Amilan Es

CHARACTERISTICS OF THE MEDICINAL PRODUCT

1. NAME OF THE MEDICINAL PRODUCT

Amylan ES, (600 mg+42.9 mg)/5 mL, powder for oral suspension

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mL of the reconstituted suspension contains 600 mg of amoxicillin (as amoxicillin trihydrate) and 42.9 mg of clavulanic acid (as potassium clavulanate). Each mL of the reconstituted suspension contains 120 mg of amoxicillin (as amoxicillin trihydrate) and 8.58 mg of clavulanic acid (as potassium clavulanate). Excipient with known effect: maltodextrin (glucose). For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder for oral suspension. White or yellowish powder. White or yellowish suspension with a strawberry flavor

4. CLINICAL PARTICULARS

4.1 THERAPEUTIC INDICATIONS

Amylan ES is indicated for the treatment of the following infections caused by or suspected to be caused by Streptococcus pneumoniaeresistant to penicillin, in children aged 3 months and older and weighing less than 40 kg (see sections 4.2, 4.4, and 5.1):

• Acute otitis media
• Community-acquired pneumonia

Official guidelines for the appropriate use of antibacterial agents should be taken into account.

4.2 DOSAGE AND ADMINISTRATION

Dosage

Doses are expressed in terms of the amoxicillin and clavulanic acid content, except when referring to a single active substance. When determining the dose of Amylan ES, the following factors should be considered:

• the predicted pathogens and their likely susceptibility to antibacterial agents (see section 4.4);
• the severity and site of infection;
• the patient's age, weight, and renal function, as described below.

Treatment should not be extended beyond 14 days without review of the patient's condition (see section 4.4 regarding extended treatment). Adults and children weighing ≥40 kg Due to the lack of experience with the use of Amylan ES suspension in adults and children weighing ≥40 kg, dosage recommendations cannot be provided. Children weighing <40 kg (aged ≥3 months) the recommended dose of amylan es suspension is (90 + 6.4 mg) body weight day divided into two doses. there are no available clinical data on use in children under 3 months age. renal impairment need to adjust patients with a creatinine clearance>30 mL/min. In patients with a creatinine clearance of <30 ml min, the use of amoxicillin with clavulanic acid is not recommended due to lack available dosage recommendations. hepatic impairment caution advised when administering dose, regular monitoring liver function (see sections 4.3 and 4.4). administration medicinal product amylan es for oral only. minimize risk gastrointestinal intolerance optimize absorption acid, should be administered at start a meal. instructions reconstitution before – see section 6.6. shake bottle well each dose 6.6). orally using spoon or measuring syringe cup provided packaging.< p>

4.3 CONTRAINDICATIONS

Hypersensitivity to the active substances, to any of the penicillins, or to any of the excipients listed in section 6.1. A history of severe immediate hypersensitivity reaction (e.g., anaphylaxis) to another beta-lactam antibacterial agent (e.g., a cephalosporin, carbapenem, or monobactam). A history of jaundice and/or hepatic dysfunction associated with the use of amoxicillin with clavulanic acid (see section 4.8).

