Coact

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT COACT (KOACT)

Composition:

Active substances: amoxicillin and clavulanic acid;

One film-coated tablet contains amoxicillin (equivalent to amoxicillin trihydrate) 875 mg and clavulanic acid (equivalent to potassium clavulanate) 125 mg;

Excipients: sodium starch glycolate (type A), microcrystalline cellulose, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry white 06B58855 (HIS): (hypromellose 5 cP, titanium dioxide (E 171), macrogol PEG 400, hypromellose 15 cP), isopropyl alcohol, methylene chloride, purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white or almost white, capsule-shaped tablets, film-coated, with the marking "A" on one side and a break line between "6" and "5" on the other side.

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 antibiotic of the penicillin class (beta-lactam antibiotic) that inhibits one or more enzymes (often referred to as penicillin-binding proteins (PBPs)) involved in the biosynthesis of bacterial peptidoglycan, an essential structural component of the bacterial cell wall. Inhibition of peptidoglycan synthesis leads to weakening of the cell wall, which typically results in cell lysis and death.

Amoxicillin is susceptible to beta-lactamases produced by resistant bacteria and is degraded by these enzymes; therefore, the spectrum of activity of amoxicillin does not include microorganisms that produce these enzymes.

Clavulanic acid has a beta-lactam structure similar to penicillins. It inactivates certain beta-lactamase enzymes, thereby preventing the inactivation of amoxicillin. Clavulanic acid does not possess clinically significant antibacterial activity.

Pharmacokinetic/pharmacodynamic relationship

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

Mechanisms of resistance

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

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

Impermeability of bacterial cells 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)

The prevalence of resistance may vary geographically and over time for individual species; therefore, local data on susceptibility are desirable, especially when treating severe infections. If necessary, expert advice should be sought when local resistance prevalence is at a level where the benefit of using the drug is at least questionable for certain types of infections.

Pharmacokinetics.

Absorption. Amoxicillin and clavulanic acid completely dissociate 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 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 approximately 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 distribute adequately into cerebrospinal fluid.

Animal studies have shown no evidence of significant retention of substances derived from any 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 in pregnancy or lactation").

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

Metabolism. Amoxicillin is partially excreted in the 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.

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

In healthy volunteers, the mean elimination half-life of amoxicillin/clavulanic acid is approximately one hour, and the mean total clearance is approximately 25 L/hour.

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 greatest amount 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 reduced 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 be adjusted to prevent excessive accumulation of amoxicillin while maintaining adequate levels of clavulanic acid (see section "Method of administration and dosage").

Hepatic impairment. Patients with hepatic insufficiency should be treated cautiously with this medicinal product, and liver function should be monitored regularly.

Clinical characteristics.

Indications.

Treatment of bacterial infections in adults and children caused by microorganisms sensitive to the drug, 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.

Contraindications.

Hypersensitivity to the components of Coact or to any penicillin-containing drug.

History of severe hypersensitivity reactions (including anaphylactoid reactions) 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 and clavulanic acid.

Interaction with other medicinal products and other forms of interaction.

Oral anticoagulants

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

Methotrexate

Penicillins may reduce methotrexate excretion, potentially leading to increased toxicity.

Probenecid

Concomitant use of probenecid is not recommended. Probenecid reduces renal tubular secretion of amoxicillin. Concomitant administration may result in elevated and prolonged blood levels of amoxicillin.

Myfortic (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 transplant dysfunction. However, close monitoring is necessary during concomitant use and for some time after antibiotic therapy.

Special precautions for use.

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

Serious and occasionally fatal hypersensitivity reactions (including anaphylactoid reactions and severe cutaneous adverse reactions) have been reported in patients receiving penicillin therapy. Hypersensitivity reactions may also progress to DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) – a serious allergic reaction that may lead to myocardial infarction (see section "Side effects"). Such reactions are more likely in patients with a history of penicillin hypersensitivity and in patients with atopic diseases. If an allergic reaction occurs, amoxicillin/clavulanic acid should be discontinued 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 (occurring 1–4 hours after drug administration) in the absence of allergic skin or respiratory symptoms. Additional symptoms may include abdominal pain, diarrhea, hypotension, or leukocytosis with neutrophilia. Serious cases have been reported, including progression to shock.

