Arlet^® (Tablets) Instructions for Use

Marketing Authorization Holder

Pollo, LLC (Russia)

Manufactured By

Sintez PJSC (Russia)

ATC Code

J01CR02 (Amoxicillin and beta-lactamase inhibitor)

Active Substances

Amoxicillin (Rec.INN registered by WHO)

Clavulanic acid (Rec.INN registered by WHO)

Dosage Forms

	Arlet®	Film-coated tablets, 250 mg+125 mg: 14 pcs.
		Film-coated tablets, 500 mg+125 mg: 14 pcs.
		Film-coated tablets, 875 mg+125 mg: 14 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets white or almost white, oblong, biconvex.

Excipients: low molecular weight povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700) – 14 mg, talc – 12.8 mg, pregelatinized starch (starch 1500) – 119.4 mg, calcium stearate – 6.4 mg, colloidal silicon dioxide (aerosil) – 6.4 mg, microcrystalline cellulose – 45.2 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 8 mg, propylene glycol – 6 mg, macrogol 4000 (polyethylene glycol 4000) – 3.9 mg, titanium dioxide – 2.1 mg.

7 pcs. – contour cell packaging (2) – bags (1) – cardboard packs.
14 pcs. – dark glass jars (1) – cardboard packs.

Film-coated tablets white or almost white, oblong, biconvex.

Excipients: low molecular weight povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700) – 20 mg, talc – 21.4 mg, pregelatinized starch (starch 1500) – 191.2 mg, calcium stearate – 10.7 mg, colloidal silicon dioxide (aerosil) – 10.7 mg, microcrystalline cellulose – 90.2 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 13 mg, propylene glycol – 10 mg, macrogol 4000 (polyethylene glycol 4000) – 6.5 mg, titanium dioxide – 3.5 mg.

7 pcs. – contour cell packaging (2) – bags (1) – cardboard packs.
14 pcs. – dark glass jars (1) – cardboard packs.

Film-coated tablets white or almost white, oblong, biconvex.

Excipients: low molecular weight povidone (low molecular weight medical polyvinylpyrrolidone 12600±2700) – 30 mg, talc – 33 mg, pregelatinized starch (starch 1500) – 249 mg, calcium stearate – 16.5 mg, colloidal silicon dioxide (aerosil) – 16.5 mg, microcrystalline cellulose – 51.7 mg.

Shell composition hypromellose (hydroxypropyl methylcellulose) – 19.1 mg, propylene glycol – 15.5 mg, macrogol 4000 (polyethylene glycol 4000) – 10 mg, titanium dioxide – 5.4 mg.

7 pcs. – contour cell packaging (2) – bags (1) – cardboard packs.
14 pcs. – dark glass jars (1) – cardboard packs.

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Antibiotic, semi-synthetic penicillin + beta-lactamase inhibitor

Pharmacological Action

A broad-spectrum antibiotic from the group of inhibitor-protected penicillins, resistant to the effects of β-lactamases produced by many pathogenic microorganisms to protect against the action of beta-lactam antibiotics (penicillins, cephalosporins, carbapenems). Bacterial β-lactamases hydrolyze the antibiotic into inactive fragments. Bacteria producing β-lactamases are resistant to penicillins and cephalosporins.

The drug Arlet^® contains 2 active substances: Amoxicillin (a semi-synthetic penicillin with a broad spectrum of antibacterial activity) and clavulanic acid (an irreversible β-lactamase inhibitor).

Amoxicillin is a semi-synthetic broad-spectrum antibiotic active against many gram-positive and gram-negative microorganisms. Amoxicillin is destroyed by β-lactamases, so its antibacterial activity spectrum does not include microorganisms that produce β-lactamases.

Clavulanic acid is a beta-lactam compound capable of inactivating a wide range of β-lactamases by forming a stable inactivated complex with them, which prevents the enzymatic destruction of amoxicillin.

