Flemoxin solutab®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLEMOXIN SOLUTAB® (FLEMOXIN SOLUTAB®)

Composition:

Active substance: amoxicillin;

1 tablet contains amoxicillin (in the form of amoxicillin trihydrate) – 125 mg, 250 mg, 500 mg, 1000 mg;

Excipients: microcrystalline cellulose, microcrystalline cellulose and sodium carmellose, crospovidone, vanillin, mandarin flavor, lemon flavor, saccharin, magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties: white or almost white tablets (a light yellow tint may appear during storage), elongated in shape, with engraving «231» for FLEMOKSIN SOLYUTAB® 125 mg, «232» – for FLEMOKSIN SOLYUTAB® 250 mg, «234» – for FLEMOKSIN SOLYUTAB® 500 mg, «236» – for FLEMOKSIN SOLYUTAB® 1000 mg, marking

on one side and a score line on the other side.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Beta-lactam antibiotics. Broad-spectrum penicillins. Amoxicillin. ATC code J01CA04.

Pharmacological properties.

Pharmacodynamics. Flemoxin Solutab® is a broad-spectrum bactericidal antibiotic of the semi-synthetic penicillin group.

In vitro data on the susceptibility of certain clinically significant microorganisms to amoxicillin.

Activity in vitro	Mean minimum inhibitory concentration (MIC)
	0.01 – 0.1 µg/mL	0.1 – 1 µg/mL	1 – 10 µg/mL
Gram-positive microorganisms	Streptococci group A Streptococci group B Str. pneumoniae Cl. welchii Cl. tetani	Staph. aureus (beta-lactamase-negative strains) B. anthracis L. subtilis L. monocytogenes	Str. faecalis
Gram-negative microorganisms	N. gonorrhoeae N. meningitidis	H. influenzae Bordetella pertussis	E. coli P. mirabilis S. typhi Sh. sonnei V. cholerae

Amoxicillin is inactive against microorganisms that produce beta-lactamases, such as Pseudomonas, Klebsiella, indole-positive strains of Proteus, and strains of Enterobacter. The level of resistance among susceptible microorganisms may vary across different regions.

Pharmacokinetics.

Absorption. After oral administration of "Flemoxin Solutab®" tablets, amoxicillin is rapidly and almost completely absorbed (85–90%); the drug is acid-resistant. Food intake has practically no effect on the absorption of the drug. Maximum plasma concentration of the active substance after administration of "Flemoxin Solutab®" tablets is achieved within 1–2 hours. Following an oral dose of 375 mg of amoxicillin, the maximum plasma concentration of the active substance reaches 6 \µg/L. Doubling (or halving) the dose of the drug results in a corresponding doubling (or halving) of the maximum plasma concentration.

Distribution. Approximately 20% of amoxicillin binds to plasma proteins. Amoxicillin penetrates mucous membranes, bone tissue, and intraocular fluid, as well as sputum, achieving therapeutically effective concentrations. The concentration of amoxicillin in bile is 2–4 times higher than its concentration in blood. In amniotic fluid and umbilical vessels, amoxicillin concentrations reach 25–30% of the levels found in the plasma of pregnant women. Amoxicillin poorly penetrates into cerebrospinal fluid; however, during inflammation of the meninges (e.g., meningitis), concentrations in cerebrospinal fluid reach approximately 20% of plasma concentrations.

Metabolism. Amoxicillin is partially metabolized; most of its metabolites are microbiologically inactive but possess allergenic properties.

Elimination. Amoxicillin is primarily eliminated by the kidneys, with approximately 80% excreted via tubular secretion and 20% via glomerular filtration. Approximately 90% of amoxicillin is excreted within 8 hours, of which 60–70% is excreted unchanged by the kidneys. In the absence of renal impairment, the elimination half-life of amoxicillin is 1–1.5 hours. In premature infants, newborns, and infants under 6 months of age, the half-life is prolonged to 3–4 hours.

In cases of impaired renal function (creatinine clearance ≤15 mL/min), the elimination half-life of amoxicillin is prolonged and reaches 8.5 hours in anuria.

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

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract;
• urinary and genital organs;
• gastrointestinal tract (GI tract);
• skin and soft tissues.

Contraindications.

Hypersensitivity to the active substance, to other penicillins, or to any of the excipients.

Severe immediate hypersensitivity reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (e.g., cephalosporin, carbapenem, or monobactam) in history.

Interaction with other medicinal products and other forms of interaction.

