Augmentin

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

Composition:

Active substances: amoxicillin, clavulanic acid;

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 400 mg and clavulanic acid (as potassium clavulanate) 57 mg;

Excipients: xanthan gum, aspartame (E 951), succinic acid, colloidal anhydrous silicon dioxide, hydroxypropylmethylcellulose, dried orange flavorings (1 and 2), dried raspberry flavoring, dried "Light Molasses" flavoring, silicon dioxide.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or off-white free-flowing powder.

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 semi-synthetic 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 organisms producing these enzymes.

Clavulanic acid is a beta-lactam 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

Time above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining efficacy for amoxicillin.

Resistance mechanisms

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

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

Impermeability of bacterial cells 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 sensitivity (μg/ml)
	Sensitive	Intermediate	Resistant
Haemophilus influenzae1	≤1	-	> 1
Moraxella catarrhalis1	≤1	-	> 1
Staphylococcus aureus2	≤2	-	>2
Coagulase-negative staphylococci2	≤ 0.25		> 0.25
Enterococcus1	≤4	8	> 8
Streptococcus A, B, C, G5	≤ 0.25	-	> 0.25
Streptococcus pneumoniae3	≤ 0.5	1–2	>2
Enterobacteriaceae1,4	-	-	> 8
Gram-negative anaerobic bacteria1	≤4	8	> 8
Gram-positive anaerobic bacteria1	≤4	8	> 8
Breakpoints not specific to individual species1	≤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 listed in the table are derived from breakpoints for ampicillin. 4 The resistance breakpoint R > 8 mg/L indicates that all strains with resistance mechanisms are classified as resistant. 5 Breakpoints listed in the table are derived from breakpoints for benzylpenicillin.

The prevalence of resistance may 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 when 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-sensitive)£, Coagulase-negative staphylococci (methicillin-sensitive), 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 acquired resistance may be a problem

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 Penicillin-resistant Streptococcus pneumoniae should not be treated with this formulation of amoxicillin/clavulanic acid (see sections "Posology 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 frequency greater than 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 amoxicillin/clavulanic acid 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 approximately 0.2 L/kg for clavulanic acid.

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

Animal studies have not revealed 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").

Biological transformation. 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 main route of elimination for amoxicillin is via the kidneys, whereas clavulanic acid is eliminated both by the kidneys and through 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. In the case of clavulanic acid, the majority of the substance is excreted within the first 2 hours after administration.

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

Age. The elimination half-life of amoxicillin is identical in children aged 3 months to 2 years, older children, and adults. For infants during the first week of life (including premature infants), the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. 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 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 with caution and require regular monitoring of liver function.

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 dentatoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, guidelines for their appropriate use 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 beta-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 commonly used together in clinical practice, with no 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. If concomitant use is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Additionally, dosage adjustment of oral anticoagulants may be required (see sections "Special precautions for use" and "Adverse reactions").

Methotrexate

Penicillins may reduce methotrexate excretion, 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 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 levels 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, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

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

Serious 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 (drug reaction with eosinophilia and systemic symptoms) — a severe allergic reaction that may lead to myocardial infarction (see section "Adverse reactions"). 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 should be initiated.

Cases of drug-induced enterocolitis syndrome (DIES), predominantly in children, have been reported in patients receiving amoxicillin/clavulanic acid (see section "Adverse reactions"). 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 confirmed 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 formulation of Augmentin is not suitable for use when there is a high risk that the likely pathogens are resistant to beta-lactam agents via mechanisms not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. This formulation should not be used to treat penicillin-resistant S. pneumoniae.

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

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 administration of allopurinol during treatment with amoxicillin increases the likelihood of skin allergic 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 "Adverse reactions"). This reaction requires discontinuation of Augmentin and constitutes a contraindication for 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 "Adverse reactions").

Hepatic complications have been reported primarily in males and elderly patients, which may be associated with prolonged treatment. Such complications have been reported very rarely in children. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may only become apparent several weeks after treatment has ended. These events are usually reversible. Hepatic complications may be severe and, in extremely rare cases, fatal. Such events have always been observed in patients with severe underlying diseases or those receiving concomitant medications known to have potential hepatotoxic effects (see section "Adverse reactions").

Antibiotic-associated colitis, with severity ranging from mild to life-threatening, has been reported with nearly all antibacterial agents, including amoxicillin (see section "Adverse reactions"). Therefore, this diagnosis should be considered in patients presenting with diarrhea during or after antibiotic therapy. If antibiotic-associated colitis occurs, Augmentin should be discontinued immediately, medical advice should be 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.

