gram-positive bacteria
Streptococcus pneumoniae with intermediate sensitivity to penicillin and penicillin-resistant
Innately resistant organisms
Aerobic gram-positive bacteria
Enterococcus faecalis
Staphylococci MRSA, MRSE*
Anaerobic bacteria
Group of bacteroides Bacteroides fragilis
*Methicillin-resistant Staphylococcus aureus has a very high prevalence of acquired resistance to macrolides and was listed here because of rare susceptibility to azithromycin.
Pharmacokinetics.
Bioavailability after oral administration is approximately 37%. The maximum concentration in blood serum is reached 2-3 hours after taking the drug.
When taken internally, azithromycin is distributed throughout the body. In pharmacokinetic studies, it was shown that the concentration of azithromycin in tissues is significantly higher (50 times) than in blood plasma, which indicates strong binding of the drug to tissues.
Binding to serum proteins varies depending on plasma concentrations and ranges 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) was 31.1 L/kg.
The final plasma half-life completely reflects the half-life from tissues within 2–4 days.
Approximately 12% of an intravenous dose of azithromycin is excreted unchanged in the urine over the next 3 days. Particularly high concentrations of unchanged azithromycin were found in human bile. Also, 10 metabolites were found in bile, which were formed as a result of N- and O-demethylation, hydroxylation of desosamine and aglycone rings, and cleavage of cladinose conjugate. A comparison of the results of liquid chromatography and microbiological analyzes showed that the metabolites of azithromycin are not microbiologically active.
Clinical characteristics.
Indication.
Infections caused by microorganisms sensitive to azithromycin:
• infections of ENT organs (bacterial pharyngitis/tonsillitis, sinusitis, otitis media);
• respiratory tract infections (bacterial bronchitis, community-acquired pneumonia);
• skin and soft tissue infections: erythema migrans (initial stage of Lyme disease), dysentery, impetigo, secondary pyodermatoses;
• sexually transmitted infections: uncomplicated genital infections caused by Chlamydia trachomatis.
Contraindication.
Hypersensitivity to azithromycin, erythromycin, to any macrolide or ketolide antibiotic, as well as to any other component of the drug.
Interaction with other medicinal products and others of interactions.
Antacids. When studying the effect of simultaneous use of antacids on the pharmacokinetics of azithromycin in general, no changes in bioavailability were observed, although the plasma peak concentration of azithromycin was reduced by approximately 25%. Do not take azithromycin and antacids at the same time.
Cetirizine. In healthy volunteers, no pharmacokinetic interaction or significant changes in the QT interval were observed during the simultaneous use of azithromycin for 5 days with cetirizine 20 mg in the steady state.
Didanosine. At the simultaneous use of daily doses of 1200 mg of azithromycin with 400 mg of didanosine per day in six HIV-positive volunteers, there was no effect on the steady-state pharmacokinetics of didanosine compared to placebo.
Digoxin and colchicine. Concomitant use of macrolide antibiotics, including azithromycin, and P-glycoprotein substrates such as digoxin and colchicine has been reported to result in increased serum P-glycoprotein substrate levels. Therefore, with the simultaneous use of azithromycin and a substrate of P-glycoprotein, such as digoxin, it is necessary to take into account the possibility of increasing the concentration of the substrate in blood serum.
Zidovudine. Single doses of 1000 mg and multiple doses of 1200 mg or 600 mg of azithromycin had little effect on the plasma pharmacokinetics or urinary excretion of zidovudine or its glucuronide metabolites. However, taking azithromycin increased the concentration of phosphorylated zidovudine, a clinically active metabolite, in mononuclear cells in the peripheral circulation. The clinical significance of these findings has not been established, but may be useful for patients.
Azithromycin has no significant interaction with the hepatic cytochrome P450 system. It is believed that the drug does not have a pharmacokinetic drug interaction characteristic of erythromycin and other macrolides. Azithromycin does not induce or inactivate hepatic cytochrome P450 through the cytochrome-metabolite complex.
Horns Given the theoretical possibility of ergotism, simultaneous administration of azithromycin with ergot derivatives is not recommended.