The concomitant use of allopurinol and amoxicillin increases the risk of developing skin allergic reactions.

There have been isolated reports of increased international normalized ratio (INR) in patients receiving amoxicillin together with acenocoumarol or warfarin. If such concomitant use is necessary, prothrombin time or INR should be carefully monitored when initiating or discontinuing amoxicillin therapy. Additionally, dose adjustment of oral anticoagulants may be required.

Methotrexate

Penicillins may reduce methotrexate excretion, potentially leading to increased toxicity of methotrexate.

When monitoring urine glucose levels during amoxicillin treatment, non-enzymatic glucose oxidase-based tests should be used, as non-enzymatic methods may yield false-positive results.

Probenecid

Concomitant use with probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration with probenecid may result in increased and prolonged blood levels of amoxicillin.

Phenylbutazone, oxyphenbutazone, and to a lesser extent acetylsalicylic acid, indomethacin, and sulfinpyrazone inhibit tubular secretion of penicillin derivatives, leading to an increased half-life and higher plasma concentrations of amoxicillin.

Like other antibiotics, amoxicillin may affect intestinal flora, resulting in reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Medicinal products with bacteriostatic activity (tetracycline antibiotics, macrolides, chloramphenicol) may antagonize the bactericidal effect of amoxicillin. Concomitant use of aminoglycosides is possible (synergistic effect).

Special precautions for use.

Hypersensitivity.

Before initiating treatment with amoxicillin, it is necessary to carefully assess the patient's history for hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Severe, and sometimes even fatal, cases of hypersensitivity (anaphylactoid reactions and severe skin adverse reactions) have been observed in patients during 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 are more likely to occur in patients with a history of penicillin hypersensitivity or with hypersensitivity to various allergens. In case of an allergic reaction, amoxicillin therapy should be discontinued and appropriate treatment initiated.

Drug-induced enterocolitis syndrome

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children receiving amoxicillin (see section "Adverse reactions"). DIES is an allergic reaction characterized primarily by persistent vomiting (1–4 hours after drug intake) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases have been reported, including progression to shock.

Resistant microorganisms

Amoxicillin is not suitable for treating certain infections when the causative pathogens are resistant or likely to be resistant to amoxicillin. Susceptibility of the probable causative agent should be considered before initiating amoxicillin therapy (see section "Pharmacological properties"). This particularly applies to the treatment of patients with urinary tract infections and severe ear, nose, and throat infections.

Infectious mononucleosis

Exanthema has frequently been observed (in 60–100% of cases) in patients with infectious mononucleosis or lymphatic-type leukemoid reactions. This exanthema is not due to penicillin hypersensitivity. Therefore, ampicillin-class antibiotics should not be used in patients with mononucleosis.

Amoxicillin is not recommended for use in patients with acute lymphoblastic leukemia due to an increased risk of erythematous skin rashes.

Cross-resistance

Cross-hypersensitivity and cross-resistance may exist between penicillins and cephalosporins.

Resistance

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms resistant to amoxicillin. As with other broad-spectrum penicillins, superinfections may occur.

Pseudomembranous colitis

Antibiotic-associated colitis, ranging from mild to life-threatening, has been reported with the use of nearly all antibacterial agents, including amoxicillin. Appropriate measures should be taken if antibiotic-associated colitis occurs. Necessary actions should also be taken in cases of hemorrhagic colitis or hypersensitivity reactions.

Antiperistaltic medicinal products are contraindicated in such cases.

Renal impairment

In patients with renal impairment, amoxicillin elimination may be reduced depending on the degree of renal dysfunction. Dosage reduction of amoxicillin is required in cases of severe renal impairment.

Seizures

Seizures may occur in rare cases in patients with impaired renal function, particularly in those receiving high doses and/or those with risk factors (e.g., history of epilepsy, seizure predisposition, concomitant antiepileptic therapy, or central nervous system disorders) (see section "Adverse reactions").

Crystalluria

When high doses of the drug are administered, sufficient fluid intake is necessary to prevent crystalluria (including acute kidney injury) that 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").

Skin reactions

The appearance of generalized erythema with fever and pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP). In such cases, treatment must be discontinued, and further 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.

Jarisch–Herxheimer reaction

The Jarisch–Herxheimer reaction has been observed after initiation of amoxicillin therapy in Lyme disease (see section "Adverse reactions"). This reaction is directly caused by the bactericidal effect of amoxicillin on Borrelia burgdorferi, the spirochete responsible for Lyme disease. Patients should be informed that this is a common consequence of antibiotic treatment for Lyme disease; symptoms usually resolve as the patient recovers.