Rare cases of prolonged prothrombin time have been reported in patients receiving amoxicillin/clavulanic acid. 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 "Adverse reactions").

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 observed very rarely in patients with reduced urine output, primarily during parenteral therapy. Adequate fluid intake and diuresis should be maintained during high-dose amoxicillin therapy to reduce the risk of amoxicillin-related crystalluria. In patients with urinary catheters, catheter patency should be checked regularly (see sections "Adverse reactions" 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 red blood cell membranes, potentially 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 non-Aspergillus polysaccharides and polyfuranoses have been reported with the Platelia Aspergillus enzyme immunoassay. Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Augmentin 457 mg/5 ml suspension contains aspartame (E 951) 2.5 mg/mL — a source of phenylalanine; therefore, the product should be used with caution in patients with phenylketonuria.

The medicinal product contains maltodextrin (glucose). It should not be administered to patients with rare hereditary problems of glucose-galactose malabsorption.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate any direct or indirect harmful effects on pregnancy, embryonal/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 components are excreted in breast milk (there are no data on the effects of clavulanic acid on breastfed infants). Therefore, diarrhea and mucosal fungal infections may occur in breastfed infants, 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 or operating machinery.

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

Dosage and Administration

Dosage is expressed in terms of amoxicillin/clavulanic acid content, except when dosage is specified in terms of an individual 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 the infection;
• the patient's age, body weight, and renal function, as indicated below.

If necessary, consideration should be given to using alternative formulations of Augmentin (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 children weighing <40 kg, this dosage form of Augmentin provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid, assuming administration as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative formulation of Augmentin is recommended to avoid administration of excessively high daily doses of clavulanic acid (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

The duration of treatment should be determined individually for each patient. For certain infections (e.g., osteomyelitis), prolonged treatment may be required. Treatment should not exceed 14 days without re-evaluation (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Children with body weight ≥ 40 kg: other formulations of Augmentin should be used.

Children with body weight <40 kg

Recommended doses:

• from 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day, divided into two doses;
• for treatment of certain infections (such as acute otitis media, sinusitis, and lower respiratory tract infections), children from 2 years of age may be given up to 70 mg/10 mg/kg/day, divided into two doses.

There are no clinical data for Augmentin 7:1 formulations at doses exceeding 45 mg/6.4 mg/kg/day in patients under 2 years of age.

There are no clinical data for Augmentin 7:1 formulations in patients under 2 months of age. Therefore, dosage recommendations for this patient group are not available.

Elderly Patients

Dosage adjustment is not required.

Renal Impairment

Dosage adjustment is not required in patients with creatinine clearance (CrCl) greater than 30 mL/min.

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 available dosage adjustment recommendations.

Hepatic Impairment

Caution is recommended, with regular monitoring of liver function (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Administration

Augmentin™ is intended for oral administration.

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

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

Instructions for Suspension Preparation

Before use, check the integrity of the seal on the cap. Shake the bottle to loosen the powder. Add the required amount of water (as indicated below), invert and shake vigorously. Alternative method: fill the bottle with water just below the mark on the label, invert and shake vigorously, then fill the bottle with water up to the mark, invert again and shake thoroughly.

Dosage	Volume of water required for dissolution (ml)	Final volume of reconstituted oral suspension (ml)
400 mg/57 mg/5 ml	62	70

Before each use, the vial should be shaken thoroughly.

Children. The drug is administered to children aged 2 months and older. For children with body weight above 40 kg, the drug should be administered in another pharmaceutical form.

Overdose.

Symptoms

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

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

Precipitation of amoxicillin in urinary catheters has been reported, mainly after high-dose intravenous administration. The patency of catheters should be checked regularly (see section "Special precautions").

Treatment

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

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

Adverse Reactions

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

Listed below are adverse drug reactions known from clinical trials and post-marketing surveillance of Augmentin, classified by MedDRA system organ class.

