pharmachologic effect
Antibiotic – glycopeptide. Produced by Amycolatopsis orientalis.
It has a bactericidal effect on most microorganisms that are sensitive to it (bacteriostatic on Enterococcus spp.). Blocks the synthesis of the bacterial cell wall in a site different from that affected by penicillins and cephalosporins (does not compete with them for binding sites), strongly binding to the D-alanyl-D-alanine part of the cell wall precursor, which leads to lysis of the bacterial cell.
Active against gram-positive microorganisms, including: Staphylococcus aureus and Staphylococcus epidermidis (including heterogeneous methicillin-resistant strains), Streptococcus spp., Enterococcus spp. (including Enterococcus faecalis), Clostridium spp. (including Clostridium difficile).
Listeria monocytogenes, Lactobacillus spp., Actinomyces spp., Bacillus spp. are sensitive to vancomycin in vitro
The optimal effect is at pH 8; when the pH decreases to 6, the effect of vancomycin sharply decreases.
Actively affects only microorganisms that are in the stage of reproduction.
Almost all gram-negative bacteria, Mycobacterium spp., fungi, viruses, and protozoa are resistant
Does not have cross-resistance with antibiotics of other groups.
When used orally, it has no systemic effect; it acts locally on sensitive microflora in the gastrointestinal tract (Staphylococcus aureus, Clostridium difficile).
Check-in and baggage drop-off
Checking in for a flight consists of two parts:
1) the airline checks your documents, makes sure you have a ticket, and gives you a boarding pass that shows your specific seat on board the plane;
2) you check your luggage and in return receive a luggage tag. Your luggage will travel on the same plane as you.
There are three ways to register: at the airport at the check-in counter, in advance online, or at the airport at a self-check-in kiosk. Now we will explain what the differences are.
How to check in for a flight at airport counters
Airport check-in usually begins 2-3 hours before departure. Sometimes earlier.
Show your passport and ticket at the check-in desk, and in return you will receive a boarding pass. Sometimes airline employees check the visa of another country and also ask for return tickets if this is required by entry rules. Occasionally they insist that the passenger show the bank card with which he paid for the tickets. Read more about what you may be asked to do at registration.
Check your luggage there. Place the suitcase on the conveyor belt: it will be weighed and a luggage tag will be attached. The second part of the tag will be attached to your boarding pass. Then the suitcase will move along the belt.
- If you want a seat by the window, emergency exit (there is more legroom) or next to a friend, tell us at check-in.
- To avoid paying for excess weight, weigh your luggage in advance and check whether it fits within the acceptable limits. If you get more, transfer some of the things to your pockets and hand luggage.
- If you are traveling with oversized luggage - alpine skis, a fishing rod, a giant tourist backpack - after check-in you may be asked to take it to a special counter (Oversized baggage desk).
- If you have a connecting ticket, please tell us at check-in. You will likely be given boarding passes for both flights and your luggage will be checked in for the rest of your route.
Pharmacokinetics
Suction and distribution
Cmax after intravenous infusion of 500 mg – 49 mcg/ml after 30 minutes and 20 mcg/ml after 1-2 hours; after intravenous infusion of 1 g - 63 mcg/ml after 60 minutes and 23-30 mcg/ml after 1-2 hours.
Plasma protein binding – 55%.
Widely distributed in most tissues and body fluids. Therapeutic concentrations are determined in ascitic, synovial, pleural, pericardial and peritoneal fluids, in urine, and atrial appendage tissue. Does not penetrate through the intact BBB (in case of meningitis, it is found in the cerebrospinal fluid in therapeutic concentrations).
Vancomycin crosses the placenta. Excreted in breast milk.
With repeated administration, cumulation is possible.
When taken orally, it is poorly absorbed and usually does not penetrate the systemic circulation. Detectable plasma concentrations of vancomycin may be observed in isolated cases with repeated oral administration in patients with acute pseudomembranous colitis caused by Clostridium difficile.
Metabolism
Vancomycin is practically not metabolized in the body.