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Before initiating therapy with amoxicillin, a careful medical history should be taken to establish whether the patient has any previous history of hypersensitivity reactions to penicillins, cephalosporins, or other beta-lactam antibacterial agents (see sections 4.3 and 4.8). Serious and occasionally fatal hypersensitivity reactions (including anaphylaxis) have been reported in patients receiving penicillins. Hypersensitivity reactions may lead to the development of Kounis syndrome, a serious allergic reaction that can lead to myocardial infarction (see section 4.8). The likelihood of such reactions is higher in individuals with a history of penicillin hypersensitivity and in individuals with atopic disorders. If an allergic reaction occurs, amoxicillin therapy should be discontinued and alternative therapy should be initiated. Drug-induced enterocolitis syndrome (DIES) has occurred mainly in children receiving amoxicillin with clavulanic acid (see section 4.8). This is an allergic reaction, the leading symptom of which is chronic vomiting (1 to 4 hours after ingestion), with no signs of allergy: skin or respiratory. Further symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Severe cases, including progression to shock, have been reported. If it is established that the infection is caused by susceptible bacteria, consideration should be given to changing the combination of amoxicillin with clavulanic acid to amoxicillin alone, in accordance with official guidelines. In patients with renal impairment or those receiving high doses of the medicinal product, seizures may occur (see section 4.8). The use of amoxicillin with clavulanic acid should be avoided if infectious mononucleosis is suspected, as a link has been established between the use of amoxicillin and the occurrence of a rash in patients with mononucleosis. The concomitant use of allopurinol during amoxicillin therapy may increase the risk of skin allergic reactions. Prolonged use may sometimes lead to an overgrowth of non-susceptible microorganisms. A generalized exanthematous pustulosis (AGEP) may occur at the beginning of treatment, which is a sign of acute generalized exanthematous pustulosis (see section 4.8). If such a reaction occurs, amoxicillin with clavulanic acid should be discontinued and should not be administered again. Amoxicillin with clavulanic acid should be used with caution in patients with hepatic dysfunction (see sections 4.2, 4.3, and 4.8). Hepatic events have been reported predominantly in males and the elderly, and may be associated with prolonged treatment. These events are very rarely reported in children. In all patient populations, signs and symptoms usually occur during or shortly after treatment, but in some cases may not become apparent until several weeks after treatment has stopped. They are usually reversible. Hepatic events can be severe, and in rare cases, fatalities have been reported. These events have almost always occurred in patients with severe underlying disease or when taking other medications known to have the potential for hepatic effects (see section 4.8). Antibiotic-associated colitis has been reported with almost all antibacterial agents, including amoxicillin, and may range in severity from mild to life-threatening (see section 4.8). Therefore, it is important to consider this diagnosis in patients who present with diarrhea during or after the use of any antibacterial agent. If antibiotic-associated colitis is suspected, amoxicillin with clavulanic acid should be discontinued immediately, and the patient should be investigated and treated accordingly. In such cases, the use of antibacterial agents that inhibit peristalsis is contraindicated. During prolonged treatment, periodic assessment of organ system functions, including renal, hepatic, and hematopoietic systems, is recommended. Prolongation of prothrombin time has been reported in patients receiving amoxicillin with clavulanic acid. When prescribing oral anticoagulants, appropriate monitoring is recommended, and adjustment of the oral anticoagulant dose may be necessary to maintain the desired level of anticoagulation (see sections 4.5 and 4.8). In patients with reduced urine output, crystalluria (including acute renal failure) has been very rarely observed, mostly with intravenous use. When using high doses of amoxicillin, adequate fluid intake and urine output should be ensured to reduce the risk of amoxicillin crystallization in the urine. In patients with a urinary catheter, regular checks of catheter patency should be performed (see section 4.8 and 4.9). During amoxicillin therapy, enzymatic methods for glucose determination in urine should be used, due to the possibility of false-positive non-enzymatic test results. The clavulanic acid component of Amylan ES may cause non-specific binding of IgG and albumin by red blood cell membranes, leading to false-positive Coombs test results. Positive results have been reported in patients receiving amoxicillin with clavulanic acid using the Bio-Rad Laboratories Platelia Aspergillus EIA test, in whom no subsequent Aspergillus infection was confirmed. Cross-reactions with non-Aspergillus polysaccharides and polyfuranoses have been observed with the Bio-Rad Laboratories Platelia Aspergillus EIA test. Therefore, positive test results in patients receiving amoxicillin with clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods. Excipients with known effects This medicinal product contains maltodextrin, a source of glucose. Patients with glucose-galactose malabsorption syndrome should not take this medicinal product. The product contains less than 1 mmol (23 mg) of sodium per dose, which is essentially sodium-free.

4.5 INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION

Oral anticoagulants Oral anticoagulants and penicillins are widely used in clinical practice without reports of interactions. However, cases of increased international normalized ratio (INR) have been reported in patients treated with acenocoumarol or warfarin and amoxicillin. If concomitant treatment is necessary, careful monitoring of prothrombin time or INR is recommended at the start of amoxicillin treatment or after its discontinuation. Additionally, modification of the oral anticoagulant dose may be necessary (see sections 4.4 and 4.8). Methotrexate Penicillins may decrease the renal clearance of methotrexate, increasing its toxicity. Probenecid The concomitant use of probenecid is not recommended. It reduces the renal tubular secretion of amoxicillin, which may lead to increased and prolonged blood levels of amoxicillin. This effect does not apply to clavulanic acid. Mycophenolate mofetil In patients receiving mycophenolate mofetil, a decrease in the minimum concentration of the active metabolite (mycophenolic acid, MPA) of approximately 50% has been reported after the initiation of oral amoxicillin with clavulanic acid therapy. Changes in the minimum concentration may not accurately reflect changes in total exposure to MPA. Therefore, dose adjustments of mycophenolate mofetil are usually not necessary in the absence of clinical signs of graft dysfunction. Nevertheless, close clinical monitoring is recommended during combined therapy and for a short period after discontinuation of the antibacterial treatment.