The following frequency classification of adverse effects is applied:

• 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 available data)

Infections and infestations

• Common: Cutaneous and mucocutaneous candidiasis
• Not known: Overgrowth of microorganisms not sensitive to the drug

Blood and lymphatic system disorders

• Rare: Reversible leukopenia (including neutropenia) and thrombocytopenia
• Not known: Reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin index¹

Cardiac disorders

• Not known: Kouwenhoven syndrome

Immune system disorders¹⁰

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

Nervous system disorders

• Uncommon: Dizziness, headache
• Not known: Reversible hyperactivity and convulsions², aseptic meningitis

Gastrointestinal disorders

• Common: Diarrhea, nausea³, vomiting
• Uncommon: Gastrointestinal disturbances
• Not known: Antibiotic-associated colitis⁴, "black hairy tongue", discoloration of tooth enamel¹¹, drug-induced enterocolitis syndrome (DIES), acute pancreatitis

Hepatobiliary disorders

• Uncommon: Increased levels of AST and/or ALT⁵
• Not known: Hepatitis⁶ and cholestatic jaundice⁶

Skin and subcutaneous tissue disorders⁷

• Uncommon: Skin rashes, pruritus, urticaria
• Rare: Erythema multiforme
• Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis⁹, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease

Renal and urinary disorders

• Very rare: Interstitial nephritis, crystalluria⁸ (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 Including pseudomembranous colitis and hemorrhagic colitis (see section "Special warnings and precautions for use").
⁵ Mild elevations in AST and/or ALT levels were 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 section "Contraindications" and "Special warnings and precautions for use".
¹¹ Tooth enamel discoloration has been very rarely reported in children. Careful oral hygiene may prevent this discoloration, as the phenomenon can be removed by tooth brushing.

Shelf life: 2 years.

Storage conditions: Store original packaging in a dry place at temperatures below 25 °C. Prepared suspension should be stored in the refrigerator at 2–8 °C for up to 7 days. Keep out of reach and sight of children.

Packaging: Powder for the preparation of 70 ml of suspension in flasks made of clear glass with a screw metal cap (with tamper-evident seal and an internal polymer film), supplied with a dosing syringe or measuring cap or measuring spoon, packed in a cardboard box; or with a child-resistant closure, supplied with a dosing syringe or measuring spoon, packed in a cardboard box.

Prescription status: Prescription only.

Manufacturer: Glaxo Wellcome Production, France.

Glaxo Wellcome Production, France

Manufacturer's name and address of the place of business:

Glaxo Wellcome Production, ZI de la Peyenniere, 53100 Mayenne, France.

Glaxo Wellcome Production, ZI de la Peyenniere, 53100 Mayenne, France.

INSTRUCTION

for medical use of the medicinal product

AUGMENTIN

(AUGMENTIN)

Composition:

Active substances: amoxicillin, clavulanic acid;

5 ml of suspension contain amoxicillin (as amoxicillin trihydrate) 400 mg and clavulanic acid (as potassium clavulanate) 57 mg;

Excipients: xanthan gum, aspartame (E 951), succinic acid, colloidal anhydrous silica, hydroxypropylmethylcellulose, dried orange flavorings (1 and 2), dried raspberry flavoring, dried "Light Molasses" flavoring, silicon dioxide.

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white or almost white, free-flowing powder.

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 antimicrobial spectrum of amoxicillin as monotherapy does not include organisms producing these enzymes.

Clavulanic acid is a beta-lactam 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 as monotherapy.

PK/PD relationship

Time above the minimum inhibitory concentration (T>MIC) is considered the primary factor determining efficacy for 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 class B, C, and D enzymes;
• Modification of PBPs, leading to reduced affinity of the antibacterial agent for its target.

Bacterial impermeability or efflux pump mechanisms may contribute to or cause 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	Breakpoint susceptibility values (µg/mL)
	Susceptible	Intermediate	Resistant
Haemophilus influenzae1	≤1	-	>1
Moraxella catarrhalis1	≤1	-	>1
Staphylococcus aureus2	≤2	-	>2
Coagulase-negative staphylococci2	≤0.25		>0.25
Enterococcus1	≤4	8	>8
Streptococcus A, B, C, G5	≤0.25	-	>0.25
Streptococcus pneumoniae3	≤0.5	1–2	>2
Enterobacteriaceae1,4	-	-	>8
Gram-negative anaerobic bacteria1	≤4	8	>8
Gram-positive anaerobic bacteria1	≤4	8	>8
Breakpoints not specific to individual species1	≤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 listed in the table are derived from breakpoints for ampicillin. 4 The resistance breakpoint R >8 mg/L indicates that all strains with resistance mechanisms are classified as resistant. 5 Breakpoints listed in the table are derived from breakpoints for benzylpenicillin.

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 for which acquired resistance may be a problem

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 Penicillin-resistant Streptococcus pneumoniae should not be treated with this amoxicillin/clavulanic acid formulation (see sections "Dosage and administration" and "Special warnings and precautions for use"). 2 Strains with reduced susceptibility have been reported in some 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% upon 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 amoxicillin/clavulanic acid are identical to those achieved following oral administration of equivalent doses of amoxicillin or clavulanic acid given separately.