If it has been 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 standard guidelines.

This medicinal product should not be used in cases of high risk of pathogens with reduced susceptibility or resistance to beta-lactam agents not mediated by beta-lactamases that are sensitive to inhibition by clavulanic acid. This product should not be used for the treatment of infections caused by penicillin-resistant S. pneumoniae strains.

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

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

Concomitant 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 "Side effects"). This reaction requires discontinuation of Coact 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 "Contraindications", "Dosage and administration", and "Side effects").

Hepatic complications have been reported, primarily in men and elderly patients, which may be associated with prolonged treatment. Reports in children are very rare. In all patient groups, symptoms usually 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 exceptionally rare cases, fatal. Such events have almost always occurred in patients with severe underlying disease or in 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 should be considered in patients presenting with diarrhea during or after antibiotic therapy. If antibiotic-associated colitis develops, Coact 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 sections "Interaction with other medicinal products and other forms of interaction" and "Side effects").

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

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

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

The presence of clavulanic acid in Coact may lead to nonspecific binding of IgG and albumin to erythrocyte 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 polysaccharides and polyfuranoses from non-Aspergillus species have also been reported during immunoassay using Platelia Aspergillus (Bio-Rad Laboratories).

Therefore, positive test results in patients receiving amoxicillin/clavulanic acid therapy should be interpreted with caution and confirmed by other diagnostic methods.

This medicinal product contains less than 1 mmol per dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

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

Breastfeeding period. Both active components are excreted in breast milk (no information is available on the effect of clavulanic acid on breastfed infants). Therefore, diarrhea and fungal mucosal infections may occur in the breastfed infant, and breastfeeding should be discontinued. The possibility of allergic reactions should also be considered.

Coact may be used during breastfeeding only if, in the physician’s opinion, the benefit outweighs the risk.

Ability to affect reaction speed when driving or operating machinery.

Studies on the effect of the medicinal product on the ability to drive or operate machinery have not been conducted. However, adverse reactions (e.g., allergic reactions, dizziness, seizures) may occur that could impair the ability to drive or operate machinery (see section "Side effects").

Method of Administration and Dosage

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

When appropriate, consideration should be given to using alternative formulations of Coact (i.e., those providing higher doses of amoxicillin and/or different ratios of amoxicillin to clavulanic acid) (see sections "Pharmacodynamics" and "Special Warnings").

The recommended dosage range depends on the expected pathogens and their susceptibility to antibacterial agents, the severity of the disease, the site of infection, as well as the patient's age, body weight, and renal function.

For adults and children with body weight ≥40 kg, the specified formulation of Coact provides a daily dose of 1750 mg amoxicillin/250 mg clavulanic acid when administered twice daily, and 2625 mg amoxicillin/375 mg clavulanic acid when administered three times daily, according to the recommended doses below.

For children with body weight <40 kg, the specified formulation of Coact provides a maximum daily dose of 1000–2800 mg amoxicillin/143–400 mg clavulanic acid, administered according to the recommendations below.

If higher daily doses of amoxicillin are required for treatment, another formulation of Coact should be used to avoid administering unnecessarily high doses of clavulanic acid.

The duration of treatment is determined by the physician based on the patient's clinical response. Some infections (e.g., osteomyelitis) require prolonged treatment. Treatment should not be continued for more than 14 days without re-evaluation of the patient's condition.

Adults and Children ≥ 40 kg

Recommended doses:

• Standard dose (for all indications): 1 tablet of 875/125 mg twice daily;
• Higher dose (particularly for infections such as otitis media, sinusitis, lower respiratory tract infections, and urinary tract infections): 1 tablet of 875/125 mg three times daily.

Children with body weight from 25 kg to 40 kg

Recommended doses:

• Dose ranging from 25 mg/3.6 mg/kg/day to 45 mg/6.4 mg/kg/day, divided into two doses;
• For certain infections (such as otitis media, sinusitis, and lower respiratory tract infections), the maximum daily dose should not exceed 70 mg/10 mg/kg body weight/day, divided into two doses.

Children with body weight between 25 and 40 kg, for whom appropriate dosing cannot be achieved, should be administered Coact as an oral suspension powder.

Since the tablets are not designed to be split for dose reduction, Coact tablets should not be administered to children with body weight <25 kg.