Removal
T1/2 with normal kidney function: adults - about 6 hours (4-11 hours), newborns - 6-10 hours, infants - 4 hours, older children - 2-3 hours.
75-90% of the drug is excreted by the kidneys by passive filtration in the first 24 hours.
In small to moderate amounts, vancomycin can be excreted in the bile. It is excreted in small quantities during hemodialysis or peritoneal dialysis.
Pharmacokinetics in special clinical situations
T1/2 for chronic renal failure (oliguria or anuria) in adults – 6-10 days.
In patients with one kidney, excretion is slow and the mechanism of elimination is unknown.
How far in advance should you arrive at the airport in order to get everything done without hassle?
Check-in for the flight ends 40–60 minutes before departure. Boarding is 15–25 minutes before departure. There’s also a lot to do: we’ll tell you soon. To avoid running around the airport in a panic, arrive 2 hours before the departure of a domestic flight and 3 hours before an international flight.
To avoid being late at the airport, find out in advance:
- how to get to the airport and how long it takes. Look for information about transport on the airport website, it is objective there. If there is a metro, train or Aeroexpress to the airport, choose them to avoid stuck in traffic jams. By taxi, car or bus, leave at least an hour earlier;
- Which terminal is the departure from? The terminal is part of the airport and may be located in a separate building. For example, in Sheremetyevo there are 4 passenger terminals, and a bus goes to one. You can find out the name of your terminal on your ticket or in the flight board on the airport website. If you don’t find it, call the airline and ask. If the airport has several terminals and they are far from each other, allow extra time for travel.
Important: the ticket shows the local departure and arrival times. “Moscow 21:45 - Bangkok 10:40” means that you depart from Moscow at 21:45 Moscow time and land in Bangkok the next day at 10:40 Thai time.
Arrive at the airport 2 hours before departure. If you are flying for the first time - 3 hours in advance.
Indications for use
Infectious and inflammatory diseases caused by microorganisms sensitive to vancomycin:
endocarditis; sepsis; meningitis; lower respiratory tract infections (pneumonia, lung abscess); infections of bones and joints (including osteomyelitis); infections of the skin and soft tissues.
In the form of an oral solution:
pseudomembranous colitis caused by Clostridium difficile; enterocolitis caused by Staphylococcus aureus.
Dosage
Vancomycin is administered as a slow intravenous infusion at a rate of no more than 10 mg/min for at least 60 minutes.
The drug cannot be administered intramuscularly or intravenously.
The concentration of the prepared vancomycin solution should not exceed 5 mg/ml.
For adults
– 0.5 g (7.5 mg/kg) every 6 hours or 1 g (15 mg/kg) every 12 hours.
Children: newborns up to 7 days of life
– initial dose 15 mg/kg body weight, then 10 mg/kg every 12 hours;
starting from the 2nd week of life
- 10 mg/kg every 8 hours;
children from 1 month and older
- 10 mg/kg every 6 hours.
Patients with impaired renal excretory function require adjustment of the dosage regimen taking into account creatinine clearance (CC) values.
Correction can be carried out by increasing the intervals between administrations, or by reducing the single dose of the drug:
Correction by increasing the intervals between injections
| CC (ml/min) | Vancomycin dose | Interval between injections |
| more than 80 | 1 g | 12 h |
| 80-50 | 1 g | 1-3 days |
| 50-10 | 1 g | 3-7 days |
| less than 10 | 1 g | 7-14 days |
Single dose correction
| CC (ml/min) | Vancomycin dose (mg/day) |
| 100 | 1545 |
| 90 | 1390 |
| 80 | 1235 |
| 70 | 1080 |
| 60 | 925 |
| 50 | 770 |
| 40 | 620 |
| 30 | 465 |
| 20 | 310 |
| 10 | 155 |
This table cannot be used to determine the dose of the drug for anuria. Such patients should be prescribed an initial dose of 15 mg/kg body weight to quickly achieve therapeutic concentrations of the drug in the serum. The dose required to maintain a stable drug concentration is 1.9 mg/kg/day.