Clavulanic acid is structurally similar to beta-lactam antibiotics but has almost no intrinsic antibacterial activity. Clavulanic acid inhibits β-lactamases of types II, III, IV, and V (according to the Richmond-Sykes classification) but is inactive against type I β-lactamases produced by Enterobacter spp., Pseudomonas aeruginosa, Serratia spp., Acinetobacter spp.

The presence of clavulanic acid in the drug protects Amoxicillin from destruction by β-lactamases and expands its spectrum of antibacterial activity to include microorganisms usually resistant to it and to other penicillins and cephalosporins.

The drug has a broad spectrum of bactericidal antibacterial action.

Active against the following microorganisms: aerobic gram-positive bacteria (Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus agalactiae, Streptococcus bovis; Staphylococcus aureus (except methicillin-resistant strains), Staphylococcus epidermidis (except methicillin-resistant strains), Staphylococcus saprophyticus and other coagulase-negative staphylococci, Enterococcus spp. (including Enterococcus faecalis), Bacillus anthracis, Corynebacterium spp., Listeria monocytogenes, Nocardia asteroides; aerobic gram-negative bacteria (Escherichia coli, Haemophilus influenzae, Klebsiella spp., Moraxella catarrhalis, Bordetella pertussis, Brucella spp., Campylobacter jejuni, Eikenella corrodens, Enterobacter spp., Gardnerella vaginalis, Haemophilus ducreyi, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus spp., Salmonella spp., Shigella spp., Vibrio cholerae, Yersinia enterocolitica; anaerobic gram-positive and gram-negative bacteria Actinomyces israelii, Bacteroides spp. (including Bacteroides fragilis), Clostridium spp. (except Clostridium difficile), Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Prevotella spp.; other microorganisms Borrelia burgdorferi, Chlamydia spp., Helicobacter pylori, Leptospira icterohaemorrhagiae, Treponema pallidum.

Pharmacokinetics

The main pharmacokinetic parameters of amoxicillin and clavulanic acid are similar. In combination, Amoxicillin and Clavulanic acid do not affect each other’s pharmacokinetics.

Absorption

After oral administration, both components are rapidly and completely absorbed from the gastrointestinal tract; food intake has almost no effect on the degree of absorption, but Clavulanic acid is better absorbed when the drug is taken at the beginning of a meal. C_max in blood plasma is reached approximately 1 hour after taking the drug and is (depending on the dose) for amoxicillin 3-12 µg/ml, for clavulanic acid – about 2 µg/ml.

Distribution

Both components are characterized by a good V_d. Therapeutic concentrations of both active substances are determined in various organs, tissues, and body fluids: in the lungs, sputum, abdominal organs, pelvic organs (uterus, ovaries, prostate gland), in the middle ear, skin, liver, palatine tonsils, paranasal sinuses, gallbladder; in adipose, bone, and muscle tissues; in pleural, synovial, and peritoneal fluids; in bile, urine, saliva, bronchial secretions, purulent discharge, interstitial fluid.

Amoxicillin and Clavulanic acid do not penetrate the blood-brain barrier when the meninges are not inflamed.

Binding to plasma proteins is moderate: 25% for clavulanic acid and 18% for amoxicillin.

Amoxicillin and Clavulanic acid cross the placental barrier (no negative effect on the fetus has been identified) and are excreted in trace concentrations in breast milk.

Metabolism

Amoxicillin is partially metabolized in the liver (10% of the administered dose) to inactive metabolites, Clavulanic acid undergoes intensive metabolism in the liver (50-70% of the administered dose).

Excretion

Amoxicillin is excreted from the body mainly by the kidneys through tubular secretion and glomerular filtration (52±15% of the dose unchanged within 7 hours) and a small amount – with bile. About 10-25% of the initial dose of amoxicillin is excreted by the kidneys as inactive penicilloic acid. Clavulanic acid is excreted by the kidneys through glomerular filtration (40-65%), partly in the form of metabolites, and also through the intestines.