During prolonged treatment, periodic evaluation of organ system function, including renal, hepatic, and hematopoietic systems, is recommended. During high-dose therapy, regular monitoring of blood parameters is advised. Elevated liver enzymes and changes in blood cell counts have been reported (see section "Adverse reactions").

Precautions in preterm infants and newborns: renal, hepatic, and blood function should be monitored.

Anticoagulants

Prolongation of prothrombin time has been rarely reported 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").

Combination therapy for eradication of Helicobacter pylori

When amoxicillin is used as part of combination therapy for Helicobacter pylori eradication, the package leaflets of the other medicinal products used in the combination regimen should be consulted.

Effect on diagnostic test results

Elevated levels of amoxicillin in serum and urine may interfere with certain laboratory tests. Due to high concentrations of amoxicillin in urine, chemical methods often yield false-positive results.

Enzymatic glucose oxidase methods are recommended for glucose testing in urine during amoxicillin therapy.

The presence of amoxicillin may affect estradiol test results in pregnant women.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have not shown direct or indirect reproductive toxicity. Limited human data on amoxicillin use during pregnancy do not indicate an increased risk of congenital malformations. Amoxicillin may be used during pregnancy if the potential benefit outweighs the potential risks of treatment.

Breastfeeding

Amoxicillin is excreted in breast milk in small amounts, posing a potential risk of sensitization. This may lead to diarrhea or fungal infection of the mucous membranes in infants and may necessitate discontinuation of breastfeeding. Amoxicillin may be used during breastfeeding only after a physician has evaluated the risk-benefit ratio.

Fertility

There are no data on the effect of amoxicillin on human fertility. Reproduction studies in animals have shown no effect on fertility.

Ability to influence reaction speed when driving or operating machinery

No studies have been conducted on the effect of amoxicillin on the ability to drive or operate machinery. However, adverse reactions (e.g., allergic reactions, dizziness, seizures) may occur that could affect the ability to drive or operate machinery (see section "Adverse effects").

Method of Administration and Dosage

For moderate to severe infections, the following doses are recommended:

Adults (including elderly patients): 500–750 mg orally twice daily or 500 mg three times daily.

Children with body weight <40 kg

The daily dose for children is 40–90 mg/kg/day, divided into 2–3 doses (should not exceed 3 g/day), depending on the indication, severity of infection, and microbial sensitivity (see sections "Special Warnings", "Pharmacological Properties").

Pharmacokinetic and pharmacodynamic data indicate that administration three times daily is more effective than twice daily (recommended when doses are at the upper limit of the recommended range).

Children with body weight exceeding 40 kg should receive adult doses.

Special recommendations

Tonsillitis: 50 mg/kg/day, divided into 2 doses.

Acute otitis media: In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, the dosing regimen should follow local guidelines.

Early stage of Lyme disease (isolated erythema migrans): 50 mg/kg/day, divided into 3 doses, for 14–21 days.

Endocarditis prophylaxis: Single dose of 50 mg amoxicillin/kg body weight, administered 1 hour before a scheduled surgical procedure.

Gonorrhea (acute, uncomplicated): Single dose of 3 g.

For infections involving hard-to-reach sites (e.g., acute bacterial otitis media), three times daily administration is preferred.

For chronic conditions, recurrences, or severe infections, administration three times daily at doses of 750–1000 mg is recommended for adults; for children – up to 60 mg/kg/day (divided into 3 doses).

Duration of treatment

For mild to moderate infections, the drug should be administered for 5–7 days. However, for streptococcal infections, treatment duration should be at least 10 days.

For chronic diseases, localized infections, or severe infections, dosage should be determined based on the clinical presentation.

Drug administration should continue for 48 hours after symptoms have resolved.

Patients with renal impairment

Dosage reduction is required in patients with severe renal impairment.

In patients with creatinine clearance below 30 mL/min, the dosing interval should be prolonged and/or the daily dose reduced (see sections "Special Warnings", "Pharmacological Properties").

Renal insufficiency in adult patients (including elderly patients)

Creatinine clearance, mL/min	Dose	Dosing interval
>30	No dose adjustment required	-
10–30	500 mg	12 hours
<10	500 mg	24 hours

Hemodialysis: at the end of the hemodialysis procedure, it is necessary to take 500 mg of amoxicillin.

