Augmentin (bd)

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AUGMENTIN (BD) [AUGMENTIN (BD)]

Composition:

Active substances: amoxicillin and clavulanic acid;

One tablet contains amoxicillin (as amoxicillin trihydrate) 875 mg, clavulanic acid (as potassium clavulanate) 125 mg;

Excipients: magnesium stearate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, microcrystalline cellulose, dimethicone;

Tablet coating: titanium dioxide (E 171), hypromellose (5 cps), hypromellose (15 cps), macrogol 4000, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped white or almost white film-coated tablets, with a break line on one side and the monograms A C on both sides.

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) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the antimicrobial spectrum of amoxicillin as monotherapy does not include microorganisms producing these enzymes.

Clavulanic acid is a beta-lactam compound structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid, when used as monotherapy, does not exhibit clinically useful antibacterial activity.

PK/PD relationship

The time during which the drug concentration remains above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining the efficacy of amoxicillin.

Resistance mechanisms

There are two main mechanisms of resistance to amoxicillin/clavulanic acid:

• Inactivation by bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including classes B, C, and D;
• Modification of PBPs, reducing the affinity of the antibacterial agent for its target.

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

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Microorganisms	Breakpoints of susceptibility (μg/ml)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae 1	≤1	-	> 1
Moraxella catarrhalis 1	≤1	-	> 1
Staphylococcus aureus 2	≤2	-	>2
Coagulase-negative staphylococci 2	≤ 0.25		> 0.25
Enterococcus 1	≤4	8	> 8
Streptococcus A, B, C, G 5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae 3	≤ 0.5	1–2	>2
Enterobacteriaceae 1, 4	-	-	> 8
Gram-negative anaerobic bacteria 1	≤4	8	> 8
Gram-positive anaerobic bacteria 1	≤4	8	> 8
Breakpoints not specific to individual species 1	≤2	4–8	> 8
1 Reported values are for amoxicillin concentrations. For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/l. 2 Reported values are for oxacillin concentrations. 3 Breakpoints are calculated based on ampicillin breakpoints. 4 The resistance breakpoint R>8 mg/l means that all strains with resistance mechanisms are classified as resistant. 5 Breakpoints are calculated based on benzylpenicillin breakpoints.

The prevalence of resistance can vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Typically susceptible species

Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes, and other beta-haemolytic streptococci, Streptococcus viridans group. Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Species for which development of resistance may be a concern

Gram-positive aerobes: Enterococcus faecium$. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.

$ Natural moderate susceptibility in the absence of acquired resistance mechanisms. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 This formulation of amoxicillin/clavulanic acid should not be used to treat patients infected with penicillin-resistant Streptococcus pneumoniae (see sections "Posology and method of administration" and "Special warnings and precautions for use"). 2 Strains with reduced susceptibility have been reported in certain EU countries with a frequency greater than 10%.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of the amoxicillin/clavulanic acid combination are identical to those achieved after oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution. Approximately 25% of total clavulanic acid in plasma and 18% of total amoxicillin in plasma are protein-bound. The apparent volume of distribution is approximately 0.3–0.4 L/kg for amoxicillin and approximately 0.2 L/kg for clavulanic acid.

Following intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluid, bile, and pus. Amoxicillin does not distribute adequately into cerebrospinal fluid.

Animal studies have not shown any evidence of significant retention of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be detected in breast milk (see section "Use during pregnancy or breastfeeding").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use during pregnancy or breastfeeding").

Biotransformation. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and excreted in urine and feces, as well as in the form of carbon dioxide in exhaled air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both renally and via extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour, and the mean total clearance is approximately 25 L/h. Various studies have shown that urinary excretion amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. The greatest amount of clavulanic acid is excreted within the first 2 hours after administration.

Concomitant administration of probenecid slows the elimination of amoxicillin but does not affect the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. Since elderly patients are more likely to have decreased renal function, dosage should be chosen with caution, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a larger fraction of amoxicillin is eliminated by the kidneys. In renal impairment, dosing should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Method of administration and dosage").

Hepatic impairment. Patients with hepatic impairment should be treated cautiously with this medicinal product, and regular monitoring of liver function is recommended.

Clinical characteristics.

Indications.

Treatment in adults and children of bacterial infections caused by microorganisms sensitive to Augmentin, such as:

• acute bacterial sinusitis (confirmed);
• acute otitis media;
• confirmed exacerbation of chronic bronchitis;
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including cellulitis, animal bites, severe odontogenic abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, appropriate use guidelines should be followed.

