Clavam

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

Composition:

Active substances: 5 ml of suspension contains amoxicillin trihydrate, equivalent to 125 mg of amoxicillin, and potassium clavulanate with silicified microcrystalline cellulose (1:1), equivalent to 31.25 mg of clavulanic acid;

Excipients: mannitol (E 421), sodium citrate, citric acid monohydrate, sodium benzoate (E 211), xanthan gum, colloidal anhydrous silicon dioxide, peppermint flavor DC-117, aspartame (E 951).

Pharmaceutical form. Powder for oral suspension.

Main physicochemical properties: white granular powder, which forms a white homogeneous suspension with peppermint odor upon reconstitution with water.

Pharmacotherapeutic group.

Antibacterials for systemic use. Beta-lactam antibiotics, penicillins. Combinations of penicillins with beta-lactamase inhibitors. ATC code J01CR02.

Pharmacological properties.

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 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 alone.

PK/PD relationship

Time above the minimum inhibitory concentration (T>MIC) is considered the primary pharmacokinetic/pharmacodynamic parameter 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;
• Alteration of PBPs, leading to reduced affinity of the antibacterial agent for its target.

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

Clinical breakpoints

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

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 medicinal product, at least for certain types of infections, is questionable.

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 fluid, bile, and pus. Amoxicillin does not distribute sufficiently into cerebrospinal fluid.

Animal studies have not revealed any evidence of significant accumulation of substances derived from either component of the drug in body tissues. Amoxicillin, like most penicillins, may be found 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 is excreted in urine and feces, as well as in the form of carbon dioxide in expired air.

Elimination. The primary route of elimination for amoxicillin is 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 affect the 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 in 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 should be chosen with caution, and monitoring of renal function is recommended.

Renal impairment. Total serum clearance of amoxicillin/clavulanic acid decreases proportionally with decreasing renal function. The reduction in clearance is more pronounced for amoxicillin than for clavulanic acid, as a greater 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. Caution is recommended when administering the drug to patients with hepatic impairment, and regular monitoring of liver function is advised.

Clinical characteristics.

Indications.

Clavam is indicated for the treatment of the following infections in children:

• 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, appropriate prescribing guidelines should be followed.

Contraindications.

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

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

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

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

Oral anticoagulants and penicillin-class antibiotics are widely used in clinical practice without reports of interaction. However, cases of increased international normalized ratio (INR) have been reported in patients receiving acenocoumarol or warfarin who were prescribed a course of amoxicillin. If concomitant use 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" 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 may lead to increased levels and prolonged duration of amoxicillin (but not clavulanic acid) in the blood.

Mycophenolate mofetil

In patients receiving mycophenolate mofetil, initiation of oral amoxicillin with clavulanic acid may reduce the pre-dose concentration of the active metabolite mycophenolic acid by approximately 50%. This change in pre-dose concentration may not fully reflect changes in total exposure to mycophenolic acid. Therefore, dosage adjustment of mycophenolate mofetil is usually not required unless there is clinical evidence of transplant 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 assessment of previous hypersensitivity reactions to penicillins, cephalosporins, or other β-lactam agents should be performed (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. Such reactions are more likely to occur in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued immediately and appropriate alternative therapy should be initiated.

If the infection is proven to be caused by organism(s) susceptible to amoxicillin alone, consideration should be given to switching from amoxicillin/clavulanic acid to amoxicillin monotherapy in accordance with standard guidelines.

This medicinal product, Clavam, is not suitable for use when there is a high likelihood that the causative pathogens are resistant to β-lactam agents through mechanisms not mediated by β-lactamases that are susceptible to inhibition by clavulanic acid. This medicinal product should not be used for the treatment of penicillin-resistant S. pneumoniae.

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

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

Concomitant administration of allopurinol during amoxicillin therapy increases the likelihood of developing 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 Clavam and constitutes a contraindication for any further use of amoxicillin.

Amoxicillin/clavulanic acid should be used with caution in patients showing signs of impaired liver function (see sections "Method of administration and dosage", "Contraindications", and "Adverse reactions").

Hepatic complications have been reported primarily in men and elderly patients, which may be associated with prolonged therapy. Reports of such complications in children are very rare. In all patient groups, symptoms typically occur during or shortly after treatment, although in some cases they may appear several weeks after completion of therapy. These events are usually reversible. Hepatic complications may be severe, and in extremely rare cases, fatal outcomes have been reported. Such events have almost always occurred 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, Clavam 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 "Method of administration and dosage").

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

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

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

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

Clavam suspension contains aspartame (E 951), a source of phenylalanine; therefore, the product should be administered with caution to patients with phenylketonuria.

Use during pregnancy or breastfeeding.

Pregnancy. Reproductive studies in animals with oral and parenteral forms of amoxicillin/clavulanate showed no teratogenic effects. In one study involving women with preterm rupture of membranes, prophylactic use of Clavam was associated with an increased risk of necrotizing enterocolitis in newborns. As with other medicinal products, Clavam should be avoided during pregnancy, especially in the first trimester, unless in the opinion of the physician the treatment is clearly necessary.

