Description
Capsule-shaped tablets of white or almost white color with a score.
Pharmacotherapeutic group:
antibiotic - semisynthetic penicillin
ATX code:
J01CA04
Pharmacological properties
Pharmacodynamics
Amoxicillin is an aminobenzyl penicillin, a semisynthetic broad-spectrum antibiotic that has a bactericidal effect due to inhibition of bacterial cell wall synthesis. Minimum inhibitory concentration (MIC) thresholds for different sensitive microorganisms vary. The prevalence of resistant strains varies geographically and over time, so it is advisable to rely on local resistance information, especially when treating severe infections.
Pharmacokinetics
Suction
Absorption is fast, high (93%), food intake does not affect absorption, and is not destroyed in the acidic environment of the stomach. When taken orally at a dose of 250 mg and 500 mg, the maximum concentration in blood plasma is 5 mcg/ml and 10 mcg/ml, respectively. The time to reach maximum concentration after oral administration is 1-2 hours.
Distribution
It has a large volume of distribution - high concentrations are found in blood plasma, bronchial secretions (in purulent bronchial secretions the distribution is weak), liver, lymph nodes, uterus, ovaries, paranasal sinuses, pleural and peritoneal fluid, saliva and tear fluid, urine, contents of skin blisters , lung tissue, intestinal mucosa, middle ear fluid and paranasal sinuses, bones, adipose tissue, gall bladder (the concentration in bile is 10 times higher than the concentration in blood plasma - with normal patency of the bile ducts), fetal tissues. When the dose is doubled, the concentration also doubles. In the amniotic fluid and umbilical cord vessels, the concentration of amoxicillin is about 50% of the concentration in the blood plasma of a pregnant woman. It penetrates poorly through the blood-brain barrier; with inflammation of the meninges (meningitis), the concentration in the cerebrospinal fluid increases to 20% of the concentration in the blood plasma. Bonding with blood plasma proteins is 15-25%.
Metabolism
Partially (10-20%) is metabolized to form inactive metabolites.
Removal
The half-life (T1/2) is 1-1.5 hours. It is excreted 50-70% unchanged by the kidneys through tubular excretion (80%) and glomerular filtration (20%), and 10-20% by the liver. A small amount is excreted in breast milk. If renal function is impaired (creatinine clearance [CC] ≤ 15 ml/min), T1/2 is extended to 8.5 hours.
Amoxicillin is removed by hemodialysis.
Special patient groups
Age
T1/2 of amoxicillin in children aged 3 months to 2 years is similar to T1/2 in older children and adults.
Since in elderly patients the likelihood of decreased renal function increases, dose selection is carried out with caution, and monitoring of renal function is also necessary.
Floor
When administered orally to healthy men and women, the gender of the patients does not have a significant effect on the pharmacokinetics of amoxicillin.
Kidney failure
The total serum clearance of amoxicillin increases in proportion to the decrease in renal function. If renal function is impaired (creatinine clearance < 15 ml/min), T1/2 lengthens and can reach 8.5 hours in anuria.
Liver failure
In patients with impaired liver function, dose selection should be carried out with caution, and regular monitoring of liver function is necessary.
Amoxicillin preparations: how to make the right choice?
In modern conditions of the progressive development of antibiotic resistance, the choice of effective drugs and antibacterial treatment regimens is difficult. In this regard, it is extremely important to identify certain predictors of the effectiveness of antimicrobial action, which would increase the chances of an adequate response when prescribing an antimicrobial drug. The main goal of research in recent years has been to identify the relationship between the minimum inhibitory concentration (MIC) of antibiotics against the infectious agent and the pharmacokinetic and pharmacodynamic parameters of the drug. Today, it is obvious that there are certain pharmacokinetic parameters, the assessment of which allows one to reliably predict bacteriological effectiveness (pathogen eradication in more than 80% of cases). Thus, for beta-lactams and macrolides (except azithromycin), it is known that the concentration of the antibiotic at the site of infection should exceed its MIC against the pathogen for more than 40% of the time from the interval between drug administrations (T > MIC). For azithromycin and fluoroquinolones, it has been proven that the ratio of the area under the curve (AUC) to the MIC value should be greater than 25 (AUC/MIC), and for severe infections this value should exceed 125. The ratio of the maximum serum concentrations to MIC [1].
The reliability of the prognostic significance of the proposed parameters has been confirmed in numerous in vivo experiments and clinical observations [2].