Contraindications.

Hypersensitivity to any component of the drug, or to any antibacterial agents of the penicillin group.

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

History of cholestatic jaundice or hepatic dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other types of interactions.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant administration of these drugs is necessary, prothrombin time or INR should be carefully monitored when starting or stopping amoxicillin. In addition, dose adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate

Penicillins may reduce the renal clearance of methotrexate, potentially increasing its toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concurrent administration of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients treated with mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite, mycophenolic acid, by approximately 50%. This change in pre-dose concentration may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dose adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of graft dysfunction. However, careful monitoring is necessary during concomitant use and for some time after completion of antibiotic therapy.

Special precautions for use.

Before initiating therapy with amoxicillin/clavulanic acid, a thorough history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

Severe and, in some cases, fatal hypersensitivity reactions (including anaphylactic reactions and severe cutaneous adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)—a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are more likely in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy initiated.

Cases of drug-induced enterocolitis syndrome (DIES), predominantly in children receiving amoxicillin/clavulanic acid, have been reported (see section "Side effects"). Drug-induced enterocolitis syndrome is an allergic reaction characterized primarily by persistent vomiting (occurring 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.

If an infection is proven to be caused by microorganism(s) susceptible to amoxicillin alone, switching from amoxicillin/clavulanic acid to amoxicillin should be considered in accordance with established guidelines.

This medicinal product of Augmentin should not be used when there is a high risk that the likely pathogens have reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are susceptible to inhibition by clavulanic acid. This formulation should not be used for treatment of patients whose infection is caused by penicillin-resistant Streptococcus pneumoniae.

Seizures may occur in patients with impaired renal function and in those receiving high doses of the drug (see section "Side effects").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as administration of amoxicillin has been associated with the development of a morbilliform rash.

Concomitant administration of allopurinol during amoxicillin therapy increases the likelihood of allergic skin reactions.

Prolonged use may occasionally lead to overgrowth of microorganisms not susceptible to the drug.

The onset of fever-associated generalized erythema with pustule formation at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Side effects"). This reaction requires discontinuation of Augmentin and constitutes a contraindication to further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients showing signs of impaired liver function (see sections "Dosage and administration", "Contraindications", and "Side effects").

Hepatic complications have been reported primarily in males and elderly patients, which may be associated with prolonged therapy. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, but in some cases may appear only several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe and, in rare instances, fatal. Such events have almost always occurred in patients with severe underlying disease or those receiving concomitant medications known to cause hepatic complications (see section "Side effects").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Side effects"). Therefore, this diagnosis must be considered in patients presenting with diarrhea during or after antibiotic use. If antibiotic-associated colitis develops, Augmentin should be discontinued immediately, medical attention sought, and appropriate treatment initiated. The use of antiperistaltic agents is contraindicated in such cases.

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

In patients receiving amoxicillin/clavulanic acid, isolated reports of prolonged prothrombin time have been documented. Appropriate monitoring is required when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria (including acute kidney injury) has been very rarely observed in patients with low urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained during administration of high doses of amoxicillin to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see section "Side effects" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used to test for glucose in urine, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Augmentin may lead to non-specific binding of IgG and albumin to erythrocyte membranes, which may result in false-positive Coombs test results.

Positive results in the enzyme immunoassay using Platelia Aspergillus (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported when using the Platelia Aspergillus immunoassay (Bio-Rad Laboratories). Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not suggest an increased risk of congenital malformations. In a single study in women with premature rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in neonates. The drug should be avoided during pregnancy unless considered necessary by the physician.

Period of breastfeeding. Both active components of the drug are excreted into breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Thus, diarrhea and fungal mucosal infections may occur in the breastfed infant; therefore, breastfeeding should be discontinued during treatment. The possibility of allergic reactions should also be considered. Use of amoxicillin/clavulanic acid during breastfeeding is possible only after a physician has evaluated the risk-benefit ratio.

Ability to affect reaction speed when driving or operating machinery.

Studies on the ability of the drug to affect reaction speed while driving or operating machinery have not been conducted. However, adverse effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery (see section "Side effects").

Dosage and Administration

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of a single component.

When selecting the dosage of Augmentin for treatment of a specific infection, the following should be considered:

• the likely pathogens involved and their probable susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use");
• the severity and site of infection;
• the patient’s age, body weight, and renal function, as indicated below.