Breastfeeding period. Both active components of the drug are excreted in breast milk (there is no information on the effect of clavulanic acid on the breastfed infant). Diarrhea and fungal mucosal infections may therefore occur in the breastfed infant, and breastfeeding should be discontinued.

The possibility of allergic reactions should also be considered. Clavam may be used during breastfeeding only if, in the opinion of the physician, the benefit outweighs the risk.

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

The drug should be used in accordance with official recommendations on antibiotic therapy and local antibiotic susceptibility data, if available. Susceptibility to amoxicillin/clavulanate varies across different regions and may change over time. When necessary, microbial susceptibility testing to the antibiotic should be performed.

The dosage of the drug is determined by a physician based on the suspected microorganisms and their susceptibility to antibacterial agents, severity of the disease, site of infection, patient's age, body weight, and renal function.

If necessary, consider the possibility of using alternative formulations of Clavamox (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Special Instructions" and "Pharmacodynamics").

For children weighing <40 kg, this medicinal form of Clavamox provides a maximum daily dose of 2400 mg amoxicillin/600 mg clavulanic acid when administered as recommended below. If higher doses of amoxicillin are required for treatment, other formulations of Clavamox should be used to avoid administering unnecessarily high doses of clavulanic acid.

The duration of treatment is determined by the patient's clinical response. Some infections (e.g., osteomyelitis) require prolonged treatment. Treatment should not exceed 14 days without consulting a physician.

Adults and children with body weight ≥ 40 kg: other formulations of Clavamox should be used.

Children with body weight < 40 kg: 20 mg/5 mg to 60 mg/15 mg per kg of body weight per day, divided into three separate doses:

• 20 mg/5 mg per kg per day for mild to moderate infections;
• 60 mg/15 mg per kg per day for severe infections.

Clinical data on the use of Clavamox with an amoxicillin to clavulanic acid ratio of 4:1 in children under 2 years of age at doses exceeding 40 mg/10 mg/kg per day are lacking.

Renal Impairment

Dose adjustment is based on the maximum recommended doses of amoxicillin and depends on glomerular filtration rate. Dose adjustment is not required for patients with creatinine clearance above 30 mL/min.

Children with body weight < 40 kg Table 2

Hepatic impairment

The drug should be used with caution. Liver function should be monitored regularly.

Method of administration

For optimal absorption and to reduce the risk of gastrointestinal adverse effects, the drug should be taken at the beginning of a meal.

Treatment may be initiated with parenteral administration of the drug and continued with an oral dosage form.

Preparation of 100 ml of suspension: before use, check the integrity of the closure cap. Shake the bottle to loosen the powder from the walls and bottom. Add drinking water in two portions (first up to 2/3, then up to the mark on the bottle), shaking the bottle each time. SHAKE WELL BEFORE EACH DOSE.

Children

The drug is used in children from the age of 2 months. Children with body weight over 40 kg should be administered another dosage form of the drug.

Overdose

Symptoms

Symptoms of gastrointestinal disturbances and fluid and electrolyte imbalance may occur. Crystalluria associated with amoxicillin intake 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, primarily after high-dose intravenous administration. The patency of catheters should be monitored regularly (see section "Special precautions").

Treatment

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

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

Adverse Reactions

The most commonly reported adverse reactions to the medicinal product (AR) are diarrhea, nausea, and vomiting. The list of known adverse reactions identified from clinical trials and post-marketing surveillance, classified by MedDRA System Organ Class, is provided below.

The following classification is used to describe the frequency of adverse reactions:

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: candidiasis of skin and mucous membranes.
Not known: overgrowth of microorganisms not sensitive to the medicinal product.

Disorders of the blood and lymphatic system

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

Immune system disorders*10*

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

Nervous system disorders

Uncommon: dizziness, headache.
Not known: reversible hyperactivity and convulsions*2*.
Not known: aseptic meningitis.

Gastrointestinal disorders

Common: diarrhea, nausea*3*, vomiting.
Uncommon: stomach discomfort.
Not known: antibiotic-associated colitis*4*, "black hairy tongue", discoloration of tooth enamel*11*.

Hepatobiliary disorders

Uncommon: increased levels of AST and/or ALT*5*.
Not known: hepatitis*6* and cholestatic jaundice*6*.

Skin and subcutaneous tissue disorders*7*

Uncommon: skin rash, pruritus, urticaria.
Rare: erythema multiforme.
Not known: Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis*9*, drug reaction with eosinophilia and systemic symptoms (DRESS).

Renal and urinary disorders

Very rare: interstitial nephritis, crystalluria*8*.

*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 can be minimized by taking Clavam 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 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* Tooth enamel discoloration has been very rarely reported in children. Careful oral hygiene may prevent this effect, as discoloration can be removed by tooth brushing.

Shelf life

2 years.

Storage conditions

Store at temperatures not exceeding 25 °C in a place inaccessible to children.
After reconstitution, the suspension should be stored for up to 7 days at 2–8 °C.

Packaging

One 100 ml bottle with a measuring cap in a cardboard box.

Prescription status

Prescription only.

Manufacturer

Alkem Laboratories Ltd.

Manufacturer's address

167 Mahatma Gandhi, Udio Nagar, Dabhel, Daman, 396210, India.