The table below shows the doses (mg/kg body weight) received by children with body weight from 25 to 40 kg when administered one 875 mg/125 mg tablet.

For children with body weight <25 kg, it is preferable to use Coact in the form of powder for oral suspension.

Clinical data on the use of Coact medicinal products with a 7:1 ratio in children under 2 years of age at doses exceeding 45 mg/6.4 mg/kg body weight per day are lacking.

Clinical data on the use of Coact medicinal products with a 7:1 ratio in patients under 2 months of age are lacking. Therefore, dosage recommendations for this patient group cannot be provided.

Method of administration

Coact is intended for oral administration.

For optimal absorption of amoxicillin/clavulanic acid and to reduce the possible gastrointestinal side effects, the medication should be taken at the beginning of a meal. Tablets should be swallowed whole, without chewing.

Treatment may be initiated with parenteral administration of amoxicillin/clavulanic acid, followed by oral therapy.

Elderly patients

Dosage adjustment is not required.

Renal impairment

Dosage adjustment is not required in patients with creatinine clearance above 30 mL/min. Coact 875/125 mg should not be used in patients with renal impairment and creatinine clearance below 30 mL/min.

Hepatic impairment

The medication should be administered with caution and liver function should be monitored regularly.

Children

This formulation of Coact should be used in children with body weight of at least 25 kg.

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 renal impairment 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 checked regularly (see section "Special precautions").

Amoxicillin crystalluria has been observed, which in some cases led to renal failure (see section "Special precautions").

Treatment

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

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

Adverse Reactions

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

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

The following frequency classification of adverse reactions is applied:

very common ≥ 1/10;

common ≥ 1/100 and < 1/10;

uncommon ≥ 1/1000 and < 1/100;

rare ≥ 1/10000 and < 1/1000;

very rare < 1/10000;

frequency not known (cannot be estimated from available data).

Infections and infestations

Common: candidiasis of skin and mucous membranes.

Frequency not known: overgrowth of microorganisms not sensitive to the drug.

Blood and lymphatic system disorders

Rare: reversible leukopenia (including neutropenia) and thrombocytopenia.

Frequency not known: reversible agranulocytosis and hemolytic anemia; prolonged bleeding time and prothrombin time¹.

Immune system disorders¹⁰

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

Nervous system disorders

Uncommon: dizziness, headache.

Frequency not known: reversible hyperactivity and convulsions², aseptic meningitis.

Gastrointestinal disorders

Very common: diarrhea.

Common: nausea³, vomiting.

Uncommon: stomach discomfort.

Frequency 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.

Frequency not known: hepatitis⁶ and cholestatic jaundice⁶.

Skin and subcutaneous tissue disorders⁷

Uncommon: skin rashes, pruritus, urticaria.

Rare: erythema multiforme.

Frequency 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

Frequency not known: interstitial nephritis.

Frequency not known: crystalluria⁸ (including acute kidney injury)

Cardiac disorders

Frequency not known: Coombs' syndrome.

1 See section "Special precautions for use".

2 See section "Special precautions for use".

3 Nausea is more frequently associated with higher oral doses of the drug. The severity of gastrointestinal reactions may be reduced by taking the drug with food.

4 Includes pseudomembranous colitis and hemorrhagic colitis (see section "Special 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 effects have been observed with other penicillin and cephalosporin antibiotics (see section "Special precautions for use").

7 If hypersensitivity reactions (dermatitis) occur, the drug should be discontinued (see section "Special precautions for use").

8 See section "Overdose".

9 See section "Special precautions for use".

10 See sections "Contraindications" and "Special precautions for use".

11 Tooth discoloration has been very rarely reported in children. This phenomenon can be prevented by maintaining good oral hygiene, as it is reversible with tooth brushing.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals are required to report any adverse reactions through the pharmacovigilance system of Ukraine.

Shelf life. 2 years.

Storage conditions. Store in a dry place, out of reach of children, at a temperature not exceeding 25 °C.

Packaging. 5 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Aurobindo Pharma Limited, Unit-XII.

Manufacturer's address and place of business.

Survey No. 314, Bachupally Village, Kuthubullapur Mandal, Ranga Reddy District, Hyderabad, Telangana State, 500090, India.