Pharmacokinetic studies of the use of azithromycin and the following drugs, the metabolism of which largely occurs with the participation of cytochrome P450, were conducted.
Atorvastatin. The simultaneous use of atorvastatin (10 mg per day) and azithromycin (500 mg per day) did not cause changes in the concentrations of atorvastatin in blood plasma (based on the analysis of inhibition of HMG CoA-reductase). However, in the post-marketing period, cases of rhabdomyolysis have been reported in patients using azithromycin with statins.
Carbamazepine. In a study of pharmacokinetic interaction in healthy volunteers, azithromycin did not show a significant effect on plasma levels of carbamazepine or its active metabolites.
Cimetidine. In a pharmacokinetic study of the effect of a single dose of cimetidine taken 2 hours before taking azithromycin on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were observed.
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. In the post-marketing period, there have been reports of potentiation of the anticoagulant effect after the simultaneous 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 coumarin-type anticoagulants.
Cyclosporine. A pharmacokinetic study in healthy volunteers treated with oral azithromycin 500 mg/day for 3 days followed by a single oral dose of cyclosporine 10 mg/kg demonstrated a significant increase in Cmax and AUC0-5 of cyclosporine. Therefore, caution should be exercised when using these drugs simultaneously. If concomitant use of these drugs is necessary, cyclosporine levels should be monitored and the dose adjusted accordingly.
Efavirenz. Concomitant administration of a single dose of 600 mg azithromycin and 400 mg efavirenz daily for 7 days did not result in any clinically significant pharmacokinetic interaction.
Fluconazole. Simultaneous use of a single dose of azithromycin 1200 mg does not change the pharmacokinetics of a single dose of fluconazole 800 mg. The total exposure and half-life of azithromycin did not change with the simultaneous use of fluconazole, but a clinically insignificant decrease in Cmax (18%) of azithromycin was observed.
Indinavir. Simultaneous use of a single dose of azithromycin 1200 mg does not cause a statistically significant effect on the pharmacokinetics of indinavir, which is taken at a dose of 800 mg 3 times a day for 5 days.
Methylprednisolone. In the study of pharmacokinetic interaction in healthy volunteers, azithromycin did not significantly affect the pharmacokinetics of methylprednisolone.
Midazolam. Simultaneous use in healthy volunteers azithromycin 500 mg per day for 3 days did not cause clinically significant changes in the pharmacokinetics and pharmacodynamics of midazolam, which was used as a single dose of 15 mg.
Nelfinavir. Simultaneous use of azithromycin (1200 mg) and nelfinavir in equilibrium concentrations (750 mg 3 times a day) causes an increase in the concentration of azithromycin. Clinically significant side effects were not observed, accordingly, there is no need to adjust the dose.
Rifabutin. Simultaneous use of azithromycin and rifabutin did not affect the concentrations of these drugs in blood serum. Neutropenia was observed in subjects who received azithromycin and rifabutin simultaneously. Although neutropenia has been associated with rifabutin, a causal relationship with concomitant azithromycin 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 and Cmax of sildenafil or its major circulating metabolite.
Terfenadine. No interaction between azithromycin and terfenadine was reported in pharmacokinetic studies. In some cases, the possibility of such interaction cannot be completely excluded; however, there are no specific data on the presence of such an interaction.
Theophylline. There are no data on a clinically significant pharmacokinetic interaction with the simultaneous use of azithromycin and theophylline in healthy volunteers.
Triazolam. Simultaneous use of azithromycin 500 mg on the first day and 250 mg on the second day with 0.125 mg of triazolam by healthy volunteers did not significantly affect all pharmacokinetic indicators of triazolam compared to the use of triazolam and placebo.
Trimethoprim/sulfamethoxazole. Coadministration of double-strength trimethoprim/sulfamethoxazole (160 mg/800 mg) for 7 days with azithromycin 1200 mg on day 7 had no significant effect on peak concentrations, total exposure, or urinary excretion of trimethoprim or sulfamethoxazole. The values of azithromycin concentrations in blood serum were consistent with those observed in other studies.
Hydroxychloroquine. Azithromycin should be used with caution in patients receiving drugs that prolong the QT interval and may cause cardiac arrhythmia, such as hydroxychloroquine.