Renal insufficiency in children with body weight less than 40 kg

Creatinine clearance, mL/min	Dose	Dosing interval
>30	Usual dose	No need to adjust
10–30	Usual dose	12 hours (equivalent to 2/3 of the dose)
<10	Usual dose	24 hours (equivalent to 1/3 of the dose)

Patients with impaired liver function.

Impaired liver function does not affect the elimination half-life of the drug.

Method of administration.

Flemoxin Solutab® is intended for oral administration.

Food intake does not affect the absorption of Flemoxin Solutab®.

Dissolve the tablet in a glass of water, mix thoroughly to obtain a homogeneous suspension, and take immediately.

Children.

For children with body weight < 40 kg, the daily dose is 40–90 mg/kg/day, divided into 2–3 doses (should not exceed 3 g/day), depending on the indication, severity of infection, and microbial susceptibility.

Pharmacokinetic/pharmacodynamic data indicate better efficacy with administration three times daily; therefore, twice-daily dosing is recommended only when using doses at the upper end of the recommended range.

Children with body weight exceeding 40 kg should receive doses recommended for adults.

Overdose.

Symptoms: overdose may cause gastrointestinal disturbances such as nausea, vomiting, and diarrhea, which may lead to fluid and electrolyte imbalance. Cases of crystalluria have been reported, sometimes leading to renal failure (see section "Special precautions").

Treatment: induce vomiting or perform gastric lavage, followed by administration of activated charcoal and an osmotic laxative (sodium sulfate). 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 to <1/10),
uncommon (≥1/1,000 to <1/100),
rare (≥1/10,000 to <1/1,000),
very rare (<1/10,000),
frequency not known (cannot be estimated from available data).

Infections and infestations
Very rare	Cutaneous and mucocutaneous candidiasis, overgrowth of non-susceptible microorganisms.
Disorders of the blood and lymphatic system
Very rare	Leukopenia (including severe, reversible); neutropenia or agranulocytosis, reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin index (see section "Special precautions for use").
Immune system disorders
Very rare	Severe allergic reactions, including anaphylactic shock, angioneurotic oedema, anaphylaxis, serum sickness, allergic vasculitis (see section "Special precautions for use").
Frequency unknown	Jarisch–Herxheimer reaction (see section "Special precautions for use").
Nervous system disorders
Very rare	Hyperactivity, dizziness, convulsions (in cases of renal impairment or in cases of overdose).
Frequency unknown	Aseptic meningitis.
Cardiac disorders
Frequency unknown	Kounis syndrome (see section "Special precautions for use").
Gastrointestinal disorders
Clinical trial data
* Frequent	Diarrhoea and nausea
* Uncommon	Vomiting
Post-marketing surveillance data
Very rare	Antibiotic-associated colitis, including pseudomembranous colitis and haemorrhagic colitis. Black hairy tongue Discoloration of the tongue #Tooth discoloration
Frequency unknown	Drug-induced enterocolitis syndrome (see section "Special precautions for use").
Hepatobiliary disorders
Very rare	Hepatitis, hepatic disorders, cholestatic jaundice, mild elevations in liver enzymes (aspartate aminotransferase, alanine aminotransferase).
Skin and subcutaneous tissue disorders
Clinical trial data
* Frequent	Skin rash
* Uncommon	Urticaria and pruritus
Post-marketing surveillance data
Very rare	Skin reactions such as erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, exfoliative bullous dermatitis, bullous dermatitis, photosensitivity reaction, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Frequency unknown	IgA linear disease.
Renal and urinary disorders
Very rare	Interstitial nephritis.
Frequency unknown	Crystalluria (including acute kidney injury) (see sections "Special precautions for use" and "Overdose").
* The frequency of the aforementioned adverse reactions was assessed based on clinical trial data involving approximately 6000 adults and children who received amoxicillin. # Superficial tooth discoloration has been observed in children. Proper dental care may help prevent tooth discoloration: staining is usually removed by brushing with a toothbrush.

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging. 5 tablets per blister, 4 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Haupt Pharma Latina S.R.L.

Manufacturer's address. Strada Statale 156 KM 47,600 FR, Borgo San Michele LT, 04100 - Latina, Italy.

Marketing Authorization Holder.

CHEPLAPHARM Arzneimittel GmbH

Address of the Marketing Authorization Holder.