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 about 0.3–0.4 L/kg for amoxicillin and about 0.2 L/kg for clavulanic acid.

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

Animal studies have not revealed 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").

Metabolism. 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 is 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 by the kidneys and through 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. In the case of clavulanic acid, the majority of the substance 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. For neonates (including premature infants) during the first week of life, the dosing frequency should not exceed twice daily due to immaturity of the renal elimination pathway. 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 larger fraction of amoxicillin is eliminated by the kidneys. In renal insufficiency, dosing 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, with regular monitoring of liver function.

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 dentoalveolar abscesses with spreading cellulitis;
• bone and joint infections, including osteomyelitis.

When prescribing antibacterial agents, the principles of their appropriate use 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 beta-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 types of interactions.

Oral anticoagulants

Oral anticoagulants and penicillin-type 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 administration of these drugs is necessary, prothrombin time or INR should be closely monitored when starting or stopping amoxicillin. Additionally, 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 the renal tubular secretion of amoxicillin. Concurrent administration of probenecid may lead to increased levels and prolonged duration of amoxicillin (but not clavulanic acid) in the blood.

Mycofenolate 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 levels 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, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

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

Serious 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 (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 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 receiving amoxicillin/clavulanic acid (see section "Side effects"). Drug-induced enterocolitis syndrome 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. Serious cases have been documented, including progression to shock.

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

This formulation of Augmentin is not suitable for use when there is a high risk that the likely pathogens have resistance to beta-lactam agents that is not mediated by beta-lactamases sensitive to inhibition by clavulanic acid. This formulation should not be used for the treatment of penicillin-resistant S. pneumoniae.

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

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

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

Prolonged use may, in some cases, 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 for 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 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 only manifest several weeks after treatment has ended. These events are usually reversible. Hepatic complications may be severe and, in extremely rare cases, fatal. Such events have always been observed in patients with severe underlying disease or those receiving concomitant medications known to have potential hepatotoxic effects (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 occurs, Augmentin should be discontinued immediately, medical advice 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.

Rare cases of prolonged prothrombin time have been reported in patients receiving amoxicillin/clavulanic acid. 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 should be made 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 diuresis, 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 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 non-specific binding of IgG and albumin to red blood cell membranes, potentially 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, in whom subsequent evaluation ruled out Aspergillus infection. Cross-reactions with polysaccharides and polyfuranoses from non-Aspergillus species have been reported when using the Platelia Aspergillus assay (Bio-Rad Laboratories). Therefore, positive test results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.

Augmentin 457 mg/5 ml suspension contains aspartame (E 951) 2.5 mg/ml – a source of phenylalanine; therefore, the product should be used with caution in patients with phenylketonuria.

The medicinal product contains maltodextrin (glucose). The product should not be administered to patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency.

Use during pregnancy or breastfeeding.

Pregnancy. Animal studies do not indicate direct or indirect harmful effects on pregnancy, embryonal/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 of women with premature rupture of membranes, prophylactic treatment with amoxicillin/clavulanic acid was associated with an increased risk of necrotizing enterocolitis in newborns. The use of this drug during pregnancy should be avoided unless considered necessary by the physician.

Breastfeeding period. Both components are excreted in breast milk (there are no data on the effects 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. The use of amoxicillin/clavulanic acid during breastfeeding is possible only after the physician has assessed the benefit-risk ratio.

Ability to affect the speed of reactions when driving or operating machinery.

Studies on the ability of the drug to affect reaction speed during driving or operating machinery have not been conducted. However, undesirable 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 an individual component.

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

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

If necessary, consider 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 children weighing <40 kg, this Augmentin formulation provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid, assuming administration as recommended below. If a higher dose of amoxicillin is considered necessary, an alternative Augmentin formulation should be selected to avoid excessive daily doses of clavulanic acid (see sections "Special Warnings and Precautions for Use" and "Pharmacodynamics").

Duration of treatment should be determined individually for each patient. Longer treatment duration may be required for certain infections (e.g. osteomyelitis). Treatment should not exceed 14 days without review (see section "Special Warnings and Precautions for Use" regarding prolonged therapy).

Children with body weight ≥ 40 kg: other Augmentin formulations should be used.

Children with body weight <40 kg

Recommended doses:

• from 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day, divided into two doses;
• for treatment of certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), children aged 2 years and older may be given up to 70 mg/10 mg/kg/day, divided into two doses.

There are no clinical data available for Augmentin 7:1 formulations at doses higher than 45 mg/6.4 mg/kg/day in patients under 2 years of age.

