Sumaсlid® capsules 250 mg №6

Sumaсlid® capsules 250 mg №6

International nonproprietary name

Azithromycin

Pharmacological group

Антибактериальные средства

Composition

Active substance:
Azithromycin dihydrate equivalent
to anhydrous azithromycin - 250 mg
Excipients:
maize starch - 40 mg
calcium stearate - 8 mg
microcrystalline cellulose - up to 350 mg
Hard gelatin capsule including: titanium dioxide - 2 % gelatin - up to 100 %

Pharmacological action

Pharmacodynamics. Azithromycin is a bacteriostatic broad-spectrum antibiotic from the group of macrolides-azalides. The drug has a wide spectrum of antimicrobial effects. The mechanism of action of azithromycin is associated with suppression of the microbial cell protein synthesis. Binding to the 50S subunit of ribosomes, the drug inhibits peptidranslokase at the stage of translation, suppresses protein synthesis, slows the growth and multiplication of bacteria, at high concentrations has a bactericidal effect.
It is active against several gram-positive, gram-negative, anaerobes, intracellular and other microorganisms.
Microorganisms can initially be resistant to the action of the antibiotic or can acquire resistance to it. In most cases, susceptible microorganisms include:
1 Gram-positive aerobes methicillin-sensitive Staphylococcus aureus, penicillin-sensitive Streptococcus pneumoniae, Streptococcus pyogenes$
2 Gram-negative aerobes: Haemophilus influenzae, Haemophilus parainfluenzae, Legionella pneumophila, Moraxella catarrhalis, Pasteurella multocida, Neisseria gonorrhoeae;
3 Anaerobes Clostridium perfringens, Fusobacterium spp., Prevotella spp., Porphyriomonas spp.;
4 Other microorganisms;
Chlamydia trachomatis, Chlamydia pneumoniae, Chlamydia psittaci, Mycoplasma pneumoniae, Mycoplasma hominis, Borrelia burgdorferi. Microorganisms that can develop resistance to azithromycin:
Gram-positive aerobes: Penicillin-resistant Streptococcus pneumoniae Initially, resistant microorganisms Gram-positive aerobes: Enterococcus faecalis, Staphylococcus spp. (methicillin-resistant staphylococci exhibit a very high degree of resistance to macrolides), Gram-positive bacteria resistant to erythromycin.
Anaerobes Bacteroides fragilis.

Pharmacokinetics

Absorption is high. Azithromycin is stable in an acidic medium and lipophilic. The drug is quickly absorbed in the gastrointestinal tract. Bioavailability after the single dose 0.5 g is 37% (the effect of first pass through the liver), the maximum plasma concentration of the drug after oral administration of 0.5 g is 0.4 mg/l, time to the maximum plasma concentration of the drug is 2,5-2.9 h; in tissues and cells the concentration is 10-50 times higher than in serum, the volume of distribution is 31.1 l/kg.
The drug easily crosses the histohematological barriers. The drug penetrates well into the respiratory tract, urino-genital organs and tissues, into the prostate gland, into the skin and soft tissues; accumulates in lysosomes (which is especially important for eradication of intracellular pathogens). It is also transported by phagocytes, polymorphonuclear leukocytes and macrophages. It crosses the membranes of cells and creates high concentrations in them.
The concentration in the infection foci is significantly higher (by 24-34%) than in healthy tissues, and correlates with the inflammatory edema severity. Azithromycin persists in effective concentrations within 5-7 days after administration of the last dose. Binding to the plasma proteins is 7-50% (inversely proportional to the concentration in the blood). The drug is demethylated in the liver, the formed metabolites are inactive.
The drug metabolism involves isozymes CYP3A4, CYP3A5, CYP3A7, as the drug is their inhibitor. Plasma clearance is 630 ml/min: the half-life of the drug within the period from 8 and 24 hours after administration is 14-20 hours, the half-life of the drug within the period from 24 to 72 hours is 41 hours. 50% is excreted with bile in unchanged form, 6% - by the kidneys. Food significantly changes the pharmacokinetics (based on the dosage form): capsules - the maximum plasma concentration of the drug decreases (by 52 %), the area under the "concentration-time" curve decreases (by 43%).
In elderly patients (65-85 years) the pharmacokinetic parameters do not change, in women the maximum plasma concentration of the drug increases (by 30-50%), in children of 3-5 years old, the maximum plasma concentration of the drug, the half-life of the drug, and the area under the concentration-time curve decrease.

