Amoxicillin + Clavulanic acid - instructions for use, dose, side effects, contraindications

A drug Amoxicillin + Clavulanic acid is a combination of amoxicillin-semisynthetic penicillin with a broad spectrum of antibacterial activity and clavulanic acid, an irreversible inhibitor of β-lactamases. Clavulanic acid forms a stable inactivated complex with these enzymes and provides stability of amoxicillin to the action of β-lactamases produced by microorganisms.

Clavulanic acid, similar in structure to β-lactam antibiotics, has a weak intrinsic antibacterial activity.

Amoxicillin + clavulanic acid has a bactericidal effect in vivo on the following microorganisms:

Gram-positive aerobes:

Staphylococcus aureus (sensitive to methicillin)

Streptococcus pneumoniae *

Streptococcus pyogenes *

Streptococcus agalactiae *

Streptococcus spp. * (other beta-hemolytic streptococci)

Gram-negative aerobes:

Haemophilus influenzae Moraxella catarrhalis Escherichia coli¹Klebsiella pneumoniae'

Amoxicillin + clavulanic acid has a bactericidal effect in vitro on the following microorganisms:

Gram-positive aerobes:

Bacillis anthracis

Enterococcus faecalis

Gardnerella vaginalis

Listeria monocytogenes

Nocardia asteroides

Streptococcus spp. groups Viridans *

Coagulase-negative staphylococci (sensitive to methicillin)

Staphylococcus saprophyticus (sensitive to methicillin)

Gram-positive anaerobes:

Clostridium spp.

Peptococcus niger

Peptostreptococcus spp.

Peptostreptococcus magnus

Peptostreptococcus micros

Gram-negative aerobes:

Bordetella pertussis

Helicobacter pylori

Neisseria gonorrhoeae

Pasleurella multocida

Vibrio cholerae

Gram-negative anaerobes:

Bacteroides spp. (including Bacteroides fragilis)

Capnocytophaga spp.

Eikenella corrodens

Fusobaclerium nucleatwn

Fusobacterium spp.

Porphyromonas spp.

Prevotella spp.

Other:

Barrelia burgdorferi

Leptospira icterohaemorrhagiae

Treponema pallidum

Microorganisms for which the acquired resistance to a combination of amoxicillin and clavulanic acid is likely:

Gram-negative aerobes:

Klebsiella spp. (including Klebsiella oxytoca)

Proteus spp. (at m. h. Proteus mirabilis, Proteus vulgaris)

Salmonella spp.

Shigella spp.

Gram-positive aerobes

Corynebacterium spp.

Enterococcus faecium

Microorganisms, possessing natural sustainability to combinations amoxicillin from clavulanate acid

Gram-negative aerobes

Acinetobacter spp.

Citrobcicter freundii

Enterobacter spp.

Hafnia alvei

Legionella pneumophila

Morganella morganii

Providencia spp.

Pseudomonas spp.

Serratia spp.

Stenotrophomonas maltophilia Yersinia enterocol, idea.

Other

Chlamydia pneumoniae,

Chlamydia psittaci,

Chlamydia spp.,

Coxiella burnetii,

Mycoplasma spp.

* strains of these bacteria do not produce beta-lactamases. Sensitivity to monotherapy with amoxicillin suggests a similar sensitivity to a combination of amoxicillin and clavulanic acid.

¹ for these microorganisms, the likely acquired resistance to combination amoxicillin with clavulanic acid.

