Amoxicillin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMOXICILLIN (AMOXICILLIN)

Composition:

Active substance: amoxicillin;

1 capsule contains 250 mg or 500 mg of amoxicillin (as amoxicillin trihydrate);

Excipients: talc, magnesium stearate;

Hard gelatin capsule (size 1 or 0): gelatin, titanium dioxide (E 171), quinoline yellow (E 104), carmoisine (E 129), methylparaben (E 218), propylparaben (E 216).

Pharmaceutical form. Capsules.

Main physicochemical properties:

250 mg capsules:

size "1" capsules with a red cap and white body, cylindrical in shape, with rounded edges, smooth, opaque, and uniform surface.

Capsules contain granular powder of white or almost white color;

500 mg capsules:

size "0" capsules with a red cap and white body, cylindrical in shape, with rounded edges, smooth, opaque, and uniform surface.

Capsules contain granular powder of white or almost white color.

Pharmacotherapeutic group. Extended-spectrum penicillins. ATC code J01CA04.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

Amoxicillin is a semisynthetic penicillin (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins, PBPs) in the bacterial peptidoglycan biosynthetic pathway, which is an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which usually results in cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the spectrum of activity of amoxicillin does not include organisms that produce these enzymes.

Pharmacokinetic/pharmacodynamic relationships

The time during which the antibiotic concentration exceeds the minimum inhibitory concentration (T > MIC) is a highly important efficacy parameter for amoxicillin.

Mechanisms of resistance development

There are two main mechanisms of resistance to amoxicillin:

• inactivation by β-lactamases;
• alteration of PBPs, reducing the antibiotic's affinity for its target.

Bacterial impermeability or efflux pump mechanisms may cause or enhance microbial resistance, particularly in Gram-negative bacteria.

Breakpoints

Minimum inhibitory concentration for amoxicillin

(according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST))

Table 1

1. Enterobacteriaceae are classified as susceptible to aminopenicillins. Some countries prefer to classify E. coli and P. mirabilis isolates as intermediates. In this case, the MIC breakpoint S ≤ 0.5 mg/L is used.

2. Most staphylococci produce penicillinase, which is resistant to amoxicillin. Isolates resistant to methicillin are, with rare exceptions, resistant to all beta-lactam agents.

3. Breakpoints are stated with reference to ampicillin breakpoints.

4. Susceptibility of Streptococcus groups A, B, C, and G to penicillins follows from susceptibility to benzylpenicillin.

5. Breakpoints apply only to non-meningitis isolates. Oral treatment with amoxicillin should be avoided for isolates classified as ampicillin-intermediate. Breakpoints are stated with reference to ampicillin breakpoints.

6. Breakpoints are based on intravenous administration. Resistance in beta-lactamase-producing isolates should be reported.

7. Resistance in beta-lactamase-producing isolates should be reported.

8. Breakpoints are stated with reference to benzylpenicillin breakpoints.

9. Breakpoints are based on epidemiological cut-off values (ECOFF), which distinguish wild-type isolates from those with reduced susceptibility.

10. Breakpoints are species-independent and based on dosing regimens of at least 0.5 g x 3 or 4 times daily (1.5–2 g/day).

The prevalence of resistance may vary geographically and over time for individual species; therefore, local information on resistance patterns is desirable, especially when treating severe infections. Expert consultation should be sought when local resistance prevalence renders the benefit of the antibiotic questionable for at least some types of infections.

In vitro susceptibility of microorganisms to Amoxicillin

Generally susceptible microorganisms

Gram-positive aerobes:

Enterococcus faecalis

Beta-hemolytic streptococci (Groups A, B, C, and G)

Listeria monocytogenes

Species for which acquired resistance may be a concern

Gram-negative aerobes:

Escherichia coli

Haemophilus influenzae

Helicobacter pylori

Proteus mirabilis

Salmonella typhi

Salmonella paratyphi

Pasteurella multocida

Gram-positive aerobes:

Coagulase-negative staphylococci

Staphylococcus aureus £

Streptococcus pneumoniae

Viridans group streptococci

Gram-positive anaerobes:

Clostridium spp.

Gram-negative anaerobes:

Fusobacterium spp.