Features of application.
As with erythromycin and other macrolide antibiotics, rare serious allergic reactions have been reported, including angioedema and anaphylaxis (in isolated cases - fatal), dermatological reactions, including acute generalized exanthematous pustulosis. Some of these azithromycin-induced reactions resulted in recurrent symptoms and required longer follow-up and treatment.
Because the liver is the major route of elimination of azithromycin, caution should be exercised when prescribing azithromycin to patients with severe liver disease. Cases of fulminant hepatitis, causing life-threatening liver failure, have been reported with azithromycin. It is possible that some patients had a history of liver disease or used other hepatotoxic drugs.
Liver function tests/tests should be performed if signs and symptoms of liver dysfunction develop, such as rapidly developing asthenia accompanied by jaundice, dark urine, bleeding tendency, or hepatic encephalopathy. In case of detection of liver dysfunction, the use of azithromycin should be stopped.
In patients taking ergot derivatives, the simultaneous use of some macrolide antibiotics contributes to the rapid development of ergotism. There are no data on the possibility of interaction between ergot and azithromycin. However, due to the theoretical possibility of ergotism, azithromycin should not be prescribed simultaneously with ergot derivatives.
As with other antibiotics, monitoring for signs of superinfection caused by nonsusceptible organisms, including fungi, is recommended.
Clostridium difficile-associated diarrhea (CDAD), ranging in severity from mild diarrhea to fatal colitis, has been reported with almost all antibacterial drugs, including azithromycin. Antibiotic treatment alters the normal flora in 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 overproduce toxins are responsible for increased morbidity and mortality, as these infections may be resistant to antimicrobial therapy and require colectomy. The possibility of CDAD should be considered in all patients with antibiotic-induced diarrhea. A careful medical history is required, as CDAD has been reported to occur within 2 months of taking antibacterial drugs.
In patients with severe renal dysfunction (glomerular filtration rate <10 mL/min), a 33% increase in systemic exposure to itromycin.
Prolongation of cardiac repolarization and QT interval, which increased the risk of cardiac arrhythmia and ventricular flutter/fibrillation (torsade de pointes), was observed with treatment with other macrolide antibiotics, including azithromycin. Because conditions associated with an increased risk of ventricular arrhythmias (including torsade de pointes) may lead to cardiac arrest, azithromycin should be administered with caution to patients with pre-existing proarrhythmic conditions (especially women and the elderly), including patients with:
with congenital or registered prolongation of the QT interval;
who are currently being treated with other active substances known to prolong the QT interval, such as class IA (quinidine and procainamide) and class III (dofetilide, amiodarone and sotalol) antiarrhythmic drugs, cisapride and terfenadine, antipsychotics such as pimozide ; antidepressants such as citalopram and fluoroquinolones such as moxifloxacin and levofloxacin;
with a violation of electrolyte metabolism, especially in the case of hypokalemia and hypomagnesemia;
with clinically relevant bradycardia, cardiac arrhythmia or severe heart failure.
Exacerbation of symptoms of myasthenia gravis or new development of myasthenic syndrome have been reported in patients receiving azithromycin therapy.
Streptococcal infections. In the treatment of pharyngitis/tonsillitis caused by Streptococcus pyogenes, penicillin is usually the drug of choice, and it is also used prophylactically in acute rheumatic fever. Azithromycin is generally effective in the treatment of streptococcal infection in the oropharynx, but there are no data demonstrating the effectiveness of azithromycin in the prevention of rheumatic attacks.
The safety and efficacy of intravenous azithromycin for the treatment of infections in children have not been established.
Safety and efficacy for prevention or treatment of Mycobacterium Avium Complex in children have not been established.
Use during pregnancy or breastfeeding.
Pregnancy.
There are no adequate data on the use of azithromycin in pregnant women. In studies of reproductive toxicity in animals, teratogenic harmful effects of azithromycin on the fetus were not noted, however, the drug penetrated the placenta. The safety of azithromycin use during pregnancy has not been confirmed. Therefore, azithromycin is prescribed during pregnancy only if the benefit outweighs the risk.
Breast-feeding.
