Erythromycin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ERYTHROMYCIN (ERYTHROMYCIN)

Composition:

Active substance: erythromycin;

1 tablet contains erythromycin 100 mg;

Excipients: potato starch, polysorbate 80, povidone, calcium stearate, acrylic yellow 93O38159 [mixture of substances: methacrylate copolymer (type C), talc, titanium dioxide (E 171), triethyl citrate, quinoline yellow (E 104), colloidal anhydrous silicon dioxide, sodium hydrogencarbonate, sodium lauryl sulfate, yellow iron oxide (E 172), Ponceau 4R (E 124)].

Medicinal form. Enteric-coated tablets.

Main physico-chemical properties: round, film-coated tablets with smooth, biconvex surfaces, light yellow to yellow in color with a slightly orange tint. When broken and examined under a magnifying lens, a core surrounded by a continuous layer is visible.

Pharmacotherapeutic group. Antibacterials for systemic use. Macrolides. Erythromycin. ATC code J01FA01.

Pharmacological properties.

Pharmacodynamics.

Erythromycin is a macrolide antibiotic with bacteriostatic activity. At high concentrations and against highly sensitive microorganisms, it may exhibit bactericidal effects. It penetrates the bacterial cell membrane and reversibly binds to the 50S subunit of bacterial ribosomes; inhibits peptide translocation from the acceptor site to the donor site of the ribosome, thereby interfering with further protein synthesis.

Active against Gram-positive bacteria: Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Staphylococcus aureus, Corynebacterium diphtheriae, Listeria monocytogenes; Gram-negative bacteria: Neisseria meningitidis, Neisseria gonorrhoeae, Bordetella pertussis, Legionella pneumophila, Moraxella catarrhalis, Campylobacter spp., certain strains of Haemophilus influenzae, Mycoplasma pneumoniae, Ureaplasma urealyticum, as well as Chlamydia trachomatis and Treponema pallidum.

Gram-negative rods such as Escherichia coli, Pseudomonas aeruginosa, Shigella spp., and Salmonella spp. are resistant to erythromycin.

Erythromycin is ineffective in the treatment of infections caused by fungi, viruses, and yeasts.

Pharmacokinetics.

Erythromycin penetrates well into most tissues and organs. In the middle ear and palatine tonsils, it reaches concentrations close to those achieved in blood serum. High therapeutic concentrations of the drug are also observed in pleural and peritoneal fluids. Erythromycin crosses the placental barrier and is excreted into breast milk. It also has the ability to penetrate into cells. It does not cross the blood-brain barrier and does not penetrate into joint fluid. It is absorbed in the gastrointestinal tract; the rate of absorption depends on individual physiological characteristics. Bioavailability ranges from 30% to 65%. Maximum blood concentration is usually reached within 2–4 hours after administration.

Plasma protein binding is approximately 70%. It is metabolized in the liver, partially forming inactive metabolites.

Erythromycin induces the activity of microsomal enzymes partially responsible for its own metabolism. In the liver, the drug is partially inactivated through demethylation.

A significant portion of erythromycin is excreted from the body via bile, and only 2–5% is excreted unchanged in urine. The elimination half-life is 1–2 hours under normal renal function, and therapeutic concentrations are maintained for approximately 6 hours.

Clinical characteristics.

Indications.

Infectious and inflammatory diseases caused by microorganisms sensitive to the drug: pneumonia, infections of the ear, nose and throat organs (otitis, sinusitis, tonsillitis), purulent and inflammatory skin diseases and its appendages; diphtheria, erythrasma, gonorrhea, syphilis, listeriosis, Legionnaires' disease, infections caused by microorganisms resistant to beta-lactam antibiotics, penicillin, tetracycline, chloramphenicol, streptomycin.

Contraindications.

• Hypersensitivity to erythromycin or to any component of the drug, or to macrolides;
• severe hepatic insufficiency;
• documented history of QT interval prolongation (congenital or acquired) or ventricular arrhythmia;
• electrolyte imbalance (hypokalemia, hypomagnesemia — due to the risk of QT interval prolongation);
• concomitant use with terfenadine, astemizole, lomitapide, simvastatin, pimozide, or cisapride, ergotamine and dihydroergotamine (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions.