If necessary, consideration should be given to using alternative Augmentin formulations (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

For adults and children with body weight ≥ 40 kg, the total daily dose is 1750 mg amoxicillin/250 mg clavulanic acid (2 tablets), divided into two doses. For children with body weight < 40 kg, the maximum daily dose is 1000–2800 mg amoxicillin/143–400 mg clavulanic acid, as specified below.

If higher doses of amoxicillin are required for treatment, other formulations of Augmentin should be used to avoid administering unnecessarily high doses of clavulanic acid (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

The duration of treatment should be determined based on the clinical response of the patient. Some infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without review (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

Recommended standard dose (for all indications): 875 mg/125 mg twice daily.

Children with body weight from 25 to 40 kg

Treatment may be carried out using Augmentin tablets or oral suspension.

Recommended doses:

• 25 mg/3.6 mg/kg body weight/day up to 45 mg/6.4 mg/kg body weight/day, divided into two doses;
• for treatment of certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), up to 70 mg/10 mg/kg body weight/day, divided into two doses.

Since the tablet cannot be split, this formulation of Augmentin should not be prescribed to children weighing less than 25 kg.

The table below indicates the dose in mg/kg body weight received by a child weighing from 25 kg to 40 kg when administered one Augmentin 875/125 mg tablet.

Body weight (kg)	40	35	30	25	Recommended single dose (mg/kg body weight) (see above)
Amount of amoxicillin (mg/kg body weight) when taking a single dose of 1 tablet of Augmentin 875/125 mg	21.9	25.0	29.2	35.0	12.5–22.5 (not exceeding 35)
Amount of clavulanic acid (mg/kg body weight) when taking a single dose of 1 tablet of Augmentin 875/125 mg	3.1	3.6	4.2	5.0	1.8–3.2 (not exceeding 5)

For children with body weight less than 25 kg, it is preferable to administer Augmentin in the form of a suspension.

There are no clinical data on the use of Augmentin 7:1 formulations at doses exceeding 45 mg/6.4 mg/kg body weight per day in children under 2 years of age.

There are no clinical data on the use of Augmentin 7:1 formulations in children under 2 months of age. Therefore, dosing recommendations for this patient group are not available.

Elderly patients

Dose adjustment is not required.

Dosing in renal impairment

In patients with creatinine clearance (CrCl) greater than 30 mL/min, dose adjustment is not required. Augmentin formulations with an amoxicillin to clavulanic acid ratio of 7:1 are not recommended in patients with creatinine clearance less than 30 mL/min, as there are no recommendations for dose adjustment.

Dosing in hepatic impairment

Use with caution; liver function should be monitored at regular intervals (see sections "Contraindications" and "Special precautions").

Administration method

The medication is intended for oral administration.

The tablet should be swallowed whole, without chewing. If necessary, the tablet may be split in half and the halves swallowed without chewing.

The medication should be taken with food to minimize potential gastrointestinal intolerance.

Treatment may be initiated with parenteral administration according to the instructions for medical use of the injectable form of Augmentin, and continued with oral formulations.

Children

This medication at this dosage and pharmaceutical form is not recommended for treatment of children with body weight less than 25 kg.

Overdose

Symptoms

Symptoms typical of gastrointestinal disturbances and disturbances in fluid and electrolyte balance may occur. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to development of renal failure (see section "Special precautions").

In patients with impaired renal function and in patients receiving high doses of the medication, seizures may occur.

Amoxicillin precipitation in urinary catheters has been reported, predominantly after high-dose intravenous administration. Catheter patency should be checked regularly (see section "Special precautions").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Side effects.

The most commonly reported adverse reactions to the medicinal product are diarrhea, nausea, and vomiting.

The list of adverse reactions known from clinical trials of Augmentin and post-marketing surveillance, classified by MedDRA system organ class, is provided below.

The following classification of adverse reaction frequency is used:

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;
Not known: frequency cannot be estimated from available data.

Infections and infestations.

Common: Candidiasis of the skin and mucous membranes.
Not known: Overgrowth of microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system.

Rare: Reversible leukopenia (including neutropenia) and thrombocytopenia.
Not known: Reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index^1.

Cardiac disorders.

Not known: Kounis syndrome.

Immune system disorders^10.

Not known: Angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders.