This approach is applicable to all antibiotics, including new ones, since on its basis it is possible to optimize the treatment regimen at the early stages of preclinical and clinical studies, reduce the risk of developing adverse drug reactions, and prevent the formation of resistance. Thus, the choice of an antibiotic, maximizing the regimens and schemes for its use in the clinic includes a number of stages: assessment of the spectrum of action and antimicrobial activity; determination of the main parameters of pharmacokinetics (PK) and pharmacodynamics (PD), selection of the most effective antibiotic from a number of evaluated ones; Recommendation of optimal treatment regimens.
Amoxicillin remains one of the most widely used antibacterial drugs, which has significant pharmacokinetic advantages over a number of other penicillins. Thus, the bioavailability of amoxicillin reaches 70–80% (up to 95% in the form of Solutab), while for phenoxymethylpenicillin this most important pharmacokinetic indicator is 50%, and for ampicillin - only 40%. The degree of binding to plasma proteins for amoxicillin, on the contrary, is minimal and amounts to 17% (phenoxymethylpenicillin - 80%, ampicillin - 22%). High bioavailability and low degree of binding to plasma proteins provide a high concentration of amoxicillin in tissues when taken orally, which makes it possible to achieve eradication of the pathogen and at the same time avoid the development of adverse events. An important advantage of amoxicillin is the independence of absorption from the gastrointestinal tract from food intake, in contrast to phenoxymethylpenicillin and ampicillin, the bioavailability of which is significantly reduced when taken simultaneously with food. In pediatric practice, it seems important to have a soluble oral form. The favorable organoleptic properties of the soluble form of amoxicillin can improve patient compliance and tolerability of antibacterial therapy [3].
On the pharmaceutical market, amoxicillin is represented both by the drug in the original dosage form Flemoxin Solutab and by generic drugs. Considering the above data on the influence of pharmacokinetics on the final antibacterial effect of the drug, it is extremely interesting to compare the pharmacokinetic parameters of the drug in the original dosage form and generic analogues.
It is important to understand that the assessment of the pharmacokinetic properties of the antibiotics under study can be made both in clinical studies and in a number of situations, when conducting a dissolution test and comparability of dissolution kinetics. In accordance with current regulatory recommendations, dissolution kinetics are studied at various pH conditions (typically pH 1.2, 4.5, 6.8). To obtain a complete profile of dissolution kinetics, sampling intervals should be fairly frequent (at least every 15 minutes), and even more frequent sampling is recommended during periods of maximum change in dissolution kinetics.
If the active substance is highly soluble, the dosage form dissolves quickly at physiological pH values, and the excipients do not affect bioavailability, then it is assumed that there is no reason to study bioavailability in vivo.
For quantitative comparability of dissolution kinetics, an assessment of the value of the similarity factor is used, the value of which from 50 to 100 confirms the comparability of dissolution kinetics [4].
The purpose of our work was to conduct a test of comparative dissolution kinetics of various amoxicillin drugs as a way to assess the comparability of the pharmacokinetic profile of these drugs.
We conducted a study of the comparative dissolution kinetics of the drug Flemoxin Solutab - dispersible tablets, 500 mg, with three generic drugs of amoxicillin in the form of regular tablets in the same dosage. In addition, a quantitative determination of the amoxicillin content in the above preparations was performed.
The studies were carried out in the testing laboratory of NAKFF LLC using existing modern equipment. All studies were carried out according to ND 42–14184–06.
The study of comparative dissolution kinetics was carried out in accordance with the basic methodology and in accordance with the requirements of the State Pharmacopoeia XI, no. 2, on a paddle mixer at pH 1.2; 4.5; 6.8. The determination was carried out in accordance with the requirements of OFS 42–0003–04, using equipment from VARIAN, model “Varian Dissolution Test VK 7025”. The amount of dissolved amoxicillin was determined by spectrophotometry at an absorption maximum at a wavelength of 271 nm in a cuvette with a layer thickness of 10 mm, using a Varian Cary 100 Scan spectrophotometer.
Research results
Based on the results obtained, graphs of the dissolution kinetics of the drug Flemoxin Solutab and other generic drugs of amoxicillin were constructed (Fig. 1–3).
Quantitative assessment of the equivalence of the dissolution kinetics of drugs was carried out in accordance with the “Guide to the Expertise of Medicines, Volume I” of the Ministry of Health of the Russian Federation, Scientific Center for the Expertise of Medicinal Products, Moscow, 2013 [4].
As a result of the calculations, the results presented in table were obtained. 1.