Ziegelhof 24, 17489 Greifswald, Germany

I N S T R U C T I O N

for medical use of the medicinal product

FLEMOKSIN SOLYUTAB®

(FLEMOXIN SOLUTAB®)

Composition:

Active substance: amoxicillin;

1 tablet contains amoxicillin (as amoxicillin trihydrate) – 125 mg, 250 mg, 500 mg, 1000 mg;

Excipients: microcrystalline cellulose, microcrystalline cellulose and sodium carmellose, crospovidone, vanillin, mandarin flavor, lemon flavor, saccharin, magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties: white or almost white tablets (a light yellow tint may develop during storage), elongated in shape, with engraving «231» for Flemoxin Solutab® 125 mg, «232» – for Flemoxin Solutab® 250 mg, «234» – for Flemoxin Solutab® 500 mg, «236» – for Flemoxin Solutab® 1000 mg, marking

on one side and a score line on the other side.

Pharmacotherapeutic group. Antimicrobial agents for systemic use. Beta-lactam antibiotics. Broad-spectrum penicillins. Amoxicillin. ATC code J01CA04.

Pharmacological properties.

Pharmacodynamics. Flemoxin Solutab® is a broad-spectrum bactericidal antibiotic of the semi-synthetic penicillin group.

In vitro data on the susceptibility of certain clinically significant microorganisms to amoxicillin.

Activity in vitro	Mean minimum inhibitory concentration (MIC)
	0.01 – 0.1 µg/ml	0.1 – 1 µg/ml	1 – 10 µg/ml
Gram-positive microorganisms	Streptococci group A Streptococci group B Str. pneumoniae Cl. welchii Cl. tetani	Staph. aureus (beta-lactamase-negative strains) B. anthracis L. subtilis L. monocytogenes	Str. faecalis
Gram-negative microorganisms	N. gonorrhoeae N. meningitidis	H. influenzae Bordetella pertussis	E. coli P. mirabilis S. typhi Sh. sonnei V. cholerae

Amoxicillin is inactive against microorganisms that produce beta-lactamases, such as Pseudomonas, Klebsiella, indole-positive strains of Proteus, and strains of Enterobacter. The resistance levels of susceptible microorganisms may vary across different regions.

Pharmacokinetics.

Absorption. After oral administration of "Flemoxin Solutab®" tablets, amoxicillin is rapidly and almost completely absorbed (85–90%); the drug is acid-resistant. Food intake has practically no effect on the absorption of the drug. Maximum plasma concentration of the active substance after administration of "Flemoxin Solutab®" tablets is achieved within 1–2 hours. After an oral dose of 375 mg of amoxicillin, the maximum plasma concentration of the active substance reaches 6 μg/mL. Doubling (or halving) the dose of the drug results in a corresponding doubling (or halving) of the maximum plasma concentration.

Distribution. Approximately 20% of amoxicillin binds to plasma proteins. Amoxicillin penetrates into mucous membranes, bone tissue, and intraocular fluid, achieving therapeutically effective concentrations. The concentration of amoxicillin in bile is 2–4 times higher than its concentration in blood. In amniotic fluid and umbilical cord vessels, the concentration of amoxicillin amounts to 25–30% of its plasma level in pregnant women. Amoxicillin poorly penetrates into cerebrospinal fluid; however, during inflammation of the meninges (e.g., in meningitis), the concentration in cerebrospinal fluid reaches approximately 20% of the plasma concentration.

Metabolism. Amoxicillin is partially metabolized; most of its metabolites are inactive against microorganisms but possess allergenic properties.

Elimination. Amoxicillin is primarily eliminated by the kidneys, with approximately 80% excreted via tubular secretion and 20% via glomerular filtration. About 90% of amoxicillin is excreted within 8 hours, of which 60–70% is excreted unchanged by the kidneys. In the absence of renal impairment, the elimination half-life of amoxicillin is 1–1.5 hours. In premature infants, newborns, and infants up to 6 months of age, the half-life is 3–4 hours.

In cases of impaired renal function (creatinine clearance equal to or less than 15 mL/min), the elimination half-life of amoxicillin increases, reaching up to 8.5 hours in anuria.

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

Clinical characteristics.

Indications.

Infections caused by microorganisms sensitive to the drug:

• respiratory tract;
• urinary and genital organs;
• gastrointestinal tract (GI tract);
• skin and soft tissues.

Contraindications.

Hypersensitivity to the active substance, to other penicillins, or to any of the excipients.