Uncommon: Dizziness, headache.
Not known: Reversible hyperactivity and convulsions^2, aseptic meningitis.

Gastrointestinal disorders.

Very common: Diarrhea.
Common: Nausea^3, vomiting.
Uncommon: Gastric disturbances.
Not known: Antibiotic-associated colitis^4, black hairy tongue, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders.

Uncommon: Increased levels of AST and/or ALT^5.
Not known: Hepatitis^6 and cholestatic jaundice^6.

Skin and subcutaneous tissue disorders^7.

Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis^9, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders.

Not known: Interstitial nephritis, crystalluria^8 (including acute kidney injury).

^1 See section "Special precautions for use".
^2 See section "Special precautions for use".
^3 Nausea is more frequently associated with higher oral doses of the medicinal product. If gastrointestinal reactions occur, their severity may be reduced by taking Augmentin with food.
^4 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special precautions for use").
^5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving beta-lactam antibiotics, but the clinical significance of these findings is unknown.
^6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special precautions for use").
^7 If hypersensitivity reactions (dermatitis) occur, the medicinal product should be discontinued (see section "Special precautions for use").
^8 See section "Overdose".
^9 See section "Special precautions for use".
^10 See sections "Contraindications" and "Special precautions for use".

Shelf life. 3 years. After opening the package – 30 days.

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

Packaging. 7 tablets per blister; 1 blister placed in an aluminum foil sachet containing desiccant granules; 2 sachets per cardboard box.

Prescription status. Prescription only.

Manufacturer: Glaxo Wellcome Production, France.

Manufacturer's address:
Glaxo Wellcome Production, ZI de la Peyenniere, 53100 Mayenne, France.

INSTRUCTIONS

for medical use of the medicinal product

AUGMENTIN (BD)

[AUGMENTIN (BD)]

Composition:

Active substances: amoxicillin and clavulanic acid;

One tablet contains amoxicillin (as amoxicillin trihydrate) 875 mg, clavulanic acid (as potassium clavulanate) 125 mg;

Excipients: magnesium stearate, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, microcrystalline cellulose, dimethicone;

Tablet coating: titanium dioxide (E 171), hypromellose (5 cps), hypromellose (15 cps), macrogol 4000, macrogol 6000.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: capsule-shaped white or off-white film-coated tablets, with a break line on one side and the monograms A C on both sides.

Pharmacotherapeutic group. Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors.

ATC code J01CR02.

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) involved in the biosynthetic metabolism of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, resulting in cell lysis and death.

Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the spectrum of activity of amoxicillin as monotherapy does not include microorganisms producing these enzymes.

Clavulanic acid is a beta-lactam compound structurally related to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid has no clinically useful antibacterial activity when used alone.

PK/PD relationship

The time during which drug concentration remains above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining the efficacy of amoxicillin.

Mechanisms of resistance

There are two main mechanisms of resistance to amoxicillin/clavulanic acid:

• Inactivation by bacterial beta-lactamases that are not themselves inhibited by clavulanic acid, including classes B, C, and D;
• Alteration of PBPs, reducing the affinity of the antibacterial agent for its target.

Bacterial impermeability or efflux pump mechanisms may cause or contribute to bacterial resistance, particularly in Gram-negative bacteria.

Breakpoints

MIC breakpoints for amoxicillin/clavulanic acid established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST)

Microorganisms	Breakpoints of susceptibility (µg/mL)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae 1	≤1	-	> 1
Moraxella catarrhalis 1	≤1	-	> 1
Staphylococcus aureus 2	≤2	-	>2
Coagulase-negative staphylococci 2	≤ 0.25		> 0.25
Enterococcus 1	≤4	8	> 8
Streptococcus A, B, C, G 5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae 3	≤ 0.5	1–2	>2
Enterobacteriaceae 1, 4	-	-	> 8
Gram-negative anaerobic bacteria 1	≤4	8	> 8
Gram-positive anaerobic bacteria 1	≤4	8	> 8
Breakpoints not specific to individual species 1	≤2	4–8	> 8
1 Reported values are for amoxicillin concentrations. For susceptibility testing, the concentration of clavulanic acid is set at 2 mg/L. 2 Reported values are for oxacillin concentrations. 3 Breakpoints are derived from ampicillin breakpoints. 4 The resistance breakpoint R>8 mg/L indicates that all strains with resistance mechanisms are classified as resistant. 5 Breakpoints are derived from benzylpenicillin breakpoints.