Others:

Borrelia burgdorferi

Inherently resistant organisms †

Gram-positive aerobes:

Enterococcus faecium †

Gram-negative aerobes:

Acinetobacter spp.

Enterobacter spp.

Klebsiella spp.

Pseudomonas spp.

Gram-negative anaerobes:

Bacteroides spp. (many strains of Bacteroides fragilis are resistant).

Others:

Chlamydia spp.

Mycoplasma spp.

Legionella spp.

† – Inherently intermediate susceptibility in the absence of acquired resistance mechanisms.

£ – Practically all S. aureus strains are resistant to amoxicillin due to penicillinase production. In addition, all methicillin-resistant strains are resistant to amoxicillin.

Pharmacokinetics.

Absorption.

Amoxicillin is completely degraded in aqueous environments at physiological pH. Amoxicillin is rapidly and well absorbed after oral administration. After oral administration, the bioavailability of amoxicillin is nearly 70%. Peak plasma concentration is reached approximately within 1 hour (Tmax).

The pharmacokinetic data below are from a study in which amoxicillin 250 mg was administered three times daily on an empty stomach to a group of healthy volunteers.

In the range of 250 to 3000 mg, bioavailability is linearly proportional to dose (measured as Cmax and AUC). Concomitant food intake does not affect absorption.

Hemodialysis may be used for amoxicillin elimination.

Distribution.

18% of amoxicillin is protein-bound in plasma. The volume of distribution of amoxicillin is 0.3–0.4 L/kg body weight.

After intravenous administration, amoxicillin has been detected in the urinary bladder, abdominal tissues, skin, adipose tissue, muscles, synovial and peritoneal fluids, bile, and exudate. Amoxicillin partially distributes into cerebrospinal fluid.

Data from animal studies provide no evidence of significant retention of active substance metabolites in tissues. Amoxicillin, like most penicillins, may pass into breast milk (see section "Use during pregnancy or breastfeeding"). Amoxicillin crosses the placental barrier.

Metabolism

Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose.

Elimination

Amoxicillin is primarily eliminated by the kidneys.

In healthy volunteers, the elimination half-life of amoxicillin is approximately 1 hour, and mean total clearance is approximately 25 L/h. After single doses of 250 mg or 500 mg amoxicillin, about 60–70% is excreted in urine within 6 hours. Various studies have shown that 50–85% of amoxicillin is excreted in urine within 24 hours.

Concomitant administration with probenecid slows renal excretion of amoxicillin (see section "Interaction with other medicinal products and other forms of interaction").

Age

The elimination half-life of amoxicillin in children aged 3 months to 2 years, older children, and adults is similar. For neonates (including preterm infants) during the first week of life, the dosing frequency should not exceed twice daily due to immature renal function. Due to the likelihood of reduced renal function, elderly patients require careful dose selection and regular monitoring of renal function.

Sex

After oral administration of amoxicillin to healthy men and women, sex does not influence the pharmacokinetic properties of amoxicillin.

Renal impairment

Total serum clearance of amoxicillin decreases proportionally with reduced renal function (see section "Method of administration and dosage").

Hepatic impairment

Patients with hepatic impairment require careful dose selection and regular monitoring of liver function.

Clinical characteristics.

Indications.

Treatment of the following infectious diseases in adults and children:

• Acute bacterial sinusitis
• Acute and otitis media
• Acute streptococcal tonsillitis and pharyngitis
• Exacerbation of chronic bronchitis
• Community-acquired pneumonia
• Acute cystitis
• Asymptomatic bacteriuria during pregnancy
• Acute pyelonephritis
• Typhoid and paratyphoid fever
• Dental abscesses with spreading cellulitis
• Prosthetic joint infections
• Eradication of Helicobacter pylori
• Lyme disease

Amoxicillin is also indicated for the prevention of endocarditis.

Official recommendations regarding appropriate use of antibacterial agents should be taken into account.

Contraindications.

Hypersensitivity to amoxicillin and to other penicillins, cephalosporins, carbapenems, or monobactams, as well as to excipients of the medicinal product.

History of severe hypersensitivity reactions (including anaphylaxis) to beta-lactam antibiotics (including cephalosporins, carbapenems, or monobactams).

Interaction with other medicinal products and other forms of interaction.