Pharmacokinetics:

Amoxicillin and clavulanic acid in combination do not affect the pharmacokinetics of each friend. Maximum plasma concentration after bolus intravenous injection amoxicillin + clavulanic acid (1000 mg + 200 mg) is 105 mg / l for amoxicillin and 28 mg / l for clavulanic acid, with the administration of 500 mg of amoxicillin and 100 mg of clavulanic acid, 32 mg / L and 10 mg / L, respectively. Both components characterized by a high volume of distribution in liquids and tissues of the body (incl. abdominal cavity, fat and muscle tissue and interstitial fluid, skin, lungs and pleural fluid, gall bladder, synovial and peritoneal fluid, bile and pus). Both components are characterized by low binding to plasma proteins (13-20%). Amoxicillin penetrates into breast milk, clavulanic acid also penetrates into breast milk in trace concentrations. Except for the possibility development of sensitization, diarrhea or candidiasis of the oral mucosa, unknown other adverse effects of amoxicillin and clavulanic acid on health of infants breast-fed. Amoxicillin and clavulanic acid penetrate through the placental barrier. Approximately 60-70% of amoxicillin and 40%65% of clavulanic acid is excreted by the kidneys unchanged in the first 6 hours after one bolus injection of 1000 mg / 200 mg. Amoxicillin in an amount equivalent to 10-25% of the initial dose of amoxicillin, is excreted by the kidneys in the form of inactive penicillic acid. Clavulanic acid in the human body is exposed intensive metabolism and is excreted by the kidneys and intestines. Half-life (T_1/2) amoxicillin (dose 1000 mg) is 0.9 hours, clavulanic acid (a dose of 200 mg) - 0.9 hours. T_1/2 with the administration of 500 mg of amoxicillin and 100 mg of clavulanic acid - 1 hour for both components. In patients with severe renal failure T_1/2increases to 7.5 h for amoxicillin and up to 4.5 h for clavulanic acid.Both components are removed by hemodialysis and minor amounts - by peritoneal dialysis.

Indications:

Bacterial infections caused by combination-sensitive amoxicillin + clavulanic acid microorganisms:

- Infections of ENT organs, incl. tonsillitis, sinusitis, otitis media.

- Infections of the lower respiratory tract, incl. exacerbation of chronic bronchitis, lobar pneumonia and bronchopneumonia.

- Urinary tract infections (including cystitis, urethritis, pyelonephritis), infections of female genital organs, gonorrhea.

- Infections of the skin and soft tissues.

- Infections of bones and joints, incl. osteomyelitis.

- Other infectious diseases: septic abortion, postpartum sepsis, septicemia, peritonitis, intra-abdominal sepsis, postoperative infections.

Prevention of postoperative infections during surgical interventions on the gastrointestinal tract, pelvic organs, head and neck, heart, kidneys, bile ducts, as well as when implanting artificial joints.

Contraindications:

- Hypersensitivity to amoxicillin, clavulanic acid and other components of the drug; to beta-lactam antibiotics, incl.to penicillins and cephalosporins;

- Infectious mononucleosis;

- previous episodes of jaundice or liver dysfunction with combination therapy amoxicillin + clavulanic acid in the anamnesis.

Carefully:

- Impaired renal function (creatinine clearance <30 mL / min);

- abnormal liver function.

Pregnancy and lactation:

Pregnancy

Parenteral administration of a combination of amoxicillin and clavulanic acid did not reveal teratogenic effects. In women with premature rupture of membranes, it was found that preventive therapy with this combination may be associated with an increased risk of developing necrotizing colitis in newborns. The drug is not recommended for use during pregnancy, except when the benefit to the mother exceeds the potential risk to the fetus.

Lactation

The drug can be used during breastfeeding. Except for the possibility of developing sensitization, diarrhea, or candidiasis of the oral mucosa, no other adverse effects of amoxicillin and clavulanic acid on the health of infants fed by breast milk are known.In case of adverse effects in infants who are breastfeeding, it is necessary to stop it.

Dosing and Administration:

Intravenously.

The dosage regimen depends on the severity of the infection, age, body weight and function of the patient's kidneys.

Doses are given in terms of the content of amoxicillin / clavulanic acid. The minimum course of antibiotic therapy should be 5 days. The maximum duration of therapy can be 14 days, after which its effectiveness and tolerability should be assessed.