The prevalence of resistance can vary geographically and over time for individual species, so local information on susceptibility is desirable, especially when treating severe infections. Expert advice should be sought if local resistance prevalence is such that the benefit of the drug, at least for certain types of infections, is questionable.

Usually susceptible species

Gram-positive aerobes: Enterococcus faecalis, Gardnerella vaginalis, Staphylococcus aureus (methicillin-susceptible)£, coagulase-negative staphylococci (methicillin-susceptible), Streptococcus agalactiae, Streptococcus pneumoniae1, Streptococcus pyogenes and other beta-haemolytic streptococci, Streptococcus viridans group. Gram-negative aerobes: Capnocytophaga spp., Eikenella corrodens, Haemophilus influenzae2, Moraxella catarrhalis, Pasteurella multocida. Anaerobes: Bacteroides fragilis, Fusobacterium nucleatum, Prevotella spp.

Species with potential resistance development issues

Gram-positive aerobes: Enterococcus faecium$. Gram-negative aerobes: Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Proteus mirabilis, Proteus vulgaris.

Naturally resistant microorganisms

Gram-negative aerobes: Acinetobacter sp., Citrobacter freundii, Enterobacter sp., Legionella pneumophila, Morganella morganii, Providencia spp., Pseudomonas sp., Serratia sp., Stenotrophomonas maltophilia. Other microorganisms: Chlamydophila pneumoniae, Chlamydophila psittaci, Coxiella burnetii, Mycoplasma pneumoniae.

$ Naturally moderate susceptibility in the absence of acquired resistance mechanisms. £ All methicillin-resistant staphylococci are resistant to amoxicillin/clavulanic acid. 1 This dosage form of amoxicillin/clavulanic acid should not be used for treatment of infections caused by penicillin-resistant Streptococcus pneumoniae (see sections "Dosage and method of administration" and "Special warnings and precautions for use"). 2 Strains with reduced susceptibility have been reported in some EU countries with a prevalence of over 10%.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH levels. Both components are rapidly and well absorbed following oral administration. The bioavailability of amoxicillin and clavulanic acid is approximately 70% following oral administration. The plasma profiles of both components are identical, and the time to reach maximum plasma concentration (Tmax) for each component is approximately one hour.

Serum concentrations of amoxicillin and clavulanic acid achieved after administration of the amoxicillin/clavulanic acid combination are identical to those achieved following oral administration of equivalent doses of amoxicillin or clavulanic acid alone.

Distribution. Approximately 25% of total clavulanic acid in plasma and 18% of total amoxicillin in plasma are protein-bound. The apparent volume of distribution is approximately 0.3–0.4 L/kg for amoxicillin and about 0.2 L/kg for clavulanic acid.

After intravenous administration, amoxicillin and clavulanic acid have been detected in the gallbladder, peritoneum, skin, adipose tissue, muscle tissue, synovial and peritoneal fluids, bile, and pus. Amoxicillin does not distribute sufficiently into cerebrospinal fluid.

Animal studies have shown no evidence of significant retention of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be detected in breast milk. A small amount of clavulanic acid may also be present in breast milk (see section "Use during pregnancy or breastfeeding").

It has been demonstrated that both amoxicillin and clavulanic acid cross the placental barrier (see section "Use during pregnancy or breastfeeding").

Biotransformation. Amoxicillin is partially excreted in urine as inactive penicilloic acid in amounts equivalent to 10–25% of the initial dose. Clavulanic acid is extensively metabolized in the human body and excreted in urine and feces, as well as in the form of carbon dioxide in expired air.

Elimination. The primary route of elimination for amoxicillin is renal, whereas clavulanic acid is eliminated both by the kidneys and via extrarenal mechanisms.

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour, and the mean total clearance is approximately 25 L/h. Various studies have shown that urinary excretion amounts to 50–85% for amoxicillin and 27–60% for clavulanic acid over a 24-hour period. The greatest amount of clavulanic acid is excreted within the first 2 hours after administration.

Concomitant administration of probenecid slows the elimination of amoxicillin but does not affect the renal excretion of clavulanic acid (see section "Interaction with other medicinal products and other forms of interaction").

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. Since elderly patients are more likely to have decreased renal function, dosage selection should be cautious, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a greater proportion of amoxicillin is eliminated by the kidneys. In renal impairment, dosage adjustments should prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Method of administration and dosage").