There are no clinical data available for Augmentin 7:1 formulations in patients under 2 months of age. Therefore, dosage recommendations for this patient group are not available.

Elderly patients

Dose adjustment is not required.

Renal impairment

No dosage adjustment is required for patients with creatinine clearance (CrCl) greater than 30 mL/min.

Augmentin formulations with an amoxicillin to clavulanic acid ratio of 7:1 are not recommended for patients with creatinine clearance less than 30 mL/min, as there are no available dosage adjustment recommendations.

Hepatic impairment

Caution is recommended and regular monitoring of liver function is advised (see sections "Contraindications" and "Special Warnings and Precautions for Use").

Administration

Augmentin™ is intended for oral administration.

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

Therapy may be initiated parenterally, according to the instructions for medical use of the injectable form of Augmentin, and continued with the oral formulation.

Instructions for preparation of suspension.

Before use, check the integrity of the seal on the cap. Shake the bottle to loosen the powder. Add the required amount of water (as indicated below), invert and shake vigorously. Alternative method: fill the bottle with water just below the mark on the label, invert and shake thoroughly, then fill the bottle with water up to the mark, invert again and shake thoroughly.

Dosage	Volume of water to be added for dissolution (ml)	Final volume of reconstituted oral suspension (ml)
400 mg/57 mg/5 ml	62	70

Before each use, the vial should be shaken thoroughly.

Children. The drug is administered to children aged 2 months and older. Children with body weight above 40 kg should be prescribed the drug in another pharmaceutical form.

Overdose.

Symptoms

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

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

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

Treatment

Gastrointestinal disturbances can be treated symptomatically, with attention to fluid/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 (MP) are diarrhoea, nausea, and vomiting.

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

The following classification of frequency of adverse effects 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 the available data).

Infections and infestations

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

Blood and lymphatic system disorders

• Rare: Reversible leucopenia (including neutropenia) and thrombocytopenia.
• Not known: Reversible agranulocytosis and haemolytic anaemia; prolonged bleeding time and prothrombin time¹.

Cardiac disorders

• Not known: Quincke's oedema.

Immune system disorders¹⁰

• Not known: Angioneurotic oedema, anaphylaxis, serum sickness-like syndrome, allergic vasculitis.

Nervous system disorders

• Uncommon: Dizziness, headache.
• Not known: Reversible hyperactivity and convulsions², aseptic meningitis.

Gastrointestinal disorders

• Common: Diarrhoea, nausea³, vomiting.
• Uncommon: Gastric disturbances.
• Not known: Antibiotic-associated colitis⁴, "black hairy tongue", discolouration of tooth enamel¹¹, drug-induced enterocolitis syndrome (DIES), acute pancreatitis.

Hepatobiliary disorders

• Uncommon: Increased levels of AST and/or ALT⁵.
• Not known: Hepatitis⁶ and cholestatic jaundice⁶.

Skin and subcutaneous tissue disorders⁷

• Uncommon: Skin rashes, pruritus, urticaria.
• Rare: Erythema multiforme.
• Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, exfoliative bullous dermatitis, acute generalized exanthematous pustulosis⁹, drug reaction with eosinophilia and systemic symptoms (DRESS), linear IgA disease.

Renal and urinary disorders

• Very rare: Interstitial nephritis, crystalluria⁸ (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 Including 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 section "Contraindications" and "Special warnings and precautions for use".
¹¹ Discolouration of tooth enamel has been very rarely reported in children. Careful oral hygiene may prevent such discolouration, as this phenomenon can be removed by tooth brushing.

Shelf life: 2 years.

Storage conditions: Store original packaging tightly closed at temperatures below 25°C in a dry place. The reconstituted suspension should be stored in the refrigerator at 2–8°C for up to 7 days. Keep out of the reach of children.

Packaging: Powder for oral suspension in 70 ml amber glass bottles with a screw cap (with tamper-evident closure and an internal polymer seal), supplied with an oral dosing syringe or measuring cap or measuring spoon, packed in a cardboard box; or in a bottle with child-resistant closure supplied with an oral dosing syringe or measuring spoon, packed in a cardboard box.

Prescription status: Prescription only.

Manufacturer: SmithKline Beecham Pharmaceuticals, United Kingdom.

SmithKline Beecham Pharmaceuticals, United Kingdom.

Manufacturer's address:
SmithKline Beecham Pharmaceuticals, Clarendon Road, Worthing, BN14 8QH, United Kingdom.
СмітКляйн Бічем Фармасьютикалс, Кларендон Роуд, Ворсінг, BN14 8QH, Велика Британія.