Adults and children over 12 years of age and weighing more than 40 kg

Infections of mild to moderate severity: 1000 mg / 200 mg every 8 hours.

Severe infections: 1000 mg / 200 mg every 4-6 hours.

Prophylaxis in surgery

Surgical interventions of less than 1 h: 1000 mg / 200 mg during the initial anesthesia.

Surgical interventions of more than 1 h: 1 dose of 1000 mg / 200 mg during the initial anesthesia and then to 4 doses of 1000 mg / 200 mg for 24 hours.

Patients with impaired function of night

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin.

Creatinine clearance (CK)> 30 ml / min	Correction of the dose is not required.
KK 10-30 ml / min	The initial dose is 1000 mg / 200 mg and then 500 mg / 100 mg twice a day.
CK <10 ml / min	The initial dose is 1000 mg / 200 mg and then 500 mg / 100 mg every 24 hours.

Patients on hemodialysis

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin. The initial dose is 1000 mg / 200 mg, then 500 mg / 100 mg every 24 hours and an additional 500 mg / 100 mg at the end of the hemodialysis session (to compensate for the decrease in concentration of amoxicillin and clavulanic acid in the blood plasma).

Patients with impaired hepatic function

Treat with caution; regularly monitor liver function. Currently, there is insufficient data to correct the dosage regimen in such patients.

Elderly patients

Correction of the dose is not required.

Children

For children weighing less than 40 kg, the dose is calculated depending on the body weight.

Less than 3 months with a body weight of less than 4 kg (25 mg / 5 mg) / kg every 12 hours.

Less than 3 months with a body weight of more than 4 kg (25 mg / 5 mg) / kg every 8 hours.

In children younger than 3 months, the drug is administered only slowly infusion for 30-40 minutes.

From 3 months to 12 years

(25 mg / 5 mg) / kg every 6-8 hours, depending on the severity of the infection

Children with impaired renal function

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin

CK> 30 ml / min	Correction of the dose is not required.
KK 10-30 ml / min	(25 mg / 5 mg) / kg 2 times a day.
CK <10 ml / min	(25 mg / 5 mg) / kg every 24 hours.

Children on hemodialysis

Correction of the dosing regimen is based on the maximum recommended dose of amoxicillin - (25 mg / 5 mg) / kg every 24 hours and additionally (12.5 mg / 2.5 mg / kg at the end of the hemodialysis session (to compensate for the decrease in concentration of amoxicillin and clavulanic acid in blood plasma) and further (25 mg / 5 mg) / kg per day.

Children with impaired liver function

Treat with caution; regularly monitor liver function. Currently, there is insufficient data to correct the dosage regimen in such patients.

Preparation of solutions for intravenous injection.

Bolus intravenous administration

Dissolve the contents of the bottle 1.2 g (1000 mg + 200 mg) in 20 ml of water for injection. Enter the finished solution slowly for 3-4 minutes directly into the vein or through the catheter.

The resulting solution should be introduced within 20 minutes after dilution.

Infusion introduction

To prepare a solution for infusion, further dilution of the prepared as described above,solution for bolus administration: the prepared solution containing 1.2 g (1000 mg + 200 mg) of the preparation is added to 100 ml of one of the infusion solutions: 0.9% sodium chloride solution, sodium solution lactate for intravenous administration, Ringer's solution, Ringer's lactate solution according to Hartman.

Side effects:

Undesirable reactions are listed below for organs and systems, indicating the frequency of their occurrence. Frequency definition: very often (> 1/10), often (> 1/100, but <1/10), sometimes (> 1/1000, but <1/100), rarely (> 1/10 000, but < 1/1000), very rarely (<1/10 000, including individual cases).

Superinfections

Often Candidiasis of the skin and mucous membranes.

On the part of the system of hematopoiesis and lymphatic system

Rarely Reversible leukopenia (including neutropenia) and reversible thrombocytopenia.

