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

Composition:

active substance: amoxicillin;

1 tablet contains amoxicillin trihydrate, calculated as amoxicillin – 250 mg or 500 mg;

excipients: sodium starch glycolate (type A), povidone, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical characteristics: white to off-white, flat cylindrical tablets with beveled edges, marked with a score line.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. ATC code J01C A04.

Pharmacological Properties.

Pharmacodynamics.

Amoxicillin is a semisynthetic aminopenicillin antibiotic with broad-spectrum activity intended for oral administration. It inhibits bacterial cell wall synthesis. It has a broad spectrum of antimicrobial activity.

The following microorganisms are susceptible to the drug:

• Gram-positive aerobes: Corynebacterium diphtheriae, Enterococcus faecalis, Listeria monocytogenes, Streptococcus agalactiae, Streptococcus bovis, Streptococcus pyogenes;
• Gram-negative aerobes: Helicobacter pylori;
• Anaerobes: Peptostreptococci;
• Others: Borrelia.

Intermediately susceptible (acquired resistance may complicate treatment): Corynebacterium spp., Enterococcus faecium, Streptococcus pneumoniae, Streptococcus viridans, Escherichia coli, Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis, Proteus mirabilis, Prevotella, Fusobacterium spp.

Resistant species include: Staphylococcus aureus, Acinetobacter, Citrobacter, Enterobacter, Klebsiella, Legionella, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas, Serratia, Bacteroides fragilis, Chlamydia, Mycoplasma, Rickettsia.

Pharmacokinetics.

Absorption.

After oral administration, amoxicillin is rapidly and almost completely absorbed (85–90%) in the small intestine. Food intake has practically no effect on the drug's absorption. After a single 500 mg dose, amoxicillin plasma concentration reaches 6–11 mg/L. Maximum plasma concentration of the active substance is achieved within 1–2 hours.

Distribution.

Approximately 20% of amoxicillin binds to plasma proteins. Amoxicillin penetrates mucous membranes, bone tissue, and intraocular fluid, reaching therapeutically effective concentrations in sputum. Amoxicillin concentration in bile is 2–4 times higher than in blood. Amoxicillin poorly diffuses into cerebrospinal fluid; however, during inflammation of the meninges (e.g., in meningitis), its concentration in cerebrospinal fluid reaches approximately 20% of plasma concentration.

Metabolism.

Amoxicillin is partially metabolized; most of its metabolites are inactive.

Excretion.

Amoxicillin is primarily excreted by the kidneys. Approximately 60–80% of the administered dose is eliminated unchanged within 6 hours. The elimination half-life of amoxicillin is 1–1.5 hours. In case of impaired renal function, the elimination half-life increases and may reach 8.5 hours in anuria.

The elimination half-life of amoxicillin remains unchanged in hepatic impairment.

Clinical characteristics.

Indications.

Infections of the respiratory tract, genitourinary system, gastrointestinal tract (including in combination with metronidazole or clarithromycin for the treatment of conditions associated with Helicobacter pylori), skin and soft tissues caused by microorganisms sensitive to the drug.

Contraindications.

Hypersensitivity to any component of the drug and/or to any beta-lactam antibiotics, including penicillins.

History of severe hypersensitivity reactions (including anaphylaxis) associated with the use of other beta-lactam agents (including cephalosporins, carbapenems, or monobactams).

Infectious mononucleosis and lymphatic-type leukemoid reactions.

Interaction with other medicinal products and other types of interactions.

Probenecid, phenylbutazone, oxyphenbutazone, and to a lesser extent acetylsalicylic acid and sulfinpyrazone inhibit tubular secretion of penicillins, resulting in prolonged elimination half-life and increased plasma concentration of amoxicillin.

Bacteriostatic agents (tetracycline antibiotics, macrolides, chloramphenicol) may antagonize the bactericidal effect of amoxicillin. Concomitant use of aminoglycosides is possible (synergistic effect).

Not recommended combinations

Allopurinol. Concurrent use with amoxicillin increases the risk of allergic skin reactions.

Digoxin. Absorption of digoxin may be increased, requiring dose adjustment.

Disulfiram. Concurrent use with amoxicillin is contraindicated.

Anticoagulants. Concurrent use of amoxicillin and coumarin-class anticoagulants may prolong bleeding time. Dose adjustment of anticoagulants is required. There have been reports of increased effect of oral anticoagulants in patients receiving amoxicillin.

Isolated cases of increased international normalized ratio (INR) have been reported in patients taking amoxicillin concurrently with acenocoumarol or warfarin. If such concomitant use is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin therapy. Additionally, dose adjustment of oral anticoagulants may be required.