T_1/2 of amoxicillin and clavulanic acid is 1-1.5 hours.

Pharmacokinetics in special clinical cases

In patients with severe renal failure (creatinine clearance 10-30 ml/min), T_1/2 increases to 7.5 hours for amoxicillin and to 4.5 hours for clavulanic acid. In anuria, the T_1/2 of both active substances ranges between 10 hours and 15 hours. Both components are removed by hemodialysis and insignificant amounts by peritoneal dialysis.

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to the drug

• Infections of the ENT organs (acute and chronic sinusitis, otitis media, retropharyngeal abscess, tonsillitis, pharyngitis);
• Infections of the lower respiratory tract (acute bronchitis with bacterial superinfection, exacerbation of chronic bronchitis, community-acquired pneumonia);
• Infections of the urinary tract (cystitis, urethritis, pyelonephritis, pyelitis);
• Infections in obstetrics and gynecology (salpingitis, salpingo-oophoritis, cervicitis, bacterial vaginitis, endometritis, pelvic peritonitis, septic abortion);
• Infections of the skin and soft tissues (erysipelas, impetigo, secondarily infected dermatoses, phlegmon, abscess, wound infection, including after animal and human bites);
• Infections of bone and connective tissue (including osteomyelitis);
• Infections of the biliary tract (cholecystitis, cholangitis);
• Chancroid;
• Odontogenic infections;
• Infections of the digestive system (dysentery, salmonellosis, salmonella carriage).

ICD codes

Dosage Regimen

The drug is taken orally. To reduce possible side effects from the digestive system, it is recommended to take the drug at the beginning of a meal. The tablet should be swallowed whole, without chewing, with a glass of water.

The dosage regimen is set individually depending on the age, body weight, renal function of the patient, as well as the severity of the infection.

For adults and children over 12 years of age (or with a body weight over 40 kg) with mild or moderate infection (except lower respiratory tract infections), 1 tab. 250 mg/125 mg 3 times/day or 1 tab. 500 mg/125 mg 2 times/day is prescribed; for severe infection or respiratory tract infection – 1 tab. 500 mg/125 mg 3 times/day or 1 tab. 875 mg/125 mg 2 times/day.

For odontogenic infections, 1 tab. 250 mg/125 mg 3 times/day or 1 tab. 500 mg/125 mg 2 times/day for 5 days is prescribed.

For children aged 6 to 12 years (with a body weight less than 40 kg), 1 tab. 250 mg/125 mg 2-3 times/day or 1 tab. 500 mg/125 mg 2 times/day is usually prescribed. For severe infections, doses can be doubled. The daily dose is usually 20-30 mg/kg of amoxicillin and 5-7.5 mg/kg of clavulanic acid.

It must be remembered that 2 tablets of 250 mg/125 mg are not equivalent to 1 tablet of 500 mg/125 mg, because they contain twice as much clavulanic acid.

The maximum daily dose of amoxicillin is: for adults and children over 12 years of age (with a body weight of 40 kg and more) – 6 g, for children under 12 years of age (with a body weight less than 40 kg) – 45 mg/kg of body weight.

The maximum daily dose of clavulanic acid (in the form of potassium clavulanate) is: for adults and children over 12 years of age (with a body weight of 40 kg and more) – 600 mg, for children under 12 years of age (with a body weight less than 40 kg) – 10 mg/kg of body weight.

The minimum course of treatment with the drug is 5 days. The duration of the treatment course is determined by the attending physician. Treatment should not be continued for more than 14 days without a repeated medical examination. The duration of treatment for acute uncomplicated otitis media is 5-7 days.