Rarely Reversible agranulocytosis and reversible hemolytic anemia, prolongation of prothrombin time and bleeding time, eosinophilia, thrombocytosis, anemia.

Allergic reactions

Infrequently Skin rashes, itching, hives.

Rarely Erythema multiforme.

Rarely Angioedema, anaphylactic reactions, syndrome, similar to serum sickness, allergic vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis,bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.

From the nervous system

Infrequently Dizziness, headache.

Rarely Convulsions (may manifest patients with impaired function kidney, as well as when taking high doses of the drug), insomnia, agitation, anxiety, behavior change.

From the gastrointestinal tract

Often Diarrhea.

Infrequently Nausea, vomiting, dyspeptic disorders.

Very rarely Antibiotic-associated colitis (including pseudomembranous and hemorrhagic).

From the liver and biliary tract

Infrequently Moderate increase in activity of aspartate aminotransferase (ACT) and alanine aminotransferase (ALT).

Rarely Hepatitis and cholestatic jaundice (noted with application other penicillins and cephalosporins), increased concentration bilirubin and / or increased activity of alkaline phosphatase. Undesirable reactions from the liver occur mainly in men and in elderly patients and can be associated with long-term therapy. Usually occur during or shortly after the end of treatment,but in some patients they develop only a few weeks after the end of treatment. Usually, unwanted reactions from the liver are reversible. It is extremely rare, in patients with serious previous diseases or in those who have received potentially hepatotoxic drugs, they can be quite severe up to a lethal outcome

From the urinary system

Rarely Interstitial nephritis, crystalluria (see section "Overdose").

Local Reactions

Rarely Thrombophlebitis.

Overdose:

Symptoms: violations of the gastrointestinal tract and violations of water electrolyte balance. Amoxicillin crystalluria in some cases led to renal failure. Cramps can occur in patients with impaired renal function, as well as in those who receive high doses of the drug.

Treatment: symptomatic. Both substances are removed from the blood by hemodialysis. In the presence of high concentrations of amoxicillin in urine, it can precipitate in urinary catheters at room temperature. It is necessary to regularly check the patency of such catheters.

Interaction:

Probenecid reduces tubular secretion of amoxicillin, which can lead to an increase and maintenance of amoxicillin concentration in the blood (but not clavulanic acid). Combined use of the drug Amoxicillin + Clavulanic acid and probenecida should be avoided.

The simultaneous use of allopurinol and amoxicillin may increase the risk of skin allergic reactions. The drug may reduce the effectiveness of oral hormonal contraceptives, which should be prevented by patients using oral hormonal contraceptives as a method of contraception.

In the literature, rare cases of an increase in the international normalized ratio (INR) in patients with simultaneous use of acenocoumarol or warfarin and amoxicillin are described. If it is necessary to simultaneously apply the drug Amoxicillin + Clavulanic acid with anticoagulants prothrombin time or INR should be carefully monitored during treatment and when drug is withdrawn Amoxicillin + Clavulanic acid.

Penicillins can slow the excretion of methotrexate from the body by inhibiting its tubular secretion,so the simultaneous use of the drug and methotrexate may increase the toxicity of methotrexate.

In patients taking mofegil mycophenolate, after the start of the combination of amoxicillin with clavulanic acid, a decrease in the concentration of the active metabolite, mycophenolic acid, was observed, before taking the next dose of the drug by approximately 50%. Changes in this concentration can not accurately reflect the overall changes in the exposure of mycophenolic acid.

Clavulanic acid can lead to nonspecific binding of immunoglobulin G and albumin with a cell membrane of erythrocytes, which can lead to a false positive reaction with a Coombs sample.

Pharmaceutical incompatibility

A drug Amoxicillin + Clavulanic acid Do not mix in one vial or syringe with blood products, other protein fluids, such as protein hydrolysates, and with intravenous lipid emulsions, aminoglycosides (decreased aminoglycoside activity).