An assessment of the values of the similarity factors given in the table allows us to conclude that the dissolution kinetics of all comparison drugs in three media is not equivalent to the dissolution kinetics of the drug Flemoxin Solutab dispersible tablets, 500 mg (Astellas Pharma Europe B.V., the Netherlands).
In addition, we carried out a quantitative determination of amoxicillin in the studied drugs (Table 2).
As follows from the presented data, in comparison drugs No. 1 and No. 2, the amount of the active component (amoxicillin) does not meet the requirements of ND 42-14184-06.
Discussion of the results obtained
The rational use of medicines is one of the most effective tools for optimizing the use of the healthcare budget, in the structure of which in some countries the costs of medicines have reached 30–40%. One of the main ways to reduce the cost of treatment is to replace original drugs (brands) with their generic analogs after the expiration of patent protection. Within the framework of subsidized medicine in all countries, generics are given preference over original drugs. In the European Union alone, generic drugs have been able to “save” (redistribute) 20 billion euros annually over the past 20 years [5].
The widespread use of generics in medical practice in our country is a benefit that allows us to provide medical care to a larger number of patients at lower material costs, since generic drugs are always cheaper (sometimes tens of times) compared to the original ones. The use of generic drugs in certain situations really helps to save budget money and cover a larger number of patients with modern pharmacotherapy. However, in this situation, it is absolutely necessary to know that the generic and the original drug are therapeutically equivalent - that is, they must be pharmaceutically equivalent and can be expected to have the same clinical effect and the same safety profile when used by patients.
As noted earlier, even a slight change in the properties of a generic drug can lead to a change in specific antibacterial activity, a decrease in tissue concentration and a weakening of the therapeutic effect. Evidence of this was given in a number of works [6–8].
In our work, using a well-known standardized test, we analyzed the comparability of dissolution parameters (and therefore pharmacokinetic parameters) of various amoxicillin preparations present on the Russian pharmaceutical market. We have found that the drug Flemoxin Solutab in the form of dispersible tablets has more stable dissolution kinetics with less dependence on the acidity of the medium compared to other studied generics of amoxicillin.
In addition, it has been proven that most of the generics studied have a lower content of active substance per tablet than in the Flemoxin Solutab dispersible tablet. It is obvious that even a slight reduction in the dose of the active substance entering the systemic circulation will inevitably affect the clinical effectiveness of the drug used. It is important to understand that reducing the dose of antibiotic entering the systemic circulation also contributes to the selection of resistance among microorganisms [1]. At the same time, one of the reference drugs (tablets of reference drug No. 1) showed the content of the active component to be higher than the upper limit required by the requirements of ND 42-14184-06, which may increase the risk of overdose.
Thus, as a result of our study, we can conclude that none of the studied drugs of amoxicillin can be considered fully equivalent to the drug Flemoxin Solutab, and therefore, it can be assumed that the use of the studied drugs may be accompanied by either less clinical efficacy, or a higher risk of developing adverse events compared to the drug Flemoxin Solutab.
Literature
- Sidorenko CB Problems of etiotropic therapy of community-acquired respiratory tract infections // Consilium medicum. 2002; vol. 4, no. 1, 4–10.
- Craig WA Antimicrobial resistance issues of the future // Diagn. Microbiol. Infect. Dis. 1996: 25, 213–217.
- Chan DS, Demers DM, Bass JW Antimicrobial liquid formulations: a blind taste comparison of three brands of penicillin VK and three brands of amoxicillin // Ann Pharmacother. 1996; 30 (2): 130–132.
- Guidelines for the examination of medicinal products. T. I. M.: Grif i K., 2013.
- Nightingale CH A survey of the quality of generic clarithromycin product from 13 countries // Clin. Drug Invest. 2000. V. 19. P. 293–305.
- Samsygina G. A. Efficacy of various fluconazole preparations in the treatment of mucocutaneous candidiasis in children in the first weeks of life // Children's Doctor. 2001, No. 3, p. 40–41.
- Nikulin A. A., Tsyuman Yu. P., Martinovich A. A., Eidelshtein M. V., Kozlov R. S. On the issue of interchangeability of intravenous forms of original and generic drugs: are comparative studies needed? // Wedge. microbiol. antimicrobial chemotherapy 2010; 12 (1): 31–40.
- Martinovich A. A., Eidelshtein M. V., Tsyuman Yu. P., Kozlov R. S. Azithromycin: comparison of the quality of injectable dosage forms of the original drug and its generic drugs // Klin. microbiol. antimicrobial chemotherapy 2011. T. 14, no. 4. pp. 252–258.