For patients with renal impairment (adults and children over 12 years of age or weighing more than 40 kg), dose adjustment and frequency of administration are performed depending on CrCl: for CrCl greater than 30 ml/min, no dose adjustment is required; for CrCl 10-30 ml/min: 1 tab. 250 mg/125 mg twice daily (for mild to moderate infections) or 1 tab. 500 mg/125 mg twice daily (for severe infections or lower respiratory tract infections); for CrCl less than 10 ml/min: 1 tab. 250 mg/125 mg once daily (for mild to moderate infections) or 1 tab. 500 mg/125 mg once daily (for severe infections or lower respiratory tract infections).

In cases of anuria, the dosing interval should be increased to 48 hours or more.

For adults on hemodialysis, the drug should be prescribed at a dose of 1 tab. 500 mg/125 mg or 2 tab. 250 mg/125 mg every 24 hours. To compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid during dialysis, an additional dose of the drug should be taken during the dialysis session and another dose at the end of the session. For children on hemodialysis, the drug should be prescribed at a dose of 15/3.75 mg/kg of body weight once daily. To compensate for the decrease in blood concentrations of amoxicillin and clavulanic acid during dialysis, an additional dose of the drug should be taken during the dialysis session and another dose at the end of the dialysis session.

In patients with hepatic impairment, treatment should be conducted with caution at usual doses; liver function should be regularly monitored.

For elderly patients, no dose adjustment is required. In elderly patients with renal impairment, the dose is adjusted as indicated above for adults with renal impairment.

Adverse Reactions

Classification of adverse reactions by frequency of occurrence: common (from 1% to 10%), uncommon (from 0.1% to 1%), rare (from 0.01% to 0.1%), very rare (less than 0.01%).

Allergic reactions uncommon – urticaria, erythematous rash, pruritus; rare – erythema multiforme; very rare – exfoliative dermatitis, malignant exudative erythema (Stevens-Johnson syndrome), anaphylactic shock, angioedema, serum sickness-like syndrome, acute generalized exanthematous pustulosis. In some cases, the so-called “fifth-day rash” (measles-like exanthema) appears.

From the digestive system common – nausea, vomiting, diarrhea, abdominal pain, hepatic failure (more often in elderly patients, men, with long-term therapy), increased activity of hepatic transaminases; rare – hepatitis, cholestatic jaundice; very rare – glossitis, gastritis, stomatitis, hemorrhagic colitis (may also develop after therapy), pseudomembranous colitis, enterocolitis, black “hairy” tongue, darkening of tooth enamel. Increased activity of transaminases (AST and ALT), bilirubin, and ALP is usually observed in males and elderly patients (especially over 65 years of age). The risk of such changes increases when the drug is used for more than 14 days. These phenomena are very rarely observed in children. The aforementioned changes usually appear during treatment or immediately after. Sometimes they may appear several weeks after discontinuation of the drug. Mostly, reactions from the digestive system are transient and minor, but sometimes they can be severe.

From the hematopoietic system rare – reversible leukopenia (including neutropenia), thrombocytopenia, reversible agranulocytosis and hemolytic anemia; very rare – prolonged bleeding time, anemia, eosinophilia, thrombocytosis.

From the CNS common – dizziness, headache, reversible hyperactivity and convulsions (convulsions may occur in patients with renal impairment or in patients receiving high doses of the drug); very rare – insomnia, agitation, anxiety, behavior change.

From the urinary system very rare – hematuria.

Other common – development of superinfection (including candidiasis), exanthema; rare – reversible increase in prothrombin time, crystalluria, interstitial nephritis, vasculitis.

If any of the side effects mentioned in the instructions worsen or any other side effects not listed in the instructions are observed, the patient should inform the doctor.

Contraindications

• Hepatic impairment (including jaundice) with a history of taking the combination Amoxicillin + Clavulanic acid;
• Infectious mononucleosis or lymphocytic leukemia (risk of exanthema);
• Chronic renal failure (CrCl <30 ml/min) only for tablets with a dosage of 875 mg+125 mg;
• Children under 6 years of age (for this dosage form);
• Children under 12 years of age with chronic renal failure (for this dosage form);
• Hypersensitivity to amoxicillin, clavulanic acid, and other components of the drug;
• Hypersensitivity to other beta-lactam antibiotics (penicillins and cephalosporins).