Solution of the drug Amoxicillin + Clavulanic acid Do not mix with solutions of dextrose, dextran or sodium bicarbonate.

Special instructions:

Before starting treatment with the drug, you need to collect a detailed history of previous hypersensitivity reactions to penicillins, cephalosporins or other allergens.

Serious, and sometimes lethal, hypersensitivity reactions (anaphylactic reactions) to penicillins are described. The risk of occurrence of such reactions is highest in patients who have a history of hypersensitivity reactions to penicillins. In case of an allergic reaction, it is necessary to stop treatment with the drug and begin the appropriate alternative therapy. If serious anaphylactic reactions occur, immediate measures should be taken (introduction of epinephrine). Oxygen therapy, intravenous glucocorticosteroids, and airway patency, including intubation, may also be required.

It is necessary to avoid the use of the drug Amoxicillin + Clavulanic acid in the case of suspected infectious mononucleosis, since patients with this disease amoxicillin can cause a skinlike skin rash, which makes it difficult to diagnose the disease.

Long-term treatment with the drug may lead to excessive reproduction of insensitive microorganisms.

Cases of pseudomembranous colitis occur when antibacterial drugs are used, the severity of which can range from mild to life-threatening. Therefore, it is important to consider the possibility of developing pseudomembranous colitis in patients with diarrhea during or after using antibacterial drugs. If diarrhea is long and severe, treatment should be discontinued and the patient should be examined. Contraindicated use of drugs that inhibit intestinal peristalsis.

If it is necessary to simultaneously use the drug with anticoagulants prothrombin time or MPO should be carefully monitored, with the appointment or cancellation of the drug may need to adjust the dose of anticoagulants for oral administration.

In patients with impaired renal function, the dosage regimen is adjusted in accordance with the degree of impairment (see section "Method of administration and dose").

In patients with reduced diuresis, crystalluria is very rare.During the administration of high doses of amoxicillin, it is recommended to take a sufficient amount of fluid and maintain an adequate diuresis to reduce the likelihood of amoxicillin crystals.

The drug should be used with caution in patients with impaired liver function.

During prolonged therapy with the drug it is recommended to periodically evaluate the function of the kidneys, liver and hematopoiesis.

The high content of amoxicillin in the urine can lead to false positive results in the determination of glucose in the urine (for example, the Benedict test, Feeling's test). In this case it is recommended to use the glucose oxidant method determination of glucose concentration in urine.

If necessary, parenteral administration of the drug Amoxicillin + Clavulanic acid patients on a diet low in salt should take into account the presence of sodium in the drug.

Effect on the ability to drive transp. cf. and fur:

Considering the possibility of developing side effects from the nervous system when using the drug, care should be taken when working with moving mechanisms and driving vehicles.

Form release / dosage:

Powder for the preparation of a solution for intravenous administration of 1000 mg + 200 mg.

Packaging:The quantity of medicinal product equivalent to 1200 mg of active substances (1000 mg of amoxicillin and 200 mg of clavulanic acid) into a bottle of colorless glass (type I) with a capacity of 30 ml, sealed with a gray bromobutyl plug and hermetically sealed aluminum cap with a removable plastic lid of dark blue color.

One bottle together with the instruction for use is placed in a cardboard box.

Storage conditions:

In dry, dark place at a temperature of no higher than 25 ° C.

Shelf life:

2 years

Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002854

Date of registration:09.02.2015

Expiration Date:09.02.2020

The owner of the registration certificate:Aurobindo Pharma Co., Ltd.Aurobindo Pharma Co., Ltd. India

Manufacturer: & nbsp

AUROBINDO PHARMA, Ltd. India

Representation: & nbspAurobindo Pharma, ZAOAurobindo Pharma, ZAO

Information update date: & nbsp19.08.2017

Illustrated instructions

Instructions

Amoxicillin + Clavulanic acid (Amoxicillin + Clavulanic acid)