Rapiklav - instructions for use, dose, side effects, contraindications

Potassium clavulanate (in the form of a mixture with microcrystalline cellulose in the ratio (1: 1) (Avicel)) - 332.830 mg, calculated as clavulanic acid - 125,000 mg.

Excipients:

core tablet: microcrystalline cellulose (Avicel PH 200) 48.440 mg, magnesium stearate 10,500 mg, croscarmellose sodium (Ac-Di-Sol®) 26.830 mg, silicon dioxide colloid (Aerosil-200) 13.970 mg,

film-coated tablets: hypromellose 16,000 mg, dibutyl phthalate 3.520 mg, talc purified 1.760 mg, titanium dioxide 8.720 mg.

Description:

Oval tablets covered with a film shell of white or almost white color with engraving "R 1 "on one side.In the cross-section: the core is from almost white to white with a yellowish hue of color.

Pharmacotherapeutic group:antibiotic-penicillin semisynthetic + beta-lactamase inhibitor

ATX: & nbsp

J.01.C.R.02 Amoxicillin in combination with enzyme inhibitors

Pharmacodynamics:

The Rapiklav® preparation is a combination of amoxicillin-semisynthetic penicillin with a broad spectrum of antibacterial activity and clavulanic acid, an irreversible inhibitor of β-lactamases. Amoxicillin is degraded by β-lactamases, therefore, the microorganisms producing β-lactamases do not enter the spectrum of its antibacterial activity.

Clavulanic acid has sufficient efficacy against plasmid beta-lactamases, which most often determine the resistance of bacteria, and is not effective against type I chromosomal beta-lactamases that are not inhibited by clavulanic acid.

Clavulanic acid forms a stable inactivated complex with these enzymes and provides stability of amoxicillin to the action of β-lactamases produced by microorganisms, which allows to expand the antibacterial spectrum of amoxicillin.

The activity of a combination of amoxicillin with clavulanic acid in vitro.

Bacteria, usually sensitive to a combination of amoxicillin and clavulanic acid:

Gram-positive aerobes:

Bacillis anthracis

Enterococcus faecalis

Listeria monocytogenes

Nocardia asteroides

Staphylococcus aureus (sensitive to methicillin)¹

Streptococcus agalactiae^1,2

Streptococcus pyogenes^1,²

Streptococcus spp. (other beta-hemolytic streptococci)^1,²

Staphylococcus saprophyticus (sensitive to methicillin)

Coagulase-negative staphylococci (sensitive to methicillin)

Gram-positive anaerobes:

Clostridium spp.

Peptococcus niger

Peptostreptococcus magnus

Peptostreptococcus micros

Peptostreptococcus spp.

Gram-negative aerobes:

Bordetella pertussis

Helicobacter pylori

Neisseria gonorrhoeae

Pasterurella multocida

Vibrio cholerae

Haemophilus influenzae¹

Moraxella catarrhalis¹

Gram-negative anaerobes:

Bacteroides spp. (including Bacteroides fragilis)

Capnocytophaga spp.

Eikenella corrodens

Fusobacterium nucleatum

Fusobacterium spp.

Porphyromonas spp.

Prevotella spp.

Other:

Borrelia burgdorferi

Leptospira icterohaemorrhagiae

Treponema pallidum

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

Gram-negative aerobes:

Escherichia coli¹

Klebsiella pneumoniae¹

Klebsiella oxytoca

Klebsiella spp.

Proteus mirabilis

Proteus vulgaris

Proteus spp.

Salmonella spp.

Shigella spp.

Gram-positive aerobes:

Corynebacterium spp.

Streptococcus pneumonia^1,2

Enterococcus faecium

Streptococcus spp. groups viridans

Bacteria that have natural resistance to a combination of amoxicillin and clavulanic acid:

Gram-negative aerobes:

Acinetobacter spp.

Citrobacter freundii

Enterobacter spp.

Hafnia alvei

Legionella pneumophila

Morganella morganii

Providencia spp.

Pseudomonas spp.

Serratia spp.

Stenotrophomonas maltophilia

Yersinia enterocolitica.

Other:

Chlamydia pneumoniae

Chlamydia psittaci

Chlamydia spp.

Coxiella burnetti

Mycoplasma spp.

1 - for these bacteria, the clinical efficacy of a combination of amoxicillin with clavulanic acid was demonstrated.

2 - strains of these bacteria do not produce beta-lactamases.