Hepatic impairment. Caution is recommended when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

Treatment in adults and children of bacterial infections caused by microorganisms sensitive to Augmentin, such as:

• acute bacterial sinusitis (confirmed);
• acute otitis media;
• confirmed exacerbation of chronic bronchitis;
• community-acquired pneumonia;
• cystitis;
• pyelonephritis;
• skin and soft tissue infections, including cellulitis, animal bites, severe odontogenic abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, appropriate use guidelines should be followed.

Contraindications.

Hypersensitivity to any component of the drug or to any antibacterial agent of the penicillin group.

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

History of jaundice or hepatic dysfunction associated with the use of amoxicillin/clavulanate.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin therapy. If concomitant use is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Dose adjustment of oral anticoagulants may also be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate

Penicillins may reduce the renal clearance of methotrexate, potentially increasing its toxicity.

Probenecid

Concomitant administration of probenecid is not recommended. Probenecid reduces the renal tubular secretion of amoxicillin. Concurrent use of probenecid may lead to increased levels and prolonged presence of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite, mycophenolic acid, by approximately 50%. This change in pre-dose concentration may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of graft dysfunction. However, careful monitoring is necessary during concomitant use and for some time after completion of antibiotic therapy.

Special precautions for use.

Before initiating therapy with amoxicillin/clavulanic acid, a thorough history of previous hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam agents should be obtained (see sections "Contraindications" and "Side effects").

Severe and, in some cases, fatal hypersensitivity reactions (including anaphylactic reactions and severe skin adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to DRESS syndrome—a serious allergic reaction that can lead to myocardial infarction (see section "Side effects"). Such reactions are more likely in patients with a history of penicillin hypersensitivity and in those with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy initiated.

Cases of drug-induced enterocolitis syndrome (DIES) have been reported, primarily in children treated with amoxicillin/clavulanic acid (see section "Side effects"). Drug-induced enterocolitis syndrome is an allergic reaction characterized primarily by persistent vomiting (occurring 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. Serious cases have been reported, including progression to shock.

If an infection is confirmed to be caused by microorganism(s) susceptible to amoxicillin alone, consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin monotherapy in accordance with established guidelines.

This pharmaceutical form of Augmentin should not be used when there is a high risk that the likely pathogens have reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. This pharmaceutical form should not be used to treat patients whose infection is caused by Streptococcus pneumoniae resistant to penicillin.

Seizures may occur in patients with impaired renal function or in those receiving high doses of the drug (see section "Side effects").

Amoxicillin/clavulanic acid should be avoided in suspected cases of infectious mononucleosis, as administration of amoxicillin has been associated with the development of a maculopapular rash.

Concomitant use of allopurinol during amoxicillin therapy increases the likelihood of allergic skin reactions.

Prolonged use may occasionally lead to overgrowth of microorganisms not susceptible to the drug.

The early onset of fever-associated generalized erythema with pustule formation during treatment may be a symptom of acute generalized exanthematous pustulosis (AGEP) (see section "Side effects"). This reaction requires discontinuation of Augmentin and constitutes a contraindication to further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients showing signs of hepatic dysfunction (see sections "Dosage and administration", "Contraindications", and "Side effects").

Hepatic complications have been reported primarily in men and elderly patients, which may be related to prolonged treatment. Reports in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may appear several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe and, in rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or those receiving concomitant medications known to cause hepatic complications (see section "Side effects").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Side effects"). Therefore, this diagnosis must be considered in patients presenting with diarrhea during or after antibiotic therapy. If antibiotic-associated colitis develops, Augmentin should be discontinued immediately, medical advice sought, and appropriate treatment initiated. Antiperistaltic agents are contraindicated in such cases.

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

In patients receiving amoxicillin/clavulanic acid, isolated cases of prolonged prothrombin time have been reported. Appropriate monitoring is required when anticoagulants are co-administered. Dose adjustment of oral anticoagulants may be necessary to maintain the desired level of anticoagulation (see section "Interaction with other medicinal products and other forms of interaction" and "Side effects").

Dosage adjustment is required in patients with impaired renal function depending on the degree of impairment (see section "Dosage and administration").

Crystalluria (including acute kidney injury) has been very rarely observed in patients with reduced urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained when high doses of amoxicillin are administered to reduce the risk of amoxicillin-related crystalluria. In patients with indwelling urinary catheters, catheter patency should be checked regularly (see sections "Side effects" and "Overdose").