With caution, the drug is prescribed during pregnancy, during lactation (breastfeeding), in cases of severe hepatic failure, gastrointestinal diseases (including a history of colitis associated with the use of penicillins), chronic renal failure.

Use in Pregnancy and Lactation

The drug should be prescribed with caution during pregnancy and during lactation (breastfeeding).

Arlet^® can be used during pregnancy only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.

The drug can be taken during lactation (breastfeeding). Except for the risk of sensitization associated with the excretion of trace amounts of the active substances of the drug into breast milk, no other adverse effects should be observed in breastfed infants. If sensitization, diarrhea, or mucosal candidiasis develops in the child, breastfeeding should be discontinued.

Use in Hepatic Impairment

In patients with hepatic impairment, treatment should be conducted with caution at usual doses; liver function should be regularly monitored. With caution, the drug is prescribed for severe hepatic failure.

The use of the drug is contraindicated in cases of hepatic impairment (including jaundice) with a history of taking the combination Amoxicillin+Clavulanic acid.

Use in Renal Impairment

The use of the drug is contraindicated in chronic renal failure (CrCl <30 ml/min) only for tablets with a dosage of 875 mg+125 mg.

With caution, the drug is prescribed for chronic renal failure.

For patients with renal impairment (adults and children over 12 years of age or weighing more than 40 kg), dose adjustment and frequency of administration are performed depending on CrCl: for CrCl greater than 30 ml/min, no dose adjustment is required; for CrCl 10-30 ml/min: 1 tab. 250 mg/125 mg twice daily (for mild to moderate infections) or 1 tab. 500 mg/125 mg twice daily (for severe infections or lower respiratory tract infections); for CrCl less than 10 ml/min: 1 tab. 250 mg/125 mg once daily (for mild to moderate infections) or 1 tab. 500 mg/125 mg once daily (for severe infections or lower respiratory tract infections).

In cases of anuria, the dosing interval should be increased to 48 hours or more.

For adults on hemodialysis, the drug should be prescribed at a dose of 1 tab. 500 mg/125 mg or 2 tab. 250 mg/125 mg every 24 hours. To compensate for the decrease in serum concentrations of amoxicillin and clavulanic acid during dialysis, an additional dose of the drug should be taken during the dialysis session and another dose at the end of the session. For children on hemodialysis, the drug should be prescribed at a dose of 15/3.75 mg/kg of body weight once daily. To compensate for the decrease in blood concentrations of amoxicillin and clavulanic acid during dialysis, an additional dose of the drug should be taken during the dialysis session and another dose at the end of the dialysis session.

Pediatric Use

The use of the drug is contraindicated in children under 6 years of age (for this dosage form), as well as in children under 12 years of age with chronic renal failure (for this dosage form).

Geriatric Use

For elderly patients, no dose adjustment is required. In elderly patients with renal impairment, the dose is adjusted as indicated above for adults with renal impairment.

Special Precautions

Before starting treatment, a detailed history should be taken regarding previous hypersensitivity reactions to penicillin or cephalosporin antibiotics or other allergens.

Serious, and sometimes fatal, hypersensitivity reactions (anaphylactic reactions) to penicillins have been reported. The risk of such reactions is highest in patients with a history of hypersensitivity reactions to antibiotics of this group. In case of an allergic reaction, treatment with the drug should be discontinued and alternative therapy initiated. For severe hypersensitivity reactions, adrenaline (epinephrine) should be administered immediately. Oxygen therapy, intravenous corticosteroids, and airway management, including intubation, may also be required.

Cases of necrotizing colitis have been identified in newborns and in pregnant women with premature rupture of fetal membranes who received prophylactic therapy with the Amoxicillin/Clavulanic acid combination.