4.6 FERTILITY, PREGNANCY, AND LACTATION

Pregnancy Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/fetal development, parturition, or postnatal development (see section 5.3). Limited data on the use of amoxicillin with clavulanic acid in pregnant women do not indicate an increased risk of congenital malformations. In a single study in women with preterm, premature rupture of the membranes, it was reported that prophylactic treatment with amoxicillin with clavulanic acid may be associated with an increased risk of necrotizing enterocolitis in neonates. The use of amoxicillin with clavulanic acid during pregnancy should be avoided unless the physician considers it essential. Breastfeeding Both active substances are excreted in human milk (the effect of clavulanic acid on the breastfed infant is not known). As a result, the possibility of diarrhea or fungal infection of the mucous membranes in the breastfed infant cannot be excluded, and breastfeeding may need to be discontinued. Amoxicillin with clavulanic acid can be used during breastfeeding only if the physician has assessed the benefit-risk ratio.

4.7 EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

No studies on the effects of Amylan ES on the ability to drive and use machines have been performed. However, adverse reactions such as allergic reactions, dizziness, and seizures may affect the ability to drive and use machines (see section 4.8).

4.8 UNDESIRABLE EFFECTS

The most frequently reported adverse reactions are diarrhea, nausea, and vomiting. The following adverse reactions have been reported during clinical trials and post-marketing use, and are classified according to the MedDRA system organ class frequency: very common (≥1/10), common (≥1/100 to <1>

Treatment should be discontinued in the event of any hypersensitivity reaction (see section 4.4). See section 4.9 See section 4.3 See section 4.4. Reporting of suspected adverse reactions After authorization of the medicinal product, it is important to report any suspected adverse reactions. This allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Department of Medicinal Product Monitoring, Office for Registration of Medicinal Products, Medical Devices, and Biocidal Products, Al. Jerozolimskie 181C, 02-222 Warsaw, Tel.: +48 22 49 21 301, Fax: +48 22 49 21 309, website: https://smz.ezdrowie.gov.pl Adverse reactions can also be reported to the marketing authorization holder.

4.9 OVERDOSAGE

Symptoms of overdosage

Gastrointestinal symptoms and fluid and electrolyte disturbances may occur. Crystalluria has been observed, in some cases leading to renal failure (see section 4.4). In patients with renal impairment or those receiving high doses of the medicinal product, seizures may occur. Amoxicillin crystallization has been reported in urinary catheters, mostly after intravenous administration of high doses of the medicinal product. Regular checks of catheter patency should be performed (see section 4.4). Overdose treatment Gastrointestinal symptoms can be treated symptomatically, with attention to fluid and electrolyte balance. Amoxicillin with clavulanic acid can be removed from the circulation by hemodialysis.

5. PHARMACOLOGICAL PROPERTIES

5.1 PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group: antibacterial agents for systemic use; combinations of penicillins with beta-lactamase inhibitors, ATC code: J01CR02 Mechanism of action Amoxicillin is a semi-synthetic penicillin (beta-lactam antibacterial agent) that inhibits the activity of one or more enzymes (often referred to as penicillin-binding proteins, PBPs) involved in the biosynthesis of peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, followed by cell lysis and death. Amoxicillin is susceptible to degradation by beta-lactamases produced by resistant bacteria; therefore, the spectrum of activity of amoxicillin alone does not include organisms that produce these enzymes. Clavulanic acid is a beta-lactam compound with a structure similar to that of penicillins. It inactivates certain beta-lactamases, thereby preventing the inactivation of amoxicillin. Clavulanic acid itself has little clinically significant antibacterial activity. Pharmacokinetic/pharmacodynamic relationship The time that the concentration of the antibacterial agent exceeds the minimum inhibitory concentration (T>MIC) is considered the main determinant of the efficacy of amoxicillin. Mechanism of resistance There are two main mechanisms of resistance to amoxicillin with clavulanic acid:

• Inactivation by bacterial beta-lactamases that are not inhibited by clavulanic acid, including class B, C, and D.
• Alteration of penicillin-binding protein (PBP) structure, which reduces the affinity of the antibacterial agent for its target site.