Methotrexate. Concomitant use of amoxicillin with methotrexate increases the toxicity of the latter. Amoxicillin reduces renal clearance of methotrexate; therefore, serum methotrexate levels should be monitored.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid decreases renal tubular secretion of amoxicillin. Concurrent administration may lead to prolonged elevated blood levels of amoxicillin.

Amoxicillin should be used with caution in combination with oral hormonal contraceptives – plasma levels of estrogens and progestogens may be temporarily reduced, potentially decreasing the efficacy of hormonal contraception. Therefore, additional non-hormonal contraceptive methods are recommended.

Concurrent administration with antacids reduces amoxicillin absorption.

Other types of interactions.

Forced diuresis leads to decreased blood concentration of amoxicillin by increasing its elimination.

Diarrhea may reduce absorption of other medicinal products and adversely affect their efficacy.

Effect on diagnostic laboratory test results: when testing for glucose in urine, enzymatic glucose oxidase methods are recommended. False-positive results are commonly observed with chemical methods.

Amoxicillin may decrease urinary estriol levels in pregnant women.

At high concentrations, amoxicillin may reduce serum glucose levels. Amoxicillin may interfere with protein determination by colorimetric methods.

Special precautions for use.

Hypersensitivity reactions. Prior to initiating therapy with amoxicillin, it is essential to carefully investigate whether the patient has a history of hypersensitivity reactions to penicillins, cephalosporins, or other allergens. Cross-hypersensitivity and cross-resistance (10–15%) may occur between penicillins and cephalosporins.

Severe and sometimes fatal hypersensitivity reactions (anaphylactoid reactions and severe cutaneous adverse reactions) have been observed in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to Kounis syndrome—a serious allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). Such reactions occur more frequently in patients with a history of severe allergic reactions. Treatment with the drug must be discontinued and replaced with appropriate alternative therapy. Management of symptoms of anaphylactic reaction may be required, for example, immediate administration of adrenaline, corticosteroids (intravenous), and emergency treatment of respiratory failure.

Acute coronary syndrome associated with hypersensitivity reaction (Kounis syndrome). Rare cases of hypersensitivity reactions (acute coronary syndrome associated with hypersensitivity reaction, see section "Adverse reactions") have been reported during amoxicillin therapy; appropriate treatment should be initiated if such reactions occur.

Renal impairment. In patients with renal impairment, elimination of amoxicillin may be reduced depending on the degree of renal dysfunction. In severe renal impairment, amoxicillin therapy should either be discontinued or the dose of amoxicillin reduced.

Seizures. Seizures may occur in patients with impaired renal function, as well as in those receiving high doses of the drug, or in individuals predisposed to seizures (e.g., history of epilepsy, seizure tendency, concomitant antiepileptic therapy, meningitis, or CNS disorders) (see section "Adverse reactions").

Jarisch-Herxheimer reaction. It should be noted that during treatment of Lyme disease with amoxicillin, the Jarisch-Herxheimer reaction may occur (see section "Adverse reactions"), which results from the bactericidal effect of amoxicillin on Borrelia burgdorferi, the spirochete causing Lyme disease. Patients should be informed that this is a common consequence of antibiotic treatment for Lyme disease; symptoms usually resolve as recovery progresses.

Crystalluria. Crystalluria (including acute kidney injury) has been very rarely observed in patients with reduced diuresis, primarily during parenteral therapy. Adequate fluid intake is necessary when high doses of the drug are administered to prevent crystalluria, which may be caused by amoxicillin. High concentrations of amoxicillin in urine may lead to sediment formation in urinary catheters; therefore, catheters should be visually inspected at regular intervals (see sections "Adverse reactions" and "Overdose").

Insensitive microorganisms. Since amoxicillin is not intended for the treatment of certain types of infections, it should be used only when the pathogenic microorganism has been identified, or when there is reason to believe that the infectious agent is likely to be susceptible to amoxicillin (see section "Pharmacological properties"). This particularly applies to the treatment of patients with urinary tract infections and severe ear, nose, and throat infections.

Resistance. Prolonged use of the drug may lead to overgrowth of insensitive microorganisms or fungi. Superinfection may occur, requiring careful monitoring of such patients.

Pseudomembranous colitis. Development of antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin. If severe diarrhea characteristic of pseudomembranous colitis (most often caused by Clostridium difficile) occurs, the drug should be discontinued and appropriate measures taken. Antiperistaltic agents are contraindicated in this case.

Appropriate measures should also be taken in the event of hemorrhagic colitis or hypersensitivity reactions.