When treating mild diarrhea caused by Clostridium difficile during a course of treatment, antidiarrheal agents that reduce intestinal motility should be avoided; antidiarrheal agents containing kaolin or attapulgite can be used. In case of severe diarrhea, a doctor should be consulted.

Treatment must be continued for another 48-72 hours after the disappearance of clinical signs of the disease.

When estrogen-containing oral contraceptives and amoxicillin are used concomitantly, other or additional methods of contraception should be used if possible.

Amoxicillin and Clavulanic acid may provoke nonspecific binding of immunoglobulins and albumin to the erythrocyte membrane, which may be the cause of a false-positive Coombs test.

The drug should be used with caution in patients with hepatic impairment.

The severity of side effects from the digestive system can be reduced by taking the drug at the beginning of a meal.

In patients receiving the drug, an increase in prothrombin time may rarely be observed, so appropriate monitoring is necessary when the drug is used concomitantly with anticoagulants.

In patients with reduced diuresis, crystalluria may very rarely occur. When using amoxicillin in high doses, it is recommended to take sufficient fluids and maintain adequate diuresis to reduce the likelihood of amoxicillin crystal formation.

During a course of treatment, monitoring of the state of the hematopoietic organs, liver, and kidneys should be carried out.

In patients with severe renal impairment, adequate dose adjustment or an increase in the dosing intervals is required.

Development of superinfection due to the growth of non-susceptible microflora is possible, which requires an appropriate change in antibacterial therapy.

In patients with hypersensitivity to penicillins, cross-allergic reactions with cephalosporin antibiotics are possible.

High concentrations of amoxicillin give a false-positive reaction for urine glucose when using Benedict’s reagent or Fehling’s solution. The use of enzymatic reactions with glucosidase is recommended.

Since Arlet^® tablets of 250 mg/125 mg and 500 mg/125 mg contain the same amount of clavulanic acid – 125 mg, 2 tablets of 250 mg/125 mg are not equivalent to 1 tablet of 500 mg/125 mg.

Effect on ability to drive vehicles and operate machinery

Caution should be exercised when driving vehicles, operating machinery, and performing other potentially hazardous activities that require increased concentration and speed of psychomotor reactions during the use of the drug.

Overdose

Symptoms in most cases of overdose include gastrointestinal disorders (abdominal pain, diarrhea, vomiting), anxiety, agitation, insomnia, dizziness may also occur, and in isolated cases – convulsions.

Treatment symptomatic therapy should be administered; in case of recent intake (less than 4 hours), gastric lavage should be performed and activated charcoal should be prescribed to reduce drug absorption; the patient should be under medical supervision. Hemodialysis is effective.

Drug Interactions

Antacids, glucosamine, laxatives, aminoglycosides slow down and reduce absorption; ascorbic acid increases absorption.

Concomitant use with allopurinol increases the frequency of exanthema.

Bactericidal antibiotics (including aminoglycosides, cephalosporins, vancomycin, rifampicin, cycloserine) have a synergistic effect when used concomitantly; bacteriostatic antibiotics (macrolides, chloramphenicol, lincosamides, tetracyclines) have an antagonistic effect.

Increases the effectiveness of indirect anticoagulants (by suppressing intestinal microflora, reduces vitamin K synthesis and the prothrombin index). When used concomitantly with anticoagulants, blood coagulation parameters should be monitored.

Reduces the effectiveness of oral contraceptives, drugs metabolized to form para-aminobenzoic acid, ethinylestradiol (risk of breakthrough bleeding).

Diuretics, allopurinol, phenylbutazone, NSAIDs that block tubular secretion increase the concentration of amoxicillin (Clavulanic acid is excreted primarily by glomerular filtration).

Concomitant use with methotrexate increases the toxicity of methotrexate.

Storage Conditions

The drug should be stored in a light-protected place, out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.