Impaired permeability of the bacterial cell wall or an active efflux mechanism may cause bacterial resistance or contribute to its development, especially in Gram-negative bacteria. Breakpoint values for susceptibility testing The European Committee on Antimicrobial Susceptibility Testing (EUCAST) has established breakpoint values for the minimum inhibitory concentration (MIC) to determine susceptibility to amoxicillin with clavulanic acid. These values are listed at: https://www.ema.europa.eu/documents/other/minimum-inhibitory-concentration-mic-breakpoints_en.xlsx The prevalence of resistance may vary geographically and over time for selected bacterial species and local information on resistance is desirable, particularly when treating severe infections. If the frequency of resistance to amoxicillin with clavulanic acid is high, as with some species and in some areas, the utility of the agent may be questioned, at least for certain types of infections.

USUALLY SUSCEPTIBLE SPECIES

Aerobic Gram-positive bacteria Staphylococcus aureus(methicillin-susceptible) Streptococcus pneumoniaeStreptococcus pyogenesand other beta-hemolytic streptococci Aerobic Gram-negative bacteria Haemophilus influenzaeMoraxella catarrhalis

SPECIES FOR WHICH ACQUIRED RESISTANCE MAY BE A PROBLEM

Aerobic Gram-negative bacteria Klebsiella pneumoniae

SPECIES WITH NATURAL RESISTANCE

Aerobic Gram-negative bacteria Legionella pneumophilaOther microorganisms Chlamydophila pneumoniaeChlamydophila psittaciCoxiella burnetiiMycoplasma pneumoniaeAll methicillin-resistant staphylococci are resistant to amoxicillin with clavulanic acid. This formulation of amoxicillin with clavulanic acid is only suitable for the treatment of infections caused by penicillin-resistant Streptococcus pneumoniaein the licensed indications (see section 4.1). In some EU countries, strains with reduced susceptibility have been reported with a frequency greater than 10%.

5.2 PHARMACOKINETIC PROPERTIES

AbsorptionAmoxicillin and clavulanic acid are completely dissociated in aqueous solutions at physiological pH. Both components are rapidly and well absorbed after oral administration. The absorption of amoxicillin with clavulanic acid is optimal when administered at the start of a meal. The bioavailability of amoxicillin and clavulanic acid after oral administration is approximately 70%. The serum concentration curves of both components are similar, and the time to reach maximum serum concentration (Tmax) is approximately 1 hour. The following are the mean (±SD) pharmacokinetic parameters of amoxicillin with clavulanic acid administered to children at a dose of 45 mg + 3.2 mg/kg body weight every 12 hours.