Pharmacokinetics:

Suction

Amoxicillin and clavulanic acid are rapidly and completely absorbed from the gastrointestinal tract (GIT) after oral administration. Absorption of amoxicillin and clavulanic acid is optimal in case of taking the drug at the beginning of the meal.

The pharmacokinetic parameters of amoxicillin and clavulanic acid obtained in the studies are shown below. Basic pharmacokinetic parameters

	Dose	FROM_m_Oh	T_m_Oh	AUC	T_1/2
Amoxicillin	875	11,64	1,5	53,52	1,36
Clavulanic acid	125	2,18	1,3	10,16	0,92

FROM_mOh - maximum concentration in blood plasma.

T_mOh - time to reach the maximum concentration in the blood plasma.

AUCis the area under the concentration-time curve.

T_1/2- half-life.

With the use of amoxicillin and clavulanic acid, the concentrations of amoxicillin in plasma are similar to those in oral administration of equivalent doses of one amoxicillin.

Distribution

Therapeutic concentrations of amoxicillin and clavulanic acid are created in various organs and tissues, interstitial fluid (lungs, abdominal organs, adipose, bone and muscle tissues, pleural, synovial and peritoneal fluids, skin, bile,purulent discharge, sputum).

Amoxicillin and clavulanic acid have a weak degree of binding to plasma proteins. Studies have shown that about 25% of the total amount of clavulanic acid and 18% of amoxicillin binds to plasma proteins.

In animal studies, cumulation of amoxicillin and clavulanic acid was not detected.

Amoxicillin, like most penicillins, penetrates into breast milk. Breast milk also found trace amounts of clavulanic acid. 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 experimental studies it was established that amoxicillin and clavulanic acid penetrate the placental barrier. However, there was no adverse effect on the fetus.

Metabolism

About 10-25% of the initial dose of amoxicillin is excreted by the kidneys in the form of an inactive metabolite (penicillic acid). Clavulanic acid in the body human is subjected to intensive metabolism to 2,5-dihydro-4- (2-hydroxyethyl) -5-oxo-1H-pyrrole-3-carboxylic acid and 1-amino-4-hydroxybutan-2-one and is excreted by the kidneys, gastrointestinal the intestinal tract and the exhaled air.

Excretion

Like other penicillins, amoxicillin is excreted mainly by the kidneys, whereas clavulanic acid - through both renal and extrarenal mechanisms. Approximately 60% of amoxicillin and about 40% of clavulanic acid is excreted by the kidneys unchanged in the first 6 hours after taking the drug.

Indications:

Infectious-inflammatory diseases caused by microorganisms sensitive to a combination of amoxicillin and clavulanic acid:

- Infections of the upper respiratory tract (including the infection of the ENT organs), for example, recurrent tonsillitis, sinusitis, otitis media, usually caused Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes.

- Infections of the lower respiratory tract, for example, exacerbation of chronic bronchitis, lobar pneumonia and bronchopneumonia, usually caused Streptococcus pnemoniae, Haemophilus influenza and Moraxella catarrhalis.

- Urinary tract infections, such as cystitis, urethritis, pyelonephritis, infections of female genitalia, usually caused by species of the family Enterobacteriaceae (mainly Escherichia coli), Staphylococcus saprophyticus and species Enterococcus, as well as gonorrhea caused by Neisseria gonorrhoeae.

- Infections of the skin and soft tissues, usually caused Staphylococcus aureus, Streptococcus pyogenes and species Bacteroides.

- Infections of bones and joints, for example, osteomyelitis, usually caused by Staphylococcus aureus, if necessary, prolonged therapy.

- Odontogenic infections, for example, periodontitis, odontogenic maxillary sinusitis, severe dental abscesses with spreading cellulitis.

- Other mixed infections (eg, septic abortion, obstetric sepsis, intra-abdominal sepsis) in the framework of stepwise therapy.

Infections caused by microorganisms sensitive to amoxicillin can be treated with Rapiklav® because amoxicillin is one of its active components.

The sensitivity of bacteria to the combination of amoxicillin and clavulanic acid varies depending on the region and over time. Where possible, Local sensitivity data should be taken into account.

Contraindications:

- Hypersensitivity to amoxicillin, clavulanic acid, other components of the drug, beta-lactam antibiotics (for example to penicillins and cephalosporins) in the anamnesis;

- previous episodes of jaundice or impaired liver function with amoxicillin / clavulanic acid in history;

- children under 12 years of age or body weight less than 40 kg (for this dosage form);

- impaired renal function (creatinine clearance less than 30 ml / min).