Oral forms of amoxicillin should not be administered to patients with severe gastrointestinal disorders accompanied by diarrhea and vomiting due to the risk of reduced absorption.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin (see section "Adverse reactions"). Drug-induced enterocolitis syndrome is an allergic reaction whose main symptom is prolonged vomiting (1–4 hours after drug administration); allergic skin or respiratory symptoms are absent. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases, including progression to shock, have been reported.

In children, amoxicillin may alter the color of tooth enamel; therefore, strict adherence to oral hygiene is necessary.

Infectious mononucleosis. Exanthema is frequently observed in patients with infectious mononucleosis or lymphatic-type leukemoid reactions, which is not due to penicillin hypersensitivity. Therefore, the drug should not be administered to patients with mononucleosis.

Amoxicillin is not recommended for treatment of patients with acute lymphoblastic leukemia or infectious mononucleosis due to the increased risk of erythematous skin rashes.

During high-dose therapy, blood parameters should be monitored regularly.

Skin reactions. The appearance of generalized erythema with fever and pustules at the beginning of treatment may indicate the development of acute generalized exanthematous pustulosis, requiring discontinuation of amoxicillin therapy. Subsequent use of amoxicillin is contraindicated.

Amoxicillin may cause severe skin reactions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and drug reaction with eosinophilia and systemic symptoms (DRESS). If severe skin reactions occur, amoxicillin should be discontinued, and appropriate treatment and/or measures should be initiated.

During prolonged therapy, periodic evaluation of organ system function, including renal, hepatic, and hematopoietic systems, is recommended.

During high-dose therapy, blood parameters should be monitored regularly. Elevated liver enzymes and changes in blood cell counts have been reported (see section "Adverse reactions").

Anticoagulants

Rarely, prolonged prothrombin time has been observed in patients receiving amoxicillin.

Appropriate monitoring is required when anticoagulants are used concomitantly.

Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of blood coagulation (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

When using amoxicillin as part of combination therapy for Helicobacter pylori eradication, the instructions for medical use of the other drugs in the combination regimen should be consulted.

The medicinal product Amoxil®, tablets, contains sodium (in the 250 mg tablet, sodium content ranges from 3.311 mg/tablet to 4.967 mg/tablet; in the 500 mg tablet, from 6.622 mg/tablet to 9.933 mg/tablet), which should be taken into account when treating patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Amoxicillin crosses the placental barrier; its concentration in fetal plasma is approximately 25–30% of that in maternal plasma. Teratogenic effects of amoxicillin have not been observed.

Limited data on the use of amoxicillin during pregnancy indicate no adverse effects on the fetus/newborn. If amoxicillin is required during pregnancy, a careful assessment of the potential risk to the fetus versus the expected benefit to the woman should be performed.

Amoxicillin is excreted in small amounts in breast milk; therefore, the risk of hypersensitivity in the infant during breastfeeding cannot be excluded. The drug may be used during this period only if the expected benefit to the woman outweighs the potential risk to the infant. Breastfeeding should be discontinued if the newborn develops gastrointestinal disturbances (diarrhea, candidiasis) or skin rash.

Fertility. There are no data on the effect of amoxicillin on human fertility. Reproductive toxicity studies in animals showed no effect on fertility.

Ability to influence reaction rate when driving or operating machinery.

Until individual response to the drug is known (dizziness, seizures may occur), caution is recommended when driving or operating complex machinery.

Method of Administration and Dosage

The dosage range for Amoxil® is very wide. The physician determines the dose, frequency of administration, and duration of treatment individually.

For adults and children with body weight over 40 kg: administer 250 mg to 500 mg of Amoxil® three times daily or 500 mg to 1000 mg twice daily. In cases of sinusitis, pneumonia, and other severe infections, administer 500 mg to 1000 mg three times daily. The daily dose may be increased up to a maximum of 6 g.

For children with body weight under 40 kg: typically administer 40–90 mg/kg/day of Amoxil® in three divided doses daily, or 25–45 mg/kg/day in two divided doses. The maximum daily dose for children is 100 mg/kg body weight.

For mild to moderate infections, treatment with the drug should last 5–7 days. However, in infections caused by streptococci, the treatment duration should be at least 10 days.

For chronic diseases, localized infectious lesions, and severe infections, dosage should be determined based on the clinical presentation of the disease.

Drug administration should continue for 48 hours after disappearance of disease symptoms.

Amoxil® can be administered to patients with renal impairment. In severe renal impairment (creatinine clearance < 10 mL/min, i.e., 0.16 mL/sec), dosing intervals should be extended to 12–24 hours, and the dose should be reduced by 15–50%.

Dosage adjustment is not required in hepatic impairment.