Concomitant use of erythromycin is contraindicated with:

• astemizole or terfenadine, cisapride, pimozide − increased risk of cardiotoxicity: QT interval prolongation, severe cardiac rhythm disturbances, including «torsades de pointes» arrhythmias, cardiac arrest;
• ergotamine or dihydroergotamine − possible acute toxicity reactions with vascular spasm, dysesthesia (erythromycin inhibits metabolism of ergotamine and dihydroergotamine, enhancing ergotamine-related vascular spasm).

Erythromycin is primarily biotransformed in the liver via the cytochrome P450 system. Due to its effect on cytochrome P450 activity, erythromycin interacts with the following drugs:

• increases serum concentrations of theophylline, aminophylline, caffeine, thereby increasing their toxicity − dose reduction of these drugs and monitoring of their serum concentrations are required;
• increases digoxin absorption and plasma concentration;
• increases cyclosporine concentration and enhances its nephrotoxicity;
• capable of reducing hepatic metabolism of carbamazepine, allowing carbamazepine dose reduction up to 50% when used concomitantly;
• increases concentration and enhances toxicity of phenytoin, alfentanil, methylprednisolone, benzodiazepines (such as triazolam, alprazolam), hexobarbital, valproic acid, tacrolimus, rifabutin, zopiclone, bromocriptine, cabergoline − dose adjustment of these drugs is required;
• with disopyramide, quinidine, procainamide may prolong QT interval or cause ventricular tachycardia;
• with oral contraceptives − reduces efficacy of oral contraceptives, increases risk of their hepatotoxicity;
• with antifungal agents: increased risk of cardiotoxicity (QT interval prolongation, paroxysmal ventricular tachycardia of "pirouette" type) and, as a consequence, cardiac arrest. The use of combination of these medicinal products is contraindicated;
• with anticoagulants (warfarin, acenocoumarol) − enhances their effects, which are more pronounced in elderly patients. Therefore, prothrombin time should be monitored continuously; enhanced anticoagulant effects have been reported with concomitant use of erythromycin and the oral anticoagulant rivaroxaban;
• increases blood concentration of HMG-CoA reductase inhibitors (e.g., lovastatin, simvastatin) − increased risk of rhabdomyolysis, which may develop after completion of erythromycin therapy. Concomitant use of erythromycin with lomitapide is contraindicated due to the possibility of significant increase in transaminase levels (see section "Contraindications");
• enhances systemic effect of sildenafil − sildenafil dose reduction is required;
• slows elimination and enhances the effect of calcium channel blockers, such as felodipine, verapamil. Cases of hypotension, bradyarrhythmia, and lactic acidosis have been reported with concomitant use;
• with zafirlukast − decreases its plasma concentration;
• drug action is enhanced in combination with sulfonamides, tetracycline, streptomycin;
• toxicity of colchicine, vinblastine has been reported with interaction with erythromycin;
• with cimetidine − increases risk of its toxicity, including reversible deafness;
• with levodopa (in combination with carbidopa) − possible inhibition of carbidopa absorption and decreased plasma levels of levodopa. Monitoring of clinical picture is required when using this combination. Dose adjustment of levodopa may be necessary;
• should not be used together with lincomycin, clindamycin, and chloramphenicol (antagonism), with drugs that increase gastric juice acidity, or with acidic beverages, as they inactivate erythromycin;
• caution is required when using erythromycin concomitantly with systemic and inhaled corticosteroids metabolized mainly by CYP3A, due to possible increased systemic exposure to corticosteroids. Close monitoring for adverse reactions is required in patients receiving systemic corticosteroids;
• hydroxychloroquine and chloroquine: erythromycin should be used with caution in patients receiving these drugs, which are known to prolong the QT interval, due to the potential for induction of cardiac arrhythmias and serious cardiovascular events.

The drug may affect the results of urinary catecholamine determination by fluorometric method.

Special precautions for use.