Severe immediate hypersensitivity reaction (e.g., anaphylaxis) to another beta-lactam antibiotic (e.g., cephalosporin, carbapenem, or monobactam) in history.

Interaction with other medicinal products and other types of interactions.

Concomitant use of allopurinol and amoxicillin increases the risk of developing skin allergic reactions.

There have been isolated reports of increased international normalized ratio (INR) in patients receiving amoxicillin together with acenocoumarol or warfarin. If concomitant use is necessary, prothrombin time or INR should be carefully monitored when initiating or discontinuing amoxicillin therapy. In addition, dose adjustment of oral anticoagulants may be required.

Methotrexate

Penicillins may reduce the elimination of methotrexate, potentially leading to increased toxicity of the latter.

During treatment with amoxicillin, non-enzymatic glucose oxidase-based tests should be used for determining glucose levels in urine, as non-enzymatic methods may yield false-positive results.

Probenecid

Concomitant use with probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration with probenecid may result in increased and prolonged blood levels of amoxicillin.

Phenylbutazone, oxyphenbutazone, and to a lesser extent acetylsalicylic acid, indomethacin, and sulfinpyrazone inhibit tubular secretion of penicillin-class drugs, resulting in prolonged elimination half-life and increased plasma concentrations of amoxicillin.

Like other antibiotics, amoxicillin may affect intestinal flora, leading to reduced reabsorption of estrogens and decreased efficacy of combined oral contraceptives.

Medicinal products with bacteriostatic activity (tetracycline-class antibiotics, macrolides, chloramphenicol) may neutralize the bactericidal effect of amoxicillin. Concomitant use of aminoglycosides is possible (synergistic effect).

Special precautions for use.

Hypersensitivity.

Before initiating amoxicillin therapy, it is necessary to carefully assess the patient's history for previous hypersensitivity reactions to penicillins, cephalosporins, or other allergens.

Severe, and sometimes even fatal, cases of hypersensitivity (anaphylactoid reactions and severe skin adverse reactions) have been observed in patients during 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 are more likely to occur in patients with a history of penicillin hypersensitivity or with known hypersensitivity to various allergens. In case of an allergic reaction, amoxicillin therapy should be discontinued and appropriate treatment initiated.

Drug-induced enterocolitis syndrome

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

Resistant microorganisms

Amoxicillin is not suitable for treating certain infections when the causative pathogens are resistant or likely to be resistant to amoxicillin. Consideration should be given to the susceptibility of the likely pathogen before initiating amoxicillin therapy (see section "Pharmacological properties"). This particularly applies to the treatment of patients with urinary tract infections and severe ear, nose, and throat infections.

Infectious mononucleosis

Exanthema has frequently been observed (in 60–100% of cases) in patients with infectious mononucleosis or lymphoid-type leukemoid reactions, which is not due to penicillin hypersensitivity. Therefore, ampicillin-class antibiotics should not be used in patients with mononucleosis.

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

Cross-resistance

Cross-hypersensitivity and cross-resistance may exist between penicillins and cephalosporins.

Resistance

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms resistant to the drug. As with other broad-spectrum penicillins, superinfections may occur.

Pseudomembranous colitis

Cases of antibiotic-associated colitis, ranging from mild to life-threatening, have been reported with nearly all antibacterial agents, including amoxicillin. Appropriate measures should be taken if antibiotic-associated colitis develops. Necessary interventions should also be implemented in cases of hemorrhagic colitis or hypersensitivity reactions.

Antiperistaltic drugs are contraindicated in such cases.

Renal impairment

In patients with renal impairment, amoxicillin elimination may be reduced depending on the degree of renal dysfunction. Dose reduction of amoxicillin is required in cases of severe renal impairment.

Seizures

Seizures may occur in patients with impaired renal function, particularly in those receiving high doses and/or those with risk factors (e.g., history of epilepsy, seizure predisposition, concomitant antiepileptic therapy, or central nervous system disorders) (see section "Adverse reactions").

Crystalluria

When high doses of the drug are administered, sufficient fluid intake is necessary to prevent crystalluria (including acute kidney injury) that 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").

Skin reactions

The early appearance of generalized erythema with fever associated with pustules during treatment may indicate acute generalized exanthematous pustulosis. In such cases, treatment should be discontinued, and further 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 interventions should be initiated.