Amoxil® may be taken independently of food intake. The tablet should be swallowed with liquid. During treatment with Amoxil®, patients are advised to drink more fluids than usual.

Children. Other dosage forms of amoxicillin are recommended for children under 5 years of age.

Overdose.

Symptoms: gastrointestinal disturbances—nausea, vomiting, diarrhea—potentially leading to fluid and electrolyte imbalance.

Cases of crystalluria have been reported, which may occasionally lead to renal failure. Seizures may occur in patients with impaired renal function or in those receiving high doses of the drug.

Treatment: induce vomiting or perform gastric lavage, followed by administration of activated charcoal and an osmotic laxative. Maintain fluid and electrolyte balance. Amoxicillin may be removed from the bloodstream by hemodialysis. No specific antidote is known.

Adverse reactions

The most commonly reported adverse reactions were diarrhea, nausea, and vomiting.

Adverse reactions observed during clinical trials and post-marketing surveillance of amoxicillin are listed below according to the MedDRA classification.

Adverse reactions are classified by frequency of occurrence:

• very common (≥1/10),
• common (≥1/100 and <1/10),
• uncommon (≥1/1,000 and <1/100),
• rare (≥1/10,000 and <1/1,000),
• very rare (<1/10,000),
• frequency not known (cannot be estimated from available data).

Infections and infestations: very rare – prolonged or repeated use of the drug may lead to development of superinfections and overgrowth of resistant microorganisms or fungi causing candidiasis of the skin and mucous membranes.

Blood and lymphatic system disorders: very rare – eosinophilia, hemolytic anemia, leukopenia (including severe neutropenia and agranulocytosis), reversible thrombocytopenia, pancytopenia, myelosuppression, granulocytopenia, prolonged bleeding time and prothrombin index. These manifestations are reversible upon discontinuation of treatment (see section "Special precautions").

Immune system disorders: as with all antibiotics – very rare: severe allergic reactions, including anaphylaxis, angioneurotic edema, laryngeal edema, serum sickness, allergic vasculitis, anaphylactic shock, exanthema, hyperemia, fever; frequency not known – Jarisch-Herxheimer reaction (see section "Special precautions"). In case of anaphylactic reaction, appropriate therapy should be initiated immediately.

Gastrointestinal disorders: common – diarrhea, nausea; uncommon – vomiting; very rare – flatulence, abdominal discomfort and pain, soft stools, perianal itching, loss of appetite, exanthema (especially in the oral area), dry mouth, taste disturbances, #change in tooth surface color (more commonly observed with use of amoxicillin suspension in children). Proper oral hygiene procedures may prevent tooth discoloration, as such deposits are usually removed by tooth brushing; antibiotic-associated colitis (including pseudomembranous and hemorrhagic colitis), intestinal candidiasis, black hairy tongue. These adverse effects are generally mild and resolve either during or immediately after completion of therapy. The occurrence of such effects may be prevented by taking amoxicillin with food. Drug-induced enterocolitis syndrome (DIES) – frequency not known.

Nervous system disorders: very rare – insomnia, loss of consciousness, headache, hyperkinesia, confusion, hyperactivity, dizziness, convulsions (in patients with epilepsy and meningitis, in case of renal impairment, when high doses of amoxicillin are used); frequency not known – aseptic meningitis. These effects occur more frequently in patients receiving very high doses.

Cardiac disorders: frequency not known – Kounis syndrome (acute coronary syndrome associated with hypersensitivity reaction).

Hepatobiliary disorders: very rare – hepatitis, cholestatic jaundice, mild and transient increase in liver enzymes (AST, ALT).

Skin and subcutaneous tissue disorders: *common – skin rashes; *uncommon – urticaria, pruritus; very rare – erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous and exfoliative dermatitis, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), acute generalized exanthematous pustulosis. Sudden onset of urticaria indicates an allergic reaction to amoxicillin and requires immediate discontinuation of therapy. Linear IgA disease – frequency not known.

Renal and urinary disorders: acute interstitial nephritis, crystalluria (including acute kidney injury) (see sections "Special precautions" and "Overdose"). In case of severe adverse effects, the drug must be discontinued.

Other: general weakness.

* The frequency of the above-mentioned adverse reactions was derived from analysis of clinical trial data involving approximately 6,000 adults and children who received amoxicillin.

tooth surface discoloration occurred in children. Proper dental care may help prevent tooth discoloration, as the deposit is usually removable by toothbrushing.

Shelf life. 4 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 10 tablets per blister, 2 blisters per carton.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder. JSC "Kyivmedpreparat".

Manufacturer's address and place of business.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.