A detailed patient history regarding hypersensitivity reactions to erythromycin, other macrolides, or other allergens should be obtained before initiating erythromycin therapy. If a hypersensitivity reaction occurs during erythromycin administration, the drug should be discontinued immediately and symptomatic treatment initiated.

Prior to initiating therapy, it is advisable to identify the causative pathogen to minimize the risk of developing resistant bacterial strains.

Hepatic dysfunction, including elevated serum "liver" enzymes, hepatocellular and/or cholestatic hepatitis, with or without jaundice, has been reported with erythromycin use. Erythromycin is primarily eliminated via the liver; therefore, caution is advised when prescribing to patients with hepatic impairment, a history of jaundice, or those receiving potentially hepatotoxic medications. Liver function should be monitored during prolonged treatment or when high doses are administered.

When treating syphilis in pregnant women, it should be noted that the drug does not achieve therapeutic concentrations in the fetus; therefore, penicillin should be administered to newborns whose mothers were treated with erythromycin.

Cases of infantile hypertrophic pyloric stenosis (HPS) have been reported following erythromycin therapy. Epidemiological studies, including meta-analyses, suggest a 2–3 fold increased risk of HPS, particularly within the first 14 days of life. Available data indicate a 2.6% risk (95% CI: 1.5–4.2%) following erythromycin exposure during this period. The baseline risk of HPS in the general population is 0.1–0.2%.

Cases of rhabdomyolysis, with or without renal failure, have been observed in seriously ill patients receiving concomitant erythromycin and lovastatin. Therefore, when combination therapy with lovastatin or other HMG-CoA reductase inhibitors and erythromycin is necessary, the benefit-risk ratio should be carefully evaluated, and patients should be monitored for symptoms such as muscle pain, weakness, and serum creatine kinase and transaminase levels.

Antibacterial therapy may disrupt the normal flora of the large intestine and promote overgrowth of resistant Clostridium difficile strains, whose toxins are the primary cause of pseudomembranous colitis. Pseudomembranous colitis may occur both during treatment and up to 2 months after discontinuation of antibacterial therapy. Cases ranging from mild to life-threatening pseudomembranous colitis have been reported with nearly all antibacterial agents. Therefore, pseudomembranous colitis should be considered in patients who develop diarrhea following antibacterial use. In mild cases, discontinuation of the drug is usually sufficient; in severe cases, metronidazole or vancomycin should be administered. Medications that slow intestinal motility or other antidiarrheal agents are contraindicated.

Patients with renal or hepatic impairment, as well as elderly patients due to age-related changes in liver and/or kidney function, are at increased risk of ototoxic effects.

Elderly patients are at increased risk of developing torsades de pointes-type arrhythmias during erythromycin therapy, and the effect of anticoagulant therapy may be enhanced when used concomitantly with erythromycin.

Due to the risk of adverse reactions such as QT interval prolongation on ECG, ventricular arrhythmias including ventricular tachycardia, and torsades de pointes, the drug should be used with caution in patients with a history of arrhythmias.

Patients with bronchial asthma who are receiving theophylline and erythromycin should be closely monitored, including assessment of serum theophylline levels, to avoid intoxication.

The drug may exacerbate symptoms in patients with myasthenia gravis.

Prolonged or repeated use of erythromycin, as with other antibacterial agents, may lead to overgrowth of non-susceptible microorganisms, including fungi. If superinfection develops during treatment, erythromycin should be discontinued and appropriate measures initiated.

The drug may interfere with fluorometric determination of urinary catecholamine levels.

Agents that increase gastric acidity and acidic beverages inactivate erythromycin. Erythromycin should not be taken with milk or dairy products.

The medicinal product contains the dye Ponceau 4R (E124), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Epidemiological data on the risk of serious congenital malformations associated with macrolide use, including erythromycin, during pregnancy are conflicting. Some observational studies in humans have reported cardiovascular malformations following exposure to erythromycin-containing drugs in early pregnancy.

The drug crosses the placenta, but fetal serum concentrations are low.

It has been reported that maternal use of macrolide antibiotics within 10 weeks postpartum increases the risk of infantile hypertrophic pyloric stenosis (HPS) in newborns.