Probenecid

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

Allopurinol

Concomitant use with amoxicillin may promote the occurrence of skin allergic reactions.

Tetracyclines

Tetracyclines and other bacteriostatic agents may interfere with the bactericidal effects of amoxicillin.

Oral anticoagulants

Oral anticoagulants and penicillin antibiotics are widely used in clinical practice without reports of interaction. However, there are literature reports of increased international normalized ratio (INR) in patients receiving acenocoumarol or warfarin during amoxicillin therapy. If concomitant use is necessary, prothrombin time or INR should be carefully monitored when starting or discontinuing amoxicillin. Additionally, dose adjustment of oral anticoagulants may be required.

Methotrexate

Concomitant use of penicillin with methotrexate may lead to increased toxicity of the latter.

Special precautions for use.

Hypersensitivity

Before initiating treatment with amoxicillin, it is necessary to ascertain the presence or absence of a history of hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam antibacterial agents.

Severe, and sometimes even fatal, cases of hypersensitivity (including anaphylactoid reactions and severe skin reactions) have been observed in patients during penicillin therapy. Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity or with hypersensitivity to various allergens. Acute coronary syndrome associated with a hypersensitivity reaction (Kounis syndrome) may lead to myocardial infarction. Symptoms of such reactions may include chest pain occurring in connection with an allergic reaction to amoxicillin.

In case of an allergic reaction, amoxicillin therapy should be discontinued and appropriate treatment initiated.

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 characterized primarily by persistent vomiting (1–4 hours after administration of the drug) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases, including progression to shock, have been reported.

Resistant microorganisms

Since amoxicillin is not intended for the treatment of certain types of infections, the drug 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 is particularly relevant for patients with urinary tract infections and severe ear, nose, and throat infections.

Seizures

Seizures may occur in patients with impaired renal function, as well as in those receiving high doses of the drug or with a predisposition to seizures (e.g., history of seizures, treated epilepsy, meningitis) (see section "Adverse reactions").

Renal impairment

The dose of amoxicillin should be adjusted in patients with renal impairment according to the degree of renal dysfunction.

Skin reactions

The appearance of generalized erythema with fever associated with pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis. In such a case, treatment must be discontinued and amoxicillin must not be used thereafter.

Amoxicillin should be avoided in suspected cases of infectious mononucleosis, as the development of a measles-like rash in this case may be associated with hypersensitivity to amoxicillin.
Amoxicillin may cause severe skin adverse reactions (SSARs), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), and acute generalized exanthematous pustulosis (AGEP). Patients should be closely monitored if a skin rash develops, and amoxicillin should be discontinued if the lesions progress.

Jarisch-Herxheimer reaction

The Jarisch-Herxheimer reaction may occur during treatment of Lyme disease (see section "Adverse reactions"), resulting from the bactericidal effect of amoxicillin on Borrelia burgdorferi, the spirochete causing Lyme disease. Patients should be reassured that this is a common and usually self-limiting consequence of antibiotic treatment for Lyme disease.

Overgrowth of resistant microorganisms

Prolonged use of the drug may occasionally lead to overgrowth of microorganisms not susceptible to the drug. Cases of antibiotic-associated colitis, ranging from mild to life-threatening, have been reported with the use of nearly all antibacterial agents (see section "Adverse reactions"); therefore, it is important to consider this possibility in patients who develop diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, amoxicillin therapy should be discontinued immediately, medical advice should be sought, and appropriate treatment initiated.

The use of agents that inhibit peristalsis is contraindicated in this situation.

Long-term therapy

During prolonged treatment, periodic evaluation of organ system function, including urinary, hepatobiliary, and hematopoietic systems, is recommended. Elevated liver enzyme levels and changes in blood parameters have been reported.

Anticoagulants

Very rarely, prolonged prothrombin time has been reported in patients receiving amoxicillin. When amoxicillin is co-administered with anticoagulants, appropriate monitoring should be performed and the dose of anticoagulants adjusted if necessary.

Crystalluria

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

Impact on diagnostic tests

Elevated levels of amoxicillin in serum and urine may interfere with certain laboratory tests. False-positive results in general chemical analyses of urine are possible due to high concentrations of amoxicillin.

It is recommended to use glucose oxidase enzymatic methods when testing for glucose in urine during amoxicillin therapy.