During amoxicillin therapy, enzymatic methods (glucose oxidase) should be used to test for glucose in urine, as non-enzymatic methods may yield false-positive results.

The presence of clavulanic acid in Augmentin may lead to nonspecific binding of IgG and albumin to erythrocyte membranes, resulting in false-positive Coombs test results.

Positive results in the Platelia Aspergillus enzyme immunoassay (Bio-Rad Laboratories) have been reported in patients receiving amoxicillin/clavulanic acid, despite subsequent confirmation of absence of Aspergillus infection. Cross-reactions with polysaccharides and non-Aspergillus polyfuranoses have been reported when using the Platelia Aspergillus immunoassay. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate a direct or indirect harmful effect on pregnancy, embryonic/fetal development, parturition, or postnatal development. Limited human data on the use of amoxicillin/clavulanic acid during pregnancy do not suggest an increased risk of congenital malformations. In a single study in women with premature rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. The drug should be avoided during pregnancy unless considered necessary by the physician.

Breastfeeding period. Both active components are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Diarrhea and fungal mucosal infections may therefore occur in the breastfed infant, and breastfeeding should be discontinued during treatment. The possibility of allergic reactions should also be considered. Use of amoxicillin/clavulanic acid during breastfeeding is possible only after a physician has evaluated the risk-benefit ratio.

Ability to affect reaction speed when driving vehicles or operating machinery.

Studies on the effect of the drug on reaction speed during driving or operating machinery have not been conducted. However, adverse effects (such as allergic reactions, dizziness, seizures) may occur, which could impair the ability to drive or operate machinery (see section "Side effects").

Dosage and Administration.

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of a single component.

When selecting the dosage of Augmentin for treatment of a specific infection, the following should be considered:

• the likely pathogens involved and their probable susceptibility to antibacterial agents (see section "Special Warnings and Precautions for Use");
• the severity and site of infection;
• the patient's age, body weight, and renal function, as outlined below.

If necessary, consideration should be given to using alternative Augmentin formulations (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

For adults and children with body weight ≥ 40 kg, the total daily dose is 1750 mg amoxicillin/250 mg clavulanic acid (2 tablets), administered in two divided doses. For children with body weight < 40 kg, the maximum daily dose is 1000–2800 mg amoxicillin/143–400 mg clavulanic acid, as specified below.

If higher doses of amoxicillin are required for treatment, other formulations of Augmentin should be used to avoid unnecessarily high doses of clavulanic acid (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

The duration of treatment should be determined based on the clinical response of the patient. Some infections (e.g., osteomyelitis) may require prolonged treatment. Treatment should not exceed 14 days without re-evaluation (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Adults and children with body weight ≥ 40 kg

Recommended standard dose (for all indications): 875 mg/125 mg twice daily.

Children with body weight from 25 to 40 kg

Treatment may be administered using Augmentin tablets or oral suspension.

Recommended doses:

• 25 mg/3.6 mg/kg body weight/day to 45 mg/6.4 mg/kg body weight/day, divided into two doses;
• for treatment of certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), up to 70 mg/10 mg/kg body weight/day, divided into two doses.

Since the tablet cannot be divided, this formulation of Augmentin should not be prescribed for children weighing less than 25 kg.

The table below indicates the dose in mg/kg body weight received by a child weighing between 25 kg and 40 kg when administered one Augmentin 875/125 mg tablet.

Body weight (kg)	40	35	30	25	Recommended single dose (mg/kg body weight) (see above)
Amount of amoxicillin (mg/kg body weight) when taking a single dose of 1 tablet of Augmentin 875/125 mg	21.9	25.0	29.2	35.0	12.5–22.5 (not exceeding 35)
Amount of clavulanic acid (mg/kg body weight) when taking a single dose of 1 tablet of Augmentin 875/125 mg	3.1	3.6	4.2	5.0	1.8–3.2 (not exceeding 5)

For children with body weight less than 25 kg, treatment with Augmentin in the form of a suspension is recommended.

There are no clinical data on the use of Augmentin 7:1 formulations at doses exceeding 45 mg/6.4 mg per kg of body weight per day in children under 2 years of age.

There are no clinical data on the use of Augmentin 7:1 formulations in children under 2 months of age. Therefore, dosing recommendations for this patient group are not available.

Elderly patients

Dose adjustment is not required.