It has been reported that azithromycin is excreted in human milk, but adequate and well-controlled clinical studies have not been conducted to characterize the pharmacokinetics of azithromycin excretion in human milk.
Fertility.
Fertility studies were performed on rats; the pregnancy rate decreased after the introduction of azithromycin. The relevance of these data to humans is unknown.
The ability to influence the speed of reaction when driving vehicles or other mechanisms.
There is no evidence that azithromycin can impair the ability to drive vehicles or operate other mechanisms, but the possibility of developing adverse reactions such as delirium, hallucinations, dizziness, drowsiness, fainting, convulsions, which may affect the ability to drive vehicles or other mechanisms, should be considered .
Method of application and dosage.
Sumamed® should be taken 1 hour before or 2 hours after a meal, because simultaneous intake disrupts the absorption of azithromycin. Capsules must be swallowed whole. Take the drug once a day.
Adults and children weighing ≥45 kg.
For infections of the ENT organs and respiratory tract, skin and soft tissues (except for chronic migratory erythema), the total dose of azithromycin is 1500 mg: 500 mg once a day. The duration of treatment is 3 days.
For erythema migrans, the total dose of azithromycin is 3 g: on the 1st day, 1 g (4 capsules at one time) should be taken, then 500 mg (2 capsules at one time) from the 2nd to the 5th day. The duration of treatment is 5 days.
For sexually transmitted infections: the total dose of azithromycin is 1 g (4 capsules at one time).
In case of missing 1 dose of the drug, the missed dose should be taken as early as possible, and the next dose should be taken at intervals of 24 hours.
Elderly patients.
There is no need to change the dosage in elderly patients.
Since elderly patients may be at risk for cardiac conduction disturbances, caution is advised when using azithromycin due to the risk of cardiac arrhythmias and torsade de pointes.
Patients with impaired renal function.
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 prescribed with caution to patients with severe renal impairment (glomerular filtration rate <10 ml/min).
Patients from monitoring of liver function.
Since azithromycin is metabolized in the liver and excreted in the bile, the drug should not be used in patients with severe hepatic impairment. Studies related to the treatment of such patients using azithromycin have not been conducted.
Children.
Sumamed®, capsules, should be used in children with a body weight of ≥45 kg.
Overdose.
The experience of clinical use of azithromycin shows that the side effects that develop when taking higher than recommended doses of the drug are similar to those observed when using usual therapeutic doses. They can include diarrhea, nausea, vomiting, reversible hearing loss. In case of overdose, if necessary, it is recommended to take activated charcoal and carry out general symptomatic and supportive medical measures.
Adverse reactions.
In the table below, according to the class of systems and organs and the frequency of occurrence, adverse reactions identified in clinical studies and in the period of post-marketing surveillance, which were observed with the use of all dosage forms of azithromycin, are indicated. Adverse reactions reported during post-marketing surveillance are highlighted in italics. Groups according to the frequency of manifestations were determined according to the following scale: very often (≥1/10); often (≥1/100 to <1/10); infrequent (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1,000), very rare (<1/10,000); unknown (cannot be determined from available data). Within each group, adverse events are listed in order of decreasing severity by frequency of occurrence.