Indications for Use

Inflammatory infections caused by microorganisms susceptible to the drug:
infections of the upper respiratory tract and ENT organs (pharyngitis, tonsillitis, sinusitis, otitis media);
the lower respiratory tract infections (acute bronchitis, exacerbation of chronic bronchitis, pneumonia, including those caused by atypical pathogens);
skin and soft tissue infections (erysipelas, impetigo, secondarily infected dermatoses);
The urinary tract infections caused by Chlamydia trachomatis (uncomplicated urethritis, cervicitis);
the initial stage of Lyme disease (borreliosis) - migratory erythema (erythema migrans)

Contraindications

Hypersensitivity to azithromycin, erythromycin; ketolides; simultaneous administration with ergotamine and dihydroergotamine, severe liver dysfunction (Child-Pugh class C); severe renal dysfunction (creatinine clearance less than 40 mL/min); In children under 12 years old with the body weight less than 45 kg; lactation period; simultaneous administration with ergotamine and dihydroergotamine.
With care
Myasthenia, mild and moderate liver dysfunction, mild and moderate renal dysfunction (creatinine clearance more than 40 ml/min), in patients with pro-arrhythmic factors (especially in elderly patients): with congenital or acquired QT interval elongation, in patients receiving antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotic drugs (pimozide), antidepressants (citalopram), fluoroquinolone and (moxifloxacin and levofloxacin), in patients with fluid and electrolytic imbalance, particularly in case of hypokalemia or hypomagnesemia with clinically significant bradycardia, cardiac arrhythmia or severe heart failure; simultaneous administration of digoxin, warfarin, cyclosporine.
Administration during pregnancy and lactation period
During pregnancy the drug administration is possible only when potential benefit to the mother outweighs any potential risk to the fetus. Breastfeeding shall be discontinued for the period of treatment.

Cautions

In case of missed dose, the missed dose should be administered as soon as possible, and the subsequent dose should be administered at intervals of 24 hours.
The drug should be administered at least one hour prior to or two hours after administration of antacid drugs. Azithromycin should be used with care in patients with mild and moderate hepatic dysfunction because of the potential fulminant hepatitis and severe hepatic failure. In case of symptoms of liver dysfunction (rapidly increasing asthenia, jaundice, darkening of the urine, a tendency to bleeding, hepatic encephalopathy) therapy with azithromycin should be discontinued and the functional state of the liver shall be examined. In case of mild and moderate renal dysfunction (creatinine clearance more than 40 ml/min), azithromycin therapy shall be conducted with care with monitoring of the kidney function state. Similar to administration of other antibacterial drugs, the patients receiving azithromycin should be examined regularly for susceptible microorganisms and signs of superinfections, including fungal ones.
Azithromycin should not be used with longer courses than indicated in the drug's use instructions, since the pharmacokinetic properties of azithromycin allow us to recommend a short and simple dosage regimen.
Data on possible interaction between azithromycin and derivatives of ergotamine and dihydroergotamine is not available, but due to development of ergotism after simultaneous administration of macrolides with derivatives of ergotamine and dihydroergotamine, this combination is not recommended. Long-term administration of the drug can cause pseudomembranous colitis caused by Clostridium difficile, both in the form of mild diarrhea and severe colitis. In case of antibiotic-associated diarrhea after administration of the drug azithromycin, and also 2 months after the end of the therapy, clostridial pseudomembranous colitis should be ruled out.
During the treatment with azithromycin, administration of the drugs inhibiting the intestinal peristalsis is contraindicated. Treatment with macrolides, including azithromycin can cause elongation of cardiac repolarization and QT interval, which increase the risk of cardiac arrhythmias, including pirouette arrhythmias.
Care shall be taken when the drug is administered in patients with pro-arrhythmic factors (especially in elderly patients): with congenital or acquired QT interval elongation, in patients receiving antiarrhythmic drugs of classes IA (quinidine, procainamide), III (dofetilide, amiodarone and sotalol), cisapride, terfenadine, antipsychotic drugs (pimozide), antidepressants (citalopram), fluoroquinolone and (moxifloxacin and levofloxacin), in patients with fluid and electrolytic imbalance, particularly in case of hypokalemia or hypomagnesemia with clinically significant bradycardia, cardiac arrhythmia or severe heart failure.
Administration of the drug may trigger development of myasthenic syndrome or cause an exacerbation of myasthenia gravis.
 