Dosing in renal impairment

For patients with creatinine clearance (CrCl) greater than 30 mL/min, dose adjustment is not required. For patients with creatinine clearance less than 30 mL/min, the use of Augmentin formulations with an amoxicillin to clavulanic acid ratio of 7:1 is not recommended, as there are no recommendations for dose adjustment.

Dosing in hepatic impairment

Use with caution; liver function should be monitored at regular intervals (see sections "Contraindications" and "Special warnings and precautions for use").

Method of administration

The medicinal product is intended for oral administration.

The tablet should be swallowed whole, without chewing. If necessary, the tablet may be split in half and the halves swallowed without chewing.

The medicinal product should be taken with food to minimize potential gastrointestinal intolerance.

Treatment may be initiated with parenteral administration according to the instructions for medical use of the injectable form of Augmentin, and continued with oral formulations.

Children

The medicinal product in this dosage and pharmaceutical form is not recommended for the treatment of children with body weight less than 25 kg.

Overdose

Symptoms

Symptoms typical of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake has been observed, which in some cases led to the development of renal failure (see section "Special warnings and precautions for use").

Seizures may occur in patients with impaired renal function and in patients receiving high doses of the medicinal product.

Amoxicillin precipitation in urinary catheters has been reported, primarily after high-dose intravenous administration. The patency of catheters should be checked regularly (see section "Special warnings and precautions for use").

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid and electrolyte balance.

Amoxicillin/clavulanic acid can be removed from the bloodstream by hemodialysis.

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product are diarrhoea, nausea and vomiting.

The list of adverse reactions known from clinical trials of Augmentin and post-marketing surveillance, classified by MedDRA system organ class, is provided below.

The following classification of frequency of adverse reactions is used:

Very common ≥ 1/10;
Common ≥ 1/100 to < 1/10;
Uncommon ≥ 1/1000 to < 1/100;
Rare ≥ 1/10,000 to < 1/1000;
Very rare < 1/10,000;
Not known (frequency cannot be estimated from the available data).

Infections and infestations

Common: Cutaneous and mucocutaneous candidiasis.
Not known: Overgrowth of microorganisms non-susceptible to the medicinal product.

Disorders of the blood and lymphatic system

Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia.
Not known: Reversible agranulocytosis and haemolytic anaemia; prolonged bleeding time and prothrombin time^1.

Cardiac disorders

Not known: Kounis syndrome.

Immune system disorders^10

Not known: Angioedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders

Uncommon: Dizziness, headache.
Not known: Reversible hyperactivity and convulsions^2, aseptic meningitis.

Gastrointestinal disorders

Very common: Diarrhoea.
Common: Nausea^3, vomiting.
Uncommon: Gastric disturbances.
Not known: Antibiotic-associated colitis^4, black hairy tongue, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders

Uncommon: Increased levels of AST and/or ALT^5.
Not known: Hepatitis^6 and cholestatic jaundice^6.

Skin and subcutaneous tissue disorders^7

Uncommon: Skin rashes, pruritus, urticaria.
Rare: Erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalised exanthematous pustulosis^9, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders

Not known: Interstitial nephritis, crystalluria^8 (including acute kidney injury).

^1 See section "Special warnings and precautions for use".
^2 See section "Special warnings and precautions for use".
^3 Nausea is more frequently associated with higher oral doses of the medicinal product. Gastrointestinal reactions may be reduced in severity by taking Augmentin with food.
^4 Includes pseudomembranous colitis and haemorrhagic colitis (see section "Special warnings and precautions for use").
^5 Mild elevations in AST and/or ALT levels have been more frequently observed in patients receiving beta-lactam antibiotics, but the clinical significance of these findings is unknown.
^6 These events have been observed with other penicillin and cephalosporin antibiotics (see section "Special warnings and precautions for use").
^7 If hypersensitivity reactions (dermatitis) occur, the medicinal product should be discontinued (see section "Special warnings and precautions for use").
^8 See section "Overdose".
^9 See section "Special warnings and precautions for use".
^10 See sections "Contraindications" and "Special warnings and precautions for use".

Shelf life. 3 years. After opening the package – 30 days.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging. Keep out of the reach and sight of children.

Packaging. 7 tablets per blister; 1 blister contained in an aluminium foil sachet with a desiccant packet; 2 sachets per cardboard box.

Prescription category. Prescription only.

Manufacturer.

SmithKline Beecham Pharmaceuticals, United Kingdom.

Manufacturer's address and place of business.

SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.