Jarisch–Herxheimer reaction

The Jarisch–Herxheimer reaction has been observed after initiation of amoxicillin therapy in Lyme disease (see section "Adverse reactions"). This reaction is directly caused by the bactericidal effect of amoxicillin on Borrelia burgdorferi, the spirochete responsible for Lyme disease. Patients should be informed that this is a common consequence of antibiotic treatment for Lyme disease; symptoms usually resolve as the patient recovers.

During prolonged therapy, periodic evaluation of organ system functions, including renal, hepatic, and hematopoietic systems, is recommended. With high-dose therapy, regular monitoring of blood parameters is advised. Elevated liver enzymes and changes in blood cell counts have been reported (see section "Adverse reactions").

Precautions in preterm infants and newborns: renal, hepatic, and blood functions should be monitored.

Anticoagulants

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

Appropriate monitoring is required when amoxicillin is used concomitantly with anticoagulants.

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").

Combination therapy for Helicobacter pylori eradication

When amoxicillin is used as part of combination therapy for Helicobacter pylori eradication, the prescribing information for the other medicinal products used in the combination regimen should be consulted.

Effect on diagnostic test results

Elevated levels of amoxicillin in serum and urine may interfere with certain laboratory tests. High concentrations of amoxicillin in urine often lead to false-positive results with chemical methods.

Enzymatic glucose oxidase methods are recommended for urine glucose testing during amoxicillin therapy.

The presence of amoxicillin may affect estriol test results in pregnant women.

Use during pregnancy or breastfeeding

Pregnancy

Animal studies have not shown direct or indirect reproductive toxicity. Limited human data on amoxicillin use during pregnancy do not indicate an increased risk of congenital malformations. Amoxicillin may be used during pregnancy if the potential benefit outweighs the potential risks of treatment.

Breastfeeding

Amoxicillin is excreted in small amounts in breast milk, posing a potential risk of sensitization. This may lead to diarrhea or fungal mucosal infection in infants and may necessitate discontinuation of breastfeeding. Amoxicillin may be used during breastfeeding only after a physician has evaluated the risk-benefit ratio.

Fertility

There are no data on the effect of amoxicillin on human fertility. Reproduction studies in animals have shown no effect on fertility.

Ability to influence reaction speed when driving or operating machinery

No studies have been conducted on the effect of amoxicillin on the ability to drive or operate machinery. However, adverse reactions (e.g., allergic reactions, dizziness, seizures) may occur that could impair the ability to drive or operate machinery (see section "Adverse effects").

Method of Administration and Dosage

For moderate to mild infections, the following doses are recommended:

Adults (including elderly patients): 500–750 mg orally twice daily or 500 mg three times daily.

Children with body weight <40 kg

The daily dose for children is 40–90 mg/kg/day, divided into 2–3 doses (should not exceed 3 g/day), depending on the indication, severity of infection, and microbial susceptibility (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").

Pharmacokinetic and pharmacodynamic data indicate that administration three times daily is more effective than twice daily (recommended when doses are at the upper limit of the recommended range).

Children with body weight exceeding 40 kg should receive adult doses.

Special Recommendations

Tonsillitis: 50 mg/kg/day, divided into 2 doses.

Acute otitis media: In areas with high prevalence of pneumococci with reduced susceptibility to penicillins, the dosing regimen should follow local guidelines.

Early stage of Lyme disease (isolated erythema migrans): 50 mg/kg/day divided into 3 doses for 14–21 days.

Endocarditis prophylaxis: Single dose of 50 mg amoxicillin/kg body weight administered 1 hour before planned surgical procedure.

Gonorrhea (acute, uncomplicated): Single dose of 3 g.

For infections involving hard-to-reach sites, such as acute bacterial otitis media, administration three times daily is preferred.

For chronic conditions, recurrent infections, or severe infections, administration three times daily at doses of 750–1000 mg is recommended; for children – up to 60 mg/kg/day (divided into 3 doses).

Treatment Duration

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

For chronic conditions, localized infectious lesions, or severe infections, dosage should be determined based on the clinical presentation.

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

Patients with Renal Impairment

Dosage reduction is required in patients with severe renal impairment.

In patients with creatinine clearance below 30 mL/min, the dosing interval should be prolonged and/or the daily dose reduced (see sections "Special Warnings and Precautions for Use", "Pharmacological Properties").

Renal Insufficiency in Adult Patients (including elderly patients)

Creatinine clearance, mL/min	Dose	Dosing interval
>30	No dose adjustment required	-
10–30	500 mg	12 hours
<10	500 mg	24 hours

Hemodialysis: at the end of the hemodialysis procedure, 500 mg of amoxicillin should be administered.