Patients with severe renal failure
It is advisable to administer maintenance doses of 250-1000 mg once every few days.
For anuria
A dose of 1 g every 7-14 days is recommended.
When only the serum creatinine concentration is known, the formula below can be used to calculate creatinine clearance:
For men:
CC = body weight (kg) × (140 – age (years))/72 × serum creatinine concentration (mg/dL).
For women:
the result obtained is multiplied by 0.85.
Preparation of solution for intravenous administration
The solution for injection is prepared immediately before administration of the drug. To do this, add 10 ml to a bottle with a dry, sterile drug with a dosage of 0.5 g, and 20 ml of sterile water for injection (solution concentration is 50 mg/ml) with a dosage of 1 g.
Prepared vancomycin solutions must be further diluted before administration to a concentration of no more than 5 mg/ml. The required dose of vancomycin diluted as above should be administered by intravenous infusion over at least 60 minutes. As solvents, you can use 5% dextrose (glucose) solution for injection or 0.9% sodium chloride solution for injection: for 0.5 g - 100 ml and for 1 g - 200 ml.
Before injection, the prepared solution for parenteral administration should be checked visually, if possible, for the presence of mechanical impurities and color changes.
Solutions prepared from 5% dextrose (glucose) solution or 0.9% sodium chloride solution can be stored in the refrigerator (2-8°C) for 14 days without significant loss of activity.
Preparation of oral solution and its use
For the treatment of pseudomembranous colitis caused by Clostridium difficile due to the use of antibiotics, as well as for the treatment of staphylococcal enterocolitis, the drug Vancorus® is prescribed orally.
Daily dose for adults
– 0.5-2 g, divided into 3-4 doses.
Daily dose for children
– 40 mg/kg, divided into 3-4 doses.
The maximum daily dose for adults and children is 2 g.
The appropriate single dose is dissolved in 30 ml of water and given to the patient to drink or administered through a tube. To improve the taste of the solution, you can add regular food syrups to it. Duration of treatment is 7-10 days.
Side effect
Post-infusion reactions (due to rapid administration): anaphylactoid reactions (decreased blood pressure, cardiac arrest, bronchospasm, dyspnea, skin rash, itching); “red man” syndrome associated with the release of histamine (chills, fever, rapid heartbeat, hyperemia of the upper half of the body and face, spasm of the chest and back muscles).
From the urinary system: nephrotoxicity (up to the development of renal failure), more often when combined with aminoglycosides or when prescribed for more than 3 weeks in high concentrations, manifested by an increase in the concentration of creatinine and urea nitrogen in the blood; interstitial nephritis.
From the digestive system: nausea, pseudomembranous colitis.
From the senses: ototoxicity – hearing loss, vertigo, tinnitus.
From the hematopoietic organs: reversible neutropenia, transient thrombocytopenia, agranulocytosis.
Allergic reactions: fever, chills, eosinophilia, rash (including exfoliative dermatitis), erythema malignant exudative (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome), vasculitis.
Local reactions (if the infusion rules are violated): pain and tissue necrosis at the injection sites, phlebitis.
Contraindications
neuritis of the auditory nerve; first trimester of pregnancy; lactation period (breastfeeding); increased sensitivity to vancomycin.
with caution in patients with impaired hearing, renal failure due to the possible development of ototoxic and nephrotoxic effects, patients with an allergy to teicoplanin (possibility of cross-allergy), pregnancy (II and III trimester).
Use during pregnancy
During pregnancy (II and III trimester), the drug is prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus and only for lifelong indications.
Vancomycin is excreted in breast milk. During treatment with the drug, breastfeeding should be stopped.