Adverse reactions possibly or probably related to azithromycin based on data from clinical trials and post-marketing surveillance
System organ class Adverse reaction Frequency
Infections and infestations Candidiasis, vaginal infections, pneumonia, fungal infection, bacterial infection, pharyngitis, gastroenteritis, respiratory disorder, rhinitis, oral candidiasis Uncommon
Pseudomembranous colitis Not known
From the blood and lymphatic system: Leukopenia, neutropenia, eosinophilia Infrequent
Thrombocytopenia, hemolytic anemia Unknown
From the side of the immune system Angioedema, hypersensitivity reactions Infrequent
Anaphylactic reaction Not known
From the side of metabolism Anorexia Infrequent
On the part of psyche Nervousness, insomnia Infrequent
Agitation Rarely
Aggressiveness, anxiety, delirium, hallucinations Not known
From the side of the nervous system Headache Often
Dizziness, drowsiness, dysgeusia, paresthesia Infrequent
Fainting, convulsions, hypoesthesia, increased psychomotor activity, anosmia, ageusia, parosmia, myasthenia gravis Unknown
On the part of the organs of vision Visual impairment Infrequent
On the part of the organs of hearing Disorders on the part of the organs of hearing, vertigo Infrequent
Hearing impairment, including deafness and/or tinnitus Not known
From the side of the heart Palpitations Infrequent
Ventricular flutter/fibrillation (torsade de pointes), arrhythmia including ventricular tachycardia, QT prolongation on ECG Not known
On the part of the vessels, Tides Infrequently
Arterial hypotension Not known
On the part of the respiratory system: Dyspnoea, epistaxis Infrequent
From the side of the digestive tract Diarrhea Very often
Vomiting, abdominal pain, nausea Often
Constipation, flatulence, dyspepsia, gastritis, dysphagia, flatulence, dry mouth, belching, oral ulcers, hypersecretion of saliva Uncommon
Pancreatitis, tongue discoloration Unknown
From the side of the hepatobiliary system Liver function disorders, cholestatic jaundice Rarely
Hepatic failure (rarely fatal), fulminant hepatitis, liver necrosis Not known
From the side of the skin and subcutaneous tissue Rash, itching, urticaria, dermatitis, dry skin, hyperhidrosis Uncommon
Photosensitivity, acute generalized exanthematous pustulosis Rare
Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, drug reaction with eosinophilia and systemic symptoms Not known
From the musculoskeletal system Osteoarthritis, myalgia, back pain, neck pain Infrequent
Arthralgia Not known
From the urinary system Dysuria, kidney pain Infrequent
Acute renal failure, interstitial nephritis Not known
From the side of the reproductive system and mammary glands. Uterine bleeding, testicular disorders Infrequent
General disorders and administration site conditions Edema, asthenia, malaise, fatigue, facial swelling, chest pain, hyperthermia, pain, peripheral edema Uncommon
Laboratory parameters Decreased number of lymphocytes, increased number of eosinophils, decreased blood bicarbonate, increased basophils, increased monocytes, increased neutrophils Often
Aspartate aminotransferase increased, Alanine aminotransferase increased, Blood bilirubin increased, Blood urea increased, Blood creatinine increased, Blood potassium changes, Alkaline phosphatase increased, Chloride increased, Glucose increased, Platelet increased, Decreased hematocrit level, increase in bicarbonate level, rejected changes in sodium level Uncommon
Injuries and poisoning Complications after the procedure Infrequent
Information on adverse reactions possibly related to the prevention and treatment of Mycobacterium Avium Complex is based on data from clinical studies and observations in the post-marketing period. These adverse reactions differ in type or frequency from those reported with the rapid-acting dosage forms and the long-acting dosage forms.
Adverse reactions possibly related to the prevention and treatment of Mycobacterium Avium Complex
System organ class Adverse reaction Frequency
Metabolism Anorexia Often
From the nervous system Dizziness, headache, paresthesia, dysgeusia Often
Hypoesthesia Infrequent
On the part of the organs of vision Visual impairment Often
Hearing Deafness Often
Hearing impairment, tinnitus Infrequent
From the side of the heart Palpitations Infrequent
From the digestive tract Diarrhea, abdominal pain, nausea, flatulence, gastrointestinal discomfort, frequent loose stools Very common
From the side of the hepatobiliary system Hepatitis Infrequently
From the side of the skin and subcutaneous tissue Rashes, itching Often
Stevens-Johnson syndrome, photosensitivity Infrequent
From the musculoskeletal system Arthralgia Often
General disorders and local reactions Increased fatigue Often
Asthenia, malaise Infrequent
The drug contains sulfur dioxide (E 220), so it can rarely cause hypersensitivity reactions and bronchospasm.
Expiration date. 3 years.
Storage conditions.
Store at a temperature not higher than 25 °C. Keep out of the reach of children.
Packaging. 6 capsules in a blister, 1 blister in a cardboard box.
Leave category. By prescription.
Producer. PLIVA Hrvatska d.o.o.
The location of the manufacturer and the address of the place of its activity.
Prilaz baruna Filipovica 25, 10000 Zagreb, Croatia.