The presence of amoxicillin may distort estriol assay results in pregnant women.

Important information on excipients

The medicinal product contains methylparaben (E 218) and propylparaben (E 216). These excipients may cause allergic reactions (possibly delayed).

Use during pregnancy or breastfeeding

Pregnancy

Animal studies do not indicate direct or indirect adverse effects on reproductive toxicity. Limited data on the use of amoxicillin during pregnancy in humans do not suggest an increased risk of congenital malformations. Amoxicillin may be used during pregnancy when the potential benefit outweighs the potential risks associated with treatment.

Breastfeeding

Amoxicillin passes into breast milk in small amounts, with a possible risk of sensitization. Therefore, diarrhea and fungal mucosal infections may occur in breastfed infants, and breastfeeding may need to be discontinued. Amoxicillin should be used during breastfeeding only after a physician has evaluated the benefit/risk ratio.

Fertility

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

Ability to influence the ability to drive and use machines

No studies on the effect on the ability to drive or operate machinery have been conducted. However, the possibility of adverse effects (allergic reactions, dizziness, seizures) that may affect the ability to drive or operate machinery should be considered (see section "Adverse reactions").

Method of Administration and Dosage.

Dosage

The dose of Amoxicillin selected for treating an individual infection should take into account:

• the expected pathogens and their possible susceptibility to antibacterial agents;
• the severity and site of infection;
• the patient's age, body weight, and renal function, as shown below.

The duration of therapy should be determined by the type of infection and the patient's response, and should generally be as short as possible. Some infections require longer treatment periods.

Adults and children with body weight ≥ 40 kg Table 1

Children with body weight < 40 kg

Children may receive amoxicillin in the form of capsules, dispersible tablets, or oral suspension prepared from powder, provided that appropriate dosage regimens can be ensured using suitable pharmaceutical forms with corresponding dosage strengths. Amoxicillin in the form of suspension may be administered to children under 6 months of age. Children with body weight above 40 kg should receive adult doses.

Table 2

Patients with renal function impairment.

For patients with a creatinine clearance below 30 ml/min, it is recommended to increase the dosing interval and reduce the daily dose of the drug.

Table 3

Patients undergoing hemodialysis.

Amoxicillin can be removed from the bloodstream by hemodialysis.

In patients undergoing peritoneal dialysis

The maximum daily dose of amoxicillin is 500 mg/day.

Hepatic impairment.

Dosage should be administered with caution and liver function should be monitored regularly.

Method of administration.

Amoxicillin is intended for oral use.

Food intake does not affect the absorption of amoxicillin.

Treatment may be initiated parenterally according to dosing recommendations for intravenous formulation and continued with oral formulation.

Swallow with sufficient amount of water; do not open the capsule.

Children.

The medicinal product can be used in pediatric practice (see section "Method of administration and dosage").

Overdose.

Symptoms: gastrointestinal disturbances – nausea, vomiting, diarrhea; vomiting and diarrhea may lead to fluid and electrolyte imbalance.

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

Treatment: gastrointestinal symptoms can be treated symptomatically, with monitoring of electrolyte balance.

Amoxicillin can be removed from the bloodstream by hemodialysis.

Amoxicillin crystalluria has been observed, which in some cases led to renal failure (see section "Special precautions for use").

Adverse reactions.

The most commonly reported adverse reactions were diarrhea, nausea, and severe skin adverse reactions (see section "Special precautions").

Adverse reactions identified 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 (≥1/1000 to <1/100);
• rare (≥1/10000 to <1/1000);
• very rare (<1/10000);
• frequency not known (cannot be estimated based on available data).

* The frequency of the reported adverse reactions was obtained from the evaluation of clinical trial data involving approximately 6000 adults and children who received amoxicillin.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life. 5 years.

Storage conditions.

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

Keep out of the reach of children.

Packaging.

250 mg: 10 capsules in a blister, 2 blisters in a cardboard box.

500 mg: 10 capsules in a blister, 1 blister in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

ANTIBIOTICE SA

ANTIBIOTICE SA

Manufacturer's address and place of business.

1, Valea Lupului Street, Iasi 707410, Romania

1, Valea Lupului Street, 707410, Iasi, Romania