S. K. Zyryanov*, Doctor of Medical Sciences, Professor Yu. B. Belousov*, Doctor of Medical Sciences, Professor A. V. Kamaev**, 1 A. A. Lelishentsev**
* GBOU VPO RNIMU im. N. I. Pirogova Ministry of Health of the Russian Federation, Moscow ** National Agency of Clinical Pharmacology and Pharmacy, Moscow
1 Contact information
Indications for use
Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:
- upper respiratory tract infections (tonsillopharyngitis, sinusitis, acute otitis media);
- lower respiratory tract infections (acute bacterial bronchitis, exacerbation of chronic bronchitis, community-acquired pneumonia);
- infections of the genitourinary system (pyelonephritis, pyelitis, cystitis, urethritis, endometritis, cervicitis, gonorrhea);
- abdominal infections (cholangitis, cholecystitis);
- eradication of Helicobacter pylori
in patients with duodenal or gastric ulcers (always in combination with other drugs); - infections of the skin and soft tissues (erysipelas, impetigo, secondary infected dermatoses);
- leptospirosis, listeriosis;
- Lyme disease;
- infections of the gastrointestinal tract (enterocolitis, typhoid fever, dysentery, salmonellosis (caused by Salmonella typhi
, sensitive to ampicillin), salmonella carriage; - prevention of bacterial endocarditis during surgical procedures in the oral cavity and upper respiratory tract.
Adverse reactions from treatment with Amoxicillin
Therapeutic manipulations cause the occurrence of:
- nettle fever, erythema, Quincke's edema;
- runny nose, conjunctivitis, joint pain;
- anaphylactic shock, febrile conditions;
- superinfections – with a reduced level of resistance or chronic diseases;
- attacks of dizziness, depression, convulsive syndrome;
- ataxia, peripheral neuropathies, anorexia;
- constipation, nausea, diarrhea, stomatitis;
- glossitis, discomfort in the epigastric region;
- hepatitis, pseudomembranous colitis, interstitial nephritis;
- erythema multiforme, epidermal toxic necrolysis, etc.
The instructions indicate that accidental overdoses of Amoxicillin do not provoke severe intoxication, even with large doses of the drug. Standard adverse reactions manifest themselves in the form of symptoms of gastrointestinal disorders and disturbances in water and electrolyte balance.
In case of renal failure, an overdose provokes crystalluria (formation of sand in the urinary tract) and nephrotoxicity (toxic damage to the kidneys). Therapeutic assistance consists of taking activated carbon (1 tablet per kilogram of weight); in difficult cases, the patient is sent for hemodialysis. A specific antidote against the antibiotic has not been developed.
Use during pregnancy and breastfeeding
Results from animal studies do not indicate direct or indirect effects on reproductive toxicity. Limited data on the use of amoxicillin during human pregnancy do not indicate an increased risk of congenital malformations. Amoxicillin can be used during pregnancy only in cases where the expected benefit to the mother outweighs the potential risk to the fetus.
Amoxicillin is excreted into breast milk in small quantities; if necessary, the drug can be used during breastfeeding. A breastfed baby may develop diarrhea, sensitization and fungal infection of the mucous membranes, so it may be necessary to stop breastfeeding. Amoxicillin should be used during breastfeeding only after the attending physician has assessed the benefit/risk ratio.
Directions for use and doses
Inside, before or after meals.
The dose of Amoxicillin depends on the sensitivity of the infectious agent, the severity of the disease and the localization of the infectious process.
Adults and children over 13 years of age and/or weighing more than 40 kg
Usually prescribed 250 mg - 500 mg 3 times a day or 500 mg - 1000 mg 2 times a day. For sinusitis, community-acquired pneumonia and other severe infections, it is recommended to prescribe 500 mg - 1000 mg 3 times a day. The maximum daily dose is 6 g.
Children from 3 to 5 years old and/or weighing from 15 kg to 19 kg
Usually prescribed 250 mg 2 times a day. In cases where there is a high likelihood of infection caused by resistant Streptococcus
pneumoniae
, higher doses of 500 mg 2-3 times daily are recommended.
Children from 5 to 13 years old and/or weighing from 19 kg to 40 kg
Usually recommended is 250 mg 3 times a day. In cases where there is a high likelihood of infection caused by resistant Streptococcus
pneumoniae
, higher doses are recommended - 500-1000 mg 3 times a day.
The maximum daily dose for children is 100 mg/kg/day.