The serum concentrations of amoxicillin and clavulanic acid after administration of amoxicillin with clavulanic acid are similar to those achieved after separate administration of equivalent doses of amoxicillin or clavulanic acid. DistributionApproximately 25% of clavulanic acid and 18% of amoxicillin are bound to plasma proteins. The apparent volume of distribution is approximately 0.3-0.4 L/kg body weight for amoxicillin and approximately 0.2 L/kg body weight for clavulanic acid. After intravenous administration, both amoxicillin and clavulanic acid have been found in the bile, abdominal tissue, skin, fat, muscle, synovial fluid, and peritoneal fluid. Amoxicillin does not penetrate adequately into the cerebrospinal fluid. In animal studies, no significant tissue retention of either component has been observed. Amoxicillin, like most penicillins, can be detected in human milk. Small amounts of clavulanic acid have also been detected in human milk (see section 4.6). Both amoxicillin and clavulanic acid cross the placental barrier (see section 4.6). MetabolismAmoxicillin is partially excreted in the urine as the inactive penicilloic acid in amounts representing 10-25% of the initial dose. In humans, clavulanic acid is extensively metabolized and eliminated in the urine and feces, as well as in the form of carbon dioxide in exhaled air. EliminationThe primary route of elimination of amoxicillin is via the kidneys, while clavulanic acid is eliminated by both renal and non-renal mechanisms. In healthy individuals, the mean elimination half-life of amoxicillin with clavulanic acid is approximately 1 hour, and the mean total clearance is approximately 25 L/h. Approximately 60-70% of amoxicillin and 40-65% of clavulanic acid are excreted unchanged in the urine during the first 6 hours after administration of a single dose of amoxicillin with clavulanic acid in the form of 250 mg + 125 mg or 500 mg + 125 mg tablets. In various studies, renal excretion over 24 hours has been reported to be 50-85% for amoxicillin and 27-60% for clavulanic acid. The majority of clavulanic acid is excreted during the first 2 hours after administration. Concomitant administration of probenecid delays the renal excretion of amoxicillin but does not delay the renal excretion of clavulanic acid (see section 4.5). AgeThe elimination half-life of amoxicillin in children aged approximately 3 months to 2 years is similar to values obtained in older children and adults. In very young children (including premature infants) in the first week of life, the medicinal product should not be administered more frequently than twice daily due to the immaturity of the renal excretion pathway. In the elderly, the likelihood of decreased renal function is greater; therefore, dose selection should be cautious, and renal function should be monitored. SexAfter oral administration of amoxicillin with clavulanic acid, no significant effect of sex on the pharmacokinetics of amoxicillin or clavulanic acid has been observed in healthy male and female subjects. Renal impairmentThe total clearance of amoxicillin with 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 renal route. Therefore, in patients with renal impairment, doses should be adjusted to avoid excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section 4.2). Hepatic impairmentIn patients with hepatic dysfunction, caution should be exercised when administering the dose, with regular monitoring of liver function

5.3 PRECLINICAL SAFETY DATA

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, and toxicity to reproduction. In a study conducted in dogs, gastrointestinal irritation and vomiting, as well as discoloration of the teeth, were observed after repeated administration of amoxicillin with clavulanic acid. No carcinogenicity studies have been conducted on amoxicillin with clavulanic acid or its components.

6. PHARMACEUTICAL PARTICULARS

6.1 LIST OF EXCIPIENTS

Crospovidone, type A Silica, colloidal anhydrous Sodium carmellose Sodium xanthan gum Acesulfame potassium (E 950) Sodium saccharin (E 954) Strawberry flavor (maltodextrin (corn), triethyl citrate, propylene glycol, flavorings, benzyl alcohol)

6.2 INCOMPATIBILITIES

None

6.3 SHELF LIFE

Dry powder: 2 years Reconstituted suspension: 7 days. The reconstituted suspension should be stored in a refrigerator at 2°C-8°C for up to 7 days. Do not freeze.

6.4 SPECIAL PRECAUTIONS FOR STORAGE

Dry powder: do not store above 25°C Store in the original package to protect from moisture. For storage conditions after reconstitution, see section 6.3.

6.5 NATURE AND CONTENTS OF CONTAINER

Orange-colored glass type III bottle containing powder for reconstitution of 50 mL or 100 mL oral suspension with a polypropylene (PP) cap. The bottle is packaged in a cardboard box with a dosing device in the form of: 6 mL polyethylene/polypropylene (PE/PS) syringe or 5 mL polystyrene (PS) measuring spoon or 5 mL polypropylene (PP) measuring cup. Not all pack sizes may be marketed.

6.6 SPECIAL PRECAUTIONS FOR DISPOSAL AND OTHER HANDLING

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

INSTRUCTIONS FOR RECONSTITUTION OF THE SUSPENSION

Before use, check that the cap seal is intact. Shake the bottle to loosen the powder. Fill the bottle with water to the mark on the label. Invert the bottle and shake well. Wait for the foam to settle. Then, fill the bottle with water to the mark on the label, invert the bottle, and shake well. Shake the bottle well before each use. Further information on the preparation of the oral suspension

7. MARKETING AUTHORIZATION HOLDER

RESPONSIBLE FOR BATCH RELEASE

Viatris Limited Damastown Industrial Park Mulhuddart Dublin 15 DUBLIN Ireland

8. MARKETING AUTHORIZATION NUMBER

Marketing authorization number: 27319

9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION

DATE OF REVISION OF THE TEXT

Date of first authorization: 31.08.2022

10. DATE OF REVISION OF THE TEXT

CHARACTERISTICS OF THE MEDICINAL PRODUCT

08/2024