Effects on ability to drive and use machines
Considering the possible adverse nervous system effects and vision disorders during administration of the drug avoid driving and performing other potential hazardous activities requiring increased attention focusing and quick psychomotor reactions.
 

Dosing and Administration

Oral administration, 1 hour before or 2 hours after meals once per day, in adults (including the elderly patients) and in children from 12 years old with the body weight more than 45 kg.
For infections of the upper and lower respiratory tract, ENT organs, skin and soft tissues - 500 mg (2 capsules) once per day during 3 days (the course dose is 1.5 g).
For Lyme disease (at the initial stage of borreliosis) - migrating erythema (erythema migrans) - once per day during 5 days: On the first day - 1.0 g (4 capsules), then from the 2nd to the 5th day - 500 mg (2 capsules) (the course dose is 3.0 g).
For theurogenital tract infections caused by Chlamydia trachomatis (uncomplicated urethritis / cervicitis) - 1.0 g (4 capsules) once.
In patients with renal disorders: administration in patients with mild and moderate renal dysfunction (creatinine clearance more than 40 ml/min) does not require dose correction.
In patients with liver dysfunction: administration in patients with mild and moderate hepatic dysfunction does not require dose correction.
In elderly patients: dose correction is not required. Since elderly patients can already have current pro-rhythmogenic conditions, the drug shall be administered with care because of the high risk of cardiac arrhythmias, including arrhythmias such as pirouettes.

Side effect

The frequency of the following possible adverse effects is indicated in accordance with the classification of the World Health Organization: very common (frequent)- more than 10%, common (frequent) - more than 1% and less than 10%, common (frequent) - more than 0.1 % and less than 1 %, rare - more than 0.01 % and less than 0.1 %, very rare - less than 0.01 %, unknown frequency - the frequency can’t be determined based on the available data. Infectious diseases: uncommon (infrequent) - candidiasis, including mucous membranes of the mouth and genitals, pneumonia, pharyngitis, gastroenteritis, respiratory diseases, rhinitis; unknown frequency - pseudomembranous colitis.
Adverse blood and lymphoid system effects: uncommon (infrequent) - leukopenia, neutropenia, eosinophilia; very rare - thrombocytopenia, hemolytic anemia.
Adverse metabolism and digestive effects: uncommon (infrequent) - anorexia.
Allergic reactions: uncommon (infrequent) - angioneurotic edema, hypersensitivity reaction; unknown frequency - anaphylactic reaction.
Adverse nervous system effects: common (frequent) - headache; uncommon (infrequent) - dizziness, dyspnoea, paresthesia, drowsiness, insomnia, nervousness; rare - agitation; unknown frequency - hypesthesia, anxiety, aggression, fainting, convulsions, psychomotor hyperactivity, loss of smell, perversion of smell, loss of taste sensations, myasthenia gravis, delirium, hallucinations.
Adverse visual organ effects: uncommon (infrequent) - impaired vision.
Hearing organ and labyrinthine disorders: uncommon (infrequent) - hearing disorder, vertigo; unknown frequency - hearing disorders, including deafness and / or tinnitus.
Adverse cardiovascular effects: uncommon (infrequent) - palpitations, face flushes, unknown frequency - blood pressure drop, the QT interval elongation on the electrocardiogram, pirouette-type arrhythmia, ventricular tachycardia.
Adverse respiratory system effects: uncommon (infrequent) - dyspnea, epistaxis.
Adverse gastrointestinal effects: very common - diarrhea; common (frequent) - nausea, vomiting, abdominal pain; uncommon (infrequent) - meteorism, dyspepsia, constipation, gastritis, dysphagia, bloating, dryness of the oral mucosa, belching, ulcers of the oral mucosa, increased secretion of the salivary glands; very rare - discoloration of the tongue, pancreatitis.
Adverse liver and biliary tract effects: uncommon (infrequent) - hepatitis; rare - liver dysfunction, cholestatic jaundice; unknown frequency - hepatic failure (in rare cases with death mainly associated with severe liver dysfunction), liver necrosis, fulminant hepatitis.
Adverse skin and subdermal tissue effects: uncommon (infrequent) - skin rash, itching, hives, dermatitis, dry skin, sweating; rare - the reaction of photosensitization; unknown frequency - Steve-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme.
Adverse locomotor system effects: uncommon (infrequent) - osteoarthritis, myalgia, back pain, neck pain, unknown frequency - arthralgia. Adverse kidney and urinary tract effects: uncommon (infrequent) - dysuria, pain in the kidney; unknown frequency - interstitial nephritis, acute renal failure.
Adverse genitals and the breast effects: uncommon (infrequent) - metrorrhagia, dysfunction of the testicles.
Other: uncommon (infrequent) - asthenia, malaise, fatigue, face swelling, chest pain, fever, peripheral edema. Investigations: in the blood plasma: common (frequent) - decreased lymphocyte count, increased count of eosinophils, basophils, monocytes, neutrophils, decreased or increased concentration of bicarbonates, uncommon (infrequent) - increased activity of aspartate aminotransferase, alanine aminotransferase, increased bilirubin concentration, increased urea concentration, increased creatinine concentration, change in potassium content, increased activity of alkaline phosphatase, increased chlorine content, increased glucose concentration, increased platelet count, increased hematocrit, change in the sodium content.
Overdose
Symptoms: severe nausea, temporary loss of hearing, vomiting, diarrhea.
Treatment: expectant.