Carefully:Violation of the function of the liver.

Pregnancy and lactation:

In studies of reproductive function in animals, the combination of amoxicillin with clavulanic acid for oral and parenteral administration did not have a teratogenic effect.

In a single study in women with premature rupture of membranes, it was found that preventive therapy with amoxicillin with clavulanic acid may be associated with an increased risk of developing necrotizing enterocolitis in newborns.

The drug "Rapiklav®" is not recommended for use during pregnancy, except when the expected benefit to the mother exceeds the potential risk to the fetus.

The drug "Rapiklav®" can be used during breastfeeding. With the exception of the possibility of developing sensitization, diarrhea, or candidiasis of the oral mucosa,related to the penetration into the breast milk of trace amounts of the active components of this drug, no other adverse effects were observed in infants fed breastfeeding. In case of adverse effects in children who are breastfeeding, it is necessary to stop breastfeeding.

Dosing and Administration:

For oral administration. The dosage regimen is set individually, depending on the age, body weight and function of the patient's kidneys.

For optimum absorption and reduction of possible side effects from the gastrointestinal tract, the drug "Rapiklav®" is recommended to be taken at the beginning of food intake.

The minimum course of antibiotic therapy is 5 days. Treatment should not last more than 14 days without reviewing the clinical situation.

The duration of treatment of acute uncomplicated otitis media is 5-7 days. If necessary, it is possible to perform stepwise therapy (at the beginning, parenteral administration of a combination of amoxicillin with clavulanic acid in the appropriate dosage form, followed by a transition to oral administration of the drug).

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

For 1 tablet 875 mg / 125 mg 2 times a day.

Children under 12 years of age with a body weight of less than 40 kg

This dosage form is not intended for use in children younger than 12 years of age or with a body weight of less than 40 kg.

Elderly patients

Correction of the dosing regimen is not required. In elderly patients with impaired renal function, the dose should be adjusted as described below for adults with impaired renal function.

Patients with impaired renal function

Tablets 875 mg / 125 mg should be used only in patients with creatinine clearance greater than 30 ml / min, with no dosage adjustment required.

In most cases, parenteral therapy should be preferred where possible.

Patients with hepatic impairment

Treat with caution; regularly monitor liver function. There is insufficient data to change the recommendation for doses in such patients.

Side effects:

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

Superinfections

Often: candidiasis of skin and mucous membranes.

On the part of the hematopoiesis and lymphatic system

Rarely: reversible leukopenia (including neutropenia) and reversible thrombocytopenia.

Very rarely: reversible agranulocytosis and reversible hemolytic anemia, lengthening prothrombin time and bleeding time, eosinophilia, thrombocytosis, anemia.

Allergic reactions

Infrequently: a false rash, itching, hives.

Rarely: erythema multiforme.

Very rarely: angioedema, anaphylactic reactions, a syndrome similar to serum sickness, allergic vasculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.

From the nervous system

Infrequent: dizziness, headache.

Very rarely: convulsions (can occur in patients with impaired renal function, as well as when using high doses of the drug), insomnia, agitation, anxiety, behavior change, reversible hyperactivity.

From the gastrointestinal tract

Adults:

Very often: diarrhea.

Often: nausea, vomiting.

Children:

Often: diarrhea, nausea, vomiting.

Total population: nausea most often occurred when using high doses of the drug.

Infrequent digestion.

Very rarely: antibiotic-associated colitis (including pseudomembranous and hemorrhagic), gastritis, stomatitis, black "hairy" tongue.

From the liver and biliary tract

Infrequent: moderate increase in activity of aspartate aminotransferase (ACT) and / or alanine aminotransferase (ALT).

Very rarely: hepatitis and cholestatic jaundice (noted when combined with other penicillins and cephalosporins), increased bilirubin concentrations and / or increased alkaline phosphatase activity.

Undesirable liver reactions have been observed predominantly in men and in elderly patients, and may be associated with prolonged therapy, usually occurring during or soon after treatment, but in some patients they develop only a few weeks after the end of treatment. These undesirable phenomena are very rare in children. 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

Very rarely: interstitial nephritis, crystalluria (see the section "Overdose"), hematuria.

Overdose:

Symptoms: gastrointestinal disorders and disturbances of the water electrolyte balance may occur. Amoxicillin crystalluria is described, in some cases leading to the development of 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 therapy, paying special attention to the normalization of the water electrolyte balance. Amoxicillin and clavulanic acid can be removed from the bloodstream by hemodialysis.

Interaction:

The simultaneous use of the drug "Rapiklav®" and probenecid is not recommended. Probenecid reduces the tubular secretion of amoxicillin, and therefore the simultaneous use of the drug Rapiklav® and probenecid can lead to an increase and persistence in the blood concentration of amoxicillin, but not clavulanic acid.

The simultaneous use of allopurinol and amoxicillin may increase the risk of skin allergic reactions.

Currently, there is no data in the literature on the simultaneous use of a combination of amoxicillin with clavulanic acid and allopurinol.

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

The drug "Rapiklav®", affecting the intestinal microflora, can lead to a decrease in the absorption of estrogens from the gastrointestinal tract, resulting in a decrease in the effectiveness of oral contraceptives.

In patients receiving mycophenolate mofetil, 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.

In the literature, rare cases of an increase in the international normalized ratio (INR) in patients with joint use of acenocoumarol or warfarin and amoxicillin are described.If simultaneous application of Rapiklav® with anticoagulants is necessary, prothrombin time or INR should be carefully monitored when the drug Rapiklav® is prescribed or discontinued; it may be necessary to adjust the dose of anticoagulants for oral administration.

Special instructions:

Before starting treatment with Rapiklav®, 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 (including skin allergic reactions), it is necessary to stop the treatment with Rapiklav® and start the appropriate alternative therapy. Serious anaphylactic reactions should be immediately taken appropriate measures (epinephrine). Oxygen therapy, intravenous glucocorticosteroids, and airway patency, including intubation, may also be required.

In case of suspected infectious mononucleosis, the drug "Rapiklav®" should not be used, since in patients with this disease amoxicillin can cause a skinlike skin rash, which makes it difficult to diagnose the disease.

Long-term treatment with Rapiklav® can lead to excessive reproduction of insensitive microorganisms.

Cases of pseudomembranous colitis are reported when taking antibacterial drugs, 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.

In general, the drug "Rapiklav®" is well tolerated and has a characteristic of all penicillins of low toxicity. During prolonged therapy with the drug "Rapiklav®" it is recommended to periodically evaluate the function of the kidneys, liver and hematopoiesis.

If simultaneous use of the drug with indirect anticoagulants is necessary, prothrombin time or INR should be carefully monitored; may require correction of the dose of indirect anticoagulants. The drug Rapiklav® should be used with caution in patients with impaired hepatic function.

Patients with impaired renal function (creatinine clearance more than 30 ml / min) correction of the dosing regimen is not required. If the creatinine clearance is less than 30 ml / min, this dosage is not used in such patients.

In patients with reduced diuresis, crystalluria is very rare, mainly with parenteral therapy. 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.

During therapy with the drug Rapiklav®, it is necessary to remember the possible development of superinfection (usually caused by bacteria of the genus Pseudomonas or fungi of the genus Candida). In this case, discontinue therapy with Rapiklav® and / or appropriate treatment.

Clavulanic acid can cause nonspecific binding of immunoglobulin G and albumin with erythrocyte membranes, which leads to false positive results of the Coombs test.

Receiving the drug "Rapiklav®" inside leads to a high content of amoxicillin in the urine, which can lead to false positive results in determining glucose in the urine (for example, the Benedict test, Feeling's test). In this case, it is recommended to use a glucose oxidant method for determining the concentration of glucose in the urine.

It is necessary to use the tablets within 30 days of the opening of the foil package.

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

Since the application of the drug "Rapiklav®" may cause side effects from the central nervous system, patients should be warned about precautions when driving vehicles or working with moving mechanisms.

Form release / dosage:

Tablets, film-coated, 875 mg + 125 mg

Packaging:

2 or 3 tablets per contour non-jawed aluminum foil Al / Al foil packaging.

For 7 contour non-jammed packages in a cardboard box together with instructions for use.

Storage conditions:

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

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003658

Date of registration:31.05.2016

Expiration Date:31.05.2021

The owner of the registration certificate:Ipka Laboratories Ltd.Ipka Laboratories Ltd. India

Manufacturer: & nbsp

IPCA LABORATORIES, Ltd. India

Representation: & nbspIPKA LABORATORIES LTD. IPKA LABORATORIES LTD. India

Information update date: & nbsp23.07.2016

Illustrated instructions

Instructions

Rapiklav® (Rapiclav®)