Renal insufficiency in children with body weight less than 40 kg

Creatinine clearance, mL/min	Dose	Dosing interval
>30	Usual dose	No need to adjust
10–30	Usual dose	12 hours (corresponds to 2/3 of the dose)
<10	Usual dose	24 hours (corresponds to 1/3 of the dose)

Patients with impaired liver function.

Impaired liver function does not affect the drug's elimination half-life.

Method of administration.

Flemoxin Solutab® is intended for oral administration.

Food intake does not affect the absorption of Flemoxin Solutab®.

Dissolve the tablet in a glass of water, mix well to obtain a homogeneous suspension, and drink immediately.

Children.

For children with body weight < 40 kg, the daily dose is 40–90 mg/kg/day, divided into 2–3 doses (should not exceed 3 g/day), depending on the indication, severity of infection, and microbial susceptibility.

Pharmacokinetic/pharmacodynamic data indicate better efficacy with administration three times daily; therefore, twice-daily dosing is recommended only when using doses at the upper end of the recommended range.

Children with body weight exceeding 40 kg should receive doses recommended for adults.

Overdose.

Symptoms: gastrointestinal disturbances such as nausea, vomiting, and diarrhea; which may lead to fluid and electrolyte imbalance. Cases of crystalluria have been reported, sometimes leading to renal failure (see section "Special precautions for use").

Treatment: induce vomiting or perform gastric lavage, followed by administration of activated charcoal and an osmotic laxative (sodium sulfate). Maintain fluid and electrolyte balance. Amoxicillin can 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	Cutaneous and mucocutaneous candidiasis, overgrowth of non-susceptible microorganisms.
Blood and lymphatic system disorders
Very rare	Leucopenia (including severe, reversible); neutropenia or agranulocytosis, reversible thrombocytopenia and haemolytic anaemia. Prolongation of bleeding time and prothrombin time (see section "Special precautions").
Immune system disorders
Very rare	Severe allergic reactions, including anaphylactic shock, angioneurotic oedema, anaphylaxis, serum sickness, allergic vasculitis (see section "Special precautions").
Frequency unknown	Herxheimer reaction (see section "Special precautions").
Nervous system disorders
Very rare	Hyperactivity, dizziness, convulsions (in cases of renal impairment or overdose).
Frequency unknown	Aseptic meningitis.
Cardiac disorders
Frequency unknown	Coats’ syndrome (see section "Special precautions").
Gastrointestinal disorders
Clinical trial data
* Frequent	Diarrhoea and nausea
* Uncommon	Vomiting
Post-marketing surveillance data
Very rare	Antibiotic-associated colitis, including pseudomembranous colitis and haemorrhagic colitis. Black hairy tongue. Discoloration of the tongue. #Tooth discoloration
Frequency unknown	Drug-induced enterocolitis syndrome (see section "Special precautions").
Hepatobiliary disorders
Very rare	Hepatitis, hepatic disorders, cholestatic jaundice, mild increases in liver enzymes (aspartate aminotransferase, alanine aminotransferase).
Skin and subcutaneous tissue disorders
Clinical trial data
* Frequent	Skin rash
* Uncommon	Urticaria and pruritus
Post-marketing surveillance data
Very rare	Skin reactions such as erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, exfoliative bullous dermatitis, bullous dermatitis, photosensitivity reaction, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).
Frequency unknown	IgA linear disease
Renal and urinary disorders
Very rare	Interstitial nephritis.
Frequency unknown	Crystalluria (including acute kidney injury) (see sections "Special precautions" and "Overdose").
* The frequency of the mentioned adverse reactions was assessed based on clinical trial data involving approximately 6000 adults and children who received amoxicillin. # Superficial tooth discoloration has been observed in children. Proper dental hygiene may help prevent tooth discoloration: plaque is usually removable by tooth brushing.

Shelf life. 5 years.

Storage conditions.

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

Keep out of reach of children.

Packaging. 5 tablets per blister, 4 blisters per cardboard pack.

Prescription status. Prescription only.

Manufacturer. Astellas Pharma Europe B.V.

Manufacturer's address. Hogehil 2, 7942 DJ Meppel, The Netherlands.

Marketing Authorisation Holder.

CEPLAPHARM Arzneimittel GmbH

Address of the Marketing Authorisation Holder.

Ziegelhof 24, 17489 Greifswald, Germany