Interaction with other medicines

Antacid drugs
Antacid drugs do not affect bioavailability of azithromycin, but reduce the maximum concentration in the blood by 30%, so the drug should be administered one hour before or two hours after administration of these drugs and food intake.
Cetirizine
Simultaneous administration of azithromycin with cetirizine (20 mg) during 5 days in healthy volunteers did not cause pharmacokinetic interaction and significant change in the QT interval.
Didanosine (dideoxyinosine)
Simultaneous administration of azithromycin (1200 mg/day) and didanosine (400 mg/day) in 6 patients with HIV did not change the pharmacokinetic indications of didanosine compared with the placebo group.
Digoxin (P-glycoprotein substrates)
Simultaneous administration of macrolide antibiotics, including azithromycin with P-glycoprotein substrates, such as digoxin, increases the concentration of the P-glycoprotein substrate in the blood serum. Therefore the simultaneous administration of azithromycin and digoxin requires consideration of possible increase in the concentration of digoxin in the blood serum.
Zidovudine
Simultaneous administration of azithromycin (at single dose 1000 mg and repeated administration of 1200 mg or 600 mg) has little effect on the pharmacokinetics, including kidney excretion, zidovudine or its glucuronide metabolite. However administration of azithromycin increase the concentration of phosphorylated zidovudine, a clinically active metabolite in the peripheral blood mononuclear cells. The clinical significance of this fact is unclear.
Azithromycin interacts slightly with cytochrome P450 isoenzymes. It has not been found that azithromycin is involved in pharmacokinetic interactions similar to erythromycin and other macrolides.
Azithromycin is not an inducer and inhibitor of cytochrome P450 isoenzymes.
Ergot alkaloids
Considering the theoretical possibility of ergotism, simultaneous administration of azithromycin with derivatives of ergot alkaloids is not recommended.
Pharmacokinetic studies of the simultaneous administration of azithromycin and drugs which metabolism involves cytochrome P450 isoenzymes were conducted.
Atorvastatin
Simultaneous administration of atorvastatin (10 mg per day on a daily basis) and azithromycin (500 mg daily) did not cause changes in the plasma concentrations of atorvastatin (based on analysis of inhibition of GMA-CoA reductase). However, individual reports have been received about rhabdomyolysis cases in patients receiving both azithromycin and statins simultaneously.
Carbamazepine
In pharmacokinetic studies with healthy volunteers, no significant effect on the plasma concentration of carbamazepine and its active metabolite were reported in patients receiving azithromycin simultaneously.
Cimetidine
In pharmacokinetic studies of the effect of a single dose of cimetidine on the pharmacokinetics of azithromycin, no changes in the pharmacokinetics of azithromycin were reported, provided that cimetidine was administered 2 hours prior to azithromycin.
Indirect anticoagulating agents (coumarin derivatives)
In pharmacokinetic studies, azithromycin did not affect the anticoagulanting effect of a single dose 15 mg of warfarin administered by healthy volunteers. Potential anticoagulanting effect was reported after simultaneous administration of azithromycin and indirect anticoagulating agents (coumarin derivatives). Although the relation is not determined, the required frequent monitoring of the prothrombin time after administration of azithromycin shall be considered in patients receiving oral indirect anticoagulating agents (coumarin derivatives).