This medicinal product should be used in pregnant women only when clearly indicated and under medical supervision. Therefore, during pregnancy, erythromycin should be used only when absolutely necessary, with careful consideration of the benefit-risk ratio.

Erythromycin is excreted in breast milk; therefore, breastfeeding should be discontinued during treatment.

Ability to affect reaction speed when driving or operating machinery.

Given the potential for adverse reactions (dizziness, hallucinations, seizures, confusion, reversible hearing loss), patients should refrain from driving or operating machinery requiring high attention during treatment with this drug.

Method of Administration and Dosage

The dose is determined individually, depending on the localization and severity of the infection, as well as the pathogen's susceptibility.

The drug is administered orally, 1–1.5 hours before meals or 2–3 hours after meals.

Adults: 200–500 mg four times daily; the maximum single dose is 500 mg, the maximum daily dose is 2 g.

Children:

• from 3 to 6 years of age: 500–700 mg per day;
• from 6 to 8 years of age: 700 mg per day;
• from 8 to 14 years of age: up to 1 g per day, divided into four doses;
• over 14 years of age: adult dosage is applied.

For elderly patients, dosage adjustment is not required. However, caution is recommended due to frequent impairment of liver or biliary tract function in this age group.

Duration of treatment is 5–14 days; the drug should be continued for an additional 2 days after symptoms have disappeared.

Children

The drug may be administered to children aged 3 years and older according to the recommendations in the section "Method of Administration and Dosage".

Overdose

Symptoms: nausea, vomiting, diarrhea, and epigastric discomfort; hepatic dysfunction, possibly progressing to acute liver failure; hearing loss, tinnitus, dizziness (especially in patients with renal and/or hepatic impairment).

Treatment: gastric lavage, administration of activated charcoal, symptomatic therapy. Hemodialysis, peritoneal dialysis, and forced diuresis are ineffective.

Adverse reactions.

Gastrointestinal disorders: nausea, vomiting, diarrhea, epigastric pain, and anorexia may occur; pseudomembranous colitis is rare. Rare cases of pancreatitis have been reported.

Hepatobiliary disorders: liver function abnormalities, including increased serum aminotransferase levels, hepatocellular and/or cholestatic hepatitis, with or without jaundice.

Sensory organs: hearing loss and/or tinnitus, which resolve upon discontinuation of the drug. Isolated reports of reversible hearing loss have been reported, primarily in patients with renal impairment and in patients receiving high doses of erythromycin (over 4 g/day).

Renal and urinary disorders: very rarely, interstitial nephritis has been observed.

Cardiac disorders: QT interval prolongation on ECG; ventricular arrhythmias, including ventricular tachycardia and torsades de pointes, palpitations, and cardiac arrest are rare. Ventricular fibrillation has been reported with unknown frequency.

Nervous system disorders: isolated reports of transient adverse reactions during erythromycin therapy have been received, including confusion, hallucinations, nightmares, seizures, increased muscle weakness in patients with myasthenia gravis, dizziness; however, a causal relationship has not been definitively established.

Blood and lymphatic system disorders: very rarely, agranulocytosis and eosinophilia may occur.

Immune system disorders: allergic reactions, including anaphylactic reactions, such as pruritus, urticaria, anaphylactic shock, skin rashes; very rarely, Stevens-Johnson syndrome, toxic epidermal necrolysis, and erythema multiforme have been reported.

In case of any of the above-mentioned allergic reactions, the drug should be discontinued immediately.

Infections and parasitic disorders: during prolonged or repeated courses of erythromycin therapy, superinfection caused by drug-resistant bacteria or fungi may develop.

Other: chemotherapeutic effects: oral candidiasis, vaginal candidiasis; onset or exacerbation of myasthenic syndrome / pre-existing myasthenia gravis; fever.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging. 10 tablets in a blister; 1 or 2 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer.

JSC "VITAMINS".

Manufacturer's address and location of operations.

31 Uspenska Street, Uman, Cherkasy region, 20300, Ukraine.

Marketing Authorization Holder.

JSC "VITAMINS".

Address of the Marketing Authorization Holder.

31 Uspenska Street, Uman, Cherkasy region, 20300, Ukraine.