How to read flight status at the airport (Status)
Status What it means What to do Registration, registration is open, Check-in, Check-in open, Open Everything is going according to plan: the plane will take off on time, and right now passengers are already being checked in for the flight. Go to check-in. The rack number (Counter, Desk) is written in the same row. If a range of numbers is indicated - for example, 114–125 - choose a counter where the queue is shorter. Empty field, Scheduled, On time, Registration at 10:00, Open 10:00You arrived with a reserve, so registration has not yet started. It will open on time. Sometimes a specific registration start time is indicated. But even if there is an empty field on the board, don’t worry: this means that the flight will depart on schedule. Drink tea and relax. 2 hours before departure or at the specified time, check the flight status again and go to the check-in counters, the numbers of which will appear on the board.Delayed, DelayedThe plane will take off later than scheduled. They usually write on the board exactly when: “Delayed till 5 pm.” This is the departure time, not the start of check-in. Check-in will open earlier. If the board does not indicate how long the flight will be delayed, check with airline representatives. If the plane is delayed for more than 2 hours, remind them that they are obligated to take care of you. Canceled, Canceled Unfortunately, the flight is cancelled. If you see this, go to the airline representative and find out what to do. Most likely, you will be offered to take a different flight. And to be fully prepared, find out in advance what you are entitled to if the airline cancels your flight. Boarding, Boarding, Check-in completed, Check-in closed. You are late for flight check-in. Run to the counters for late passengers, or to the airline representative office. But fast!At the airport, first of all, find the departure board and check the status of your flight.
Use for renal impairment
Patients with impaired renal excretory function require adjustment of the dosage regimen taking into account creatinine clearance (CC) values.
Correction can be carried out by increasing the intervals between administrations, or by reducing the single dose of the drug:
Correction by increasing the intervals between injections
| CC (ml/min) | Vancomycin dose | Interval between injections |
| more than 80 | 1 g | 12 h |
| 80-50 | 1 g | 1-3 days |
| 50-10 | 1 g | 3-7 days |
| less than 10 | 1 g | 7-14 days |
Single dose correction
| CC (ml/min) | Vancomycin dose (mg/day) |
| 100 | 1545 |
| 90 | 1390 |
| 80 | 1235 |
| 70 | 1080 |
| 60 | 925 |
| 50 | 770 |
| 40 | 620 |
| 30 | 465 |
| 20 | 310 |
| 10 | 155 |
This table cannot be used to determine the dose of the drug for anuria. Such patients should be prescribed an initial dose of 15 mg/kg body weight to quickly achieve therapeutic concentrations of the drug in the serum. The dose required to maintain a stable drug concentration is 1.9 mg/kg/day.
Patients with severe renal failure
It is advisable to administer maintenance doses of 250-1000 mg once every few days.
For anuria
A dose of 1 g every 7-14 days is recommended.
When only the serum creatinine concentration is known, the formula below can be used to calculate creatinine clearance:
For men:
CC = body weight (kg) x (140 - age (years)) .72 x serum creatinine concentration (mg/dl).
For women:
the result obtained is multiplied by 0.85.
Directions for use and dosage:
The drug should be used in accordance with official recommendations for antibiotic therapy and local antibiotic sensitivity data. Sensitivity to amoxicillin/clavulanate varies between regions and may change over time. If available, local susceptibility data should be consulted and, if necessary, microbiological determination and susceptibility testing should be performed.
The range of suggested doses depends on the expected pathogens and their sensitivity to antibacterial drugs, the severity of the disease and the location of the infection, the age, body weight and renal function of the patient.
For adults and children weighing ≥ 40 kg, the daily dose is 1750 mg amoxicillin / 250 mg clavulanic acid, divided into 2 doses.
For overweight children
If large doses of amoxicillin must be prescribed for treatment, other forms of the drug should be used to avoid the prescription of unnecessary high doses of clavulanic acid.
The duration of treatment is determined by the patient's clinical response to treatment. Some infections (such as osteomyelitis) require long-term treatment.
For optimal absorption and to reduce possible gastrointestinal side effects, the drug should be taken at the beginning of a meal.
The duration of treatment is determined individually. Treatment should not be continued for more than 14 days without assessing the patient's condition.
Treatment can be started with parenteral administration and then continued with oral administration.
The tablet should be swallowed whole without chewing.
Tablets 500 mg / 125 mg
For adults and children weighing ≥ 40 kg, the daily dose is 1500 mg amoxicillin / 375 mg