Cyclosporine
In the pharmacokinetic study with healthy volunteers receiving azithromycin (500 mg/day once) and then cyclosporine (10 mg/kg/day once) during 3 days, the maximum plasma concentration and the area under the concentration-time curve of cyclosporine increased significantly. Care should be taken for simultaneous administration of these drugs. Simultaneous administration of these drugs requires monitoring of the plasma concentration of cyclosporine and dose correction accordingly.
Efavirenz
Simultaneous administration of azithromycin (600 mg/day once) and efavirenz (400 mg/day) daily during 7 days did not cause any significant pharmacokinetic interaction.
Fluconazole
Simultaneous administration of azithromycin (1200 mg once) did not change the pharmacokinetics of fluconazole (800 mg once). The total exposure and the half-life of azithromycin did not change after simultaneous administration of fluconazole, but decreased maximum concentration of azithromycin by 18 % was observed which was not significant.
Indinavir
Simultaneous administration of azithromycin (1200 mg once) did not cause significant effect on the pharmacokinetics of indinavir (800 mg three times per day during 5 days).
Methylprednisolone
Azithromycin does not significantly affect the pharmacokinetics of methylprednisolone.
Nelfinavir
Simultaneous administration of azithromycin (1200 mg) and nelfinavir (750 mg 3 times per day) increases the equilibrium plasma concentration of azithromycin. Significant adverse effects have not been observed and azithromycin dose correction for administration with nelfinavir is not required.
Rifabutin
Simultaneous administration of azithromycin and rifabutin does not affect the concentration of each drug in the serum. Simultaneous administration of azithromycin and rifabutin simetimes caused neutropenia. Despite the fact that neutropenia was associated with administration of rifabutin, the relation to the combined administration of azithromycin and rifabutin and neutropenia has not been determined.
Sildenafil
Administration in healthy volunteers did not show the effect of azithromycin (500 mg/day during 3 days) on the area under the pharmacokinetic concentration-time curve and the maximum concentration of sildenafil or its main circulating metabolite.
Terfenadine
The pharmacokinetic studies gave no evidence of interaction between azithromycin and terfenadine. Individual cases of such possible interaction which could not be ruled out completely were reported, but no any concrete proof for this interaction were reported. It was found that simultaneous administration of terfenadine and macrolides can cause arrhythmia and the QT interval elongation.
Theophylline
No interaction between azithromycin and theophylline were revealed.
Triazolam / midazolam
Significant changes in pharmacokinetic parameters after simultaneous administration of azithromycin with triazolam or midazolam at therapeutic doses were not revealed.
Trimethoprim / sulfamethoxazole
Simultaneous administration of trimethoprim / sulfamethoxazole with azithromycin did not significantly affect the maximum concentration, total exposure or renal excretion of trimethoprim or sulfamethoxazole. The concentrations of azithromycin in the serum corresponded to those detected during other studies.

Form release

Storage conditions

In a dry and dark place at temperature maximum 25 °С.

Expiration date

2 years