Lyme disease (borreliosis)
—
early stage
Adults and children over 13 years of age and/or weighing more than 40 kg
500 mg - 1000 mg 3 times a day up to a maximum daily dose of 4 g, divided into several doses, for 14 days (10-21 days).
Children from 3 to 5 years old and/or weighing from 15 kg to 19 kg
250 mg 3 times a day.
Children from 5 to 13 years old and/or weighing from 19 kg to 40 kg
500 mg 2-3 times a day (at the rate of 50 mg/kg/day, divided into 3 doses).
Eradication of
Helicobacter pylori in patients with duodenal or gastric ulcers
(always in combination with other drugs)
Adults: 1000 mg twice daily in combination with a proton pump inhibitor (eg, omeprazole, lansoprazole) and another antibiotic (eg, clarithrominin, metronidazole) for 7 days.
Children over 13 years old and/or weighing more than 40 kg -
1000 mg 2 times as part of combination therapy.
Children from 3 to 5 years old and/or weighing from 15 kg to 19 kg
250-500 mg 2 times a day.
Children from 5 to 13 years old and/or weighing from 19 kg to 40 kg
500-1000 mg 2 times a day (at the rate of 50 mg/kg/day, divided into 2 doses).
Prevention of bacterial endocarditis
Adults and children over 13 years of age and/or weighing more than 40 kg
It is recommended 2 g (or at the rate of 50 mg/kg/day) 0.5-1 hour before surgery.
Children from 3 to 5 years old
u /or body weight from 15 kg to 19 kg
750-1000 mg (at the rate of 50 mg/kg/day) before the procedure.
Children from 5 to 13 years old and/or with a body weight of 19 kg and up to 40 kg
1000-2000 mg (at the rate of 50 mg/kg/day) before the procedure.
For renal failure
In patients with CC > 30 ml/min, there is no need for dose adjustment. When CC < 30 ml/min, it is recommended to increase the interval between doses or reduce subsequent doses.
AMOXICILLIN (tablets)
some kind of potion from this medicine.
In general, in Yaroslavl we left with nothing. But in Uglich we still managed to purchase the medicine. For comparison, I will say that Amoxiclav cost about 400 rubles, that is, due to the acid included in its composition, it costs several times more. So, let's look at our antibiotic Amoxcillin, which we managed to purchase for only 64 rubles. His dosage is 500 mg. Well, in general we were recommended 500 + 125 mg or 625 mg. But there was only one there, and we no longer had time to think. We had to take what they gave us because we were already late for our ship. We were recommended to take antibiotics for 5 days, and it helped. The reason I had to take it was an infection that caused a large boil to form above my eyebrow and cause swelling in my eye. When we were still in Moscow, we managed to see a doctor, so he prescribed me to take this medicine. We did not take any bifidobacteria, and nothing happened. The antibiotic was tolerated quite easily and we did not notice any side effects, and the boil, meanwhile, began to decrease.
This medicine is produced “which is located in the city of Kirov by order of the Ecoland-Krylatskoye company.
The shelf life of this medicine is three years, as indicated on the box.
It says here that this drug should be taken only as prescribed by a doctor and that it is actually available with a prescription. Well, we had an appointment, but for some reason they didn’t give us a prescription.
This box contains 20 tablets of this medicine.
There are instructions in the box and they are as big as a sheet. Moreover, it is written on both sides in small print. So I advise you to familiarize yourself with it before taking this medicine. It is not necessary to read everything, and people far from medicine will understand little of it, but you must read the contraindications and side effects. Here's what the instructions look like:
And this is her rear view:
So the instructions are quite large in size, and such huge canvases always scare me, but since the doctor prescribed it, then I need to drink it. Moreover, all these boils cannot be picked, but this happened to us, so it was impossible to do without an antibiotic. And this is what the tablets look like. They are quite large and divisible, that is, you can take only half of such a tablet:
Here we can look at the blister with tablets from the back side. It says their name and dosage, and also that there are 20 of these tablets in the package.
In general, summing up the results of using this drug, I would like to say that it helped us a lot. But I do not advise you to neglect bifidobacteria. This is not a fact that nothing will happen. It is still better to take these same biphyobacteria when taking antibiotics. Here's what the tablet itself looks like:
Here we see that our tablets are divisible:
I will recommend this antibiotic to everyone, but only with a doctor’s prescription, and ask for a prescription. Better yet, don’t get sick, which is what I sincerely wish for everyone. I wish everyone that they would have to take antibiotics less often. I give this medicine an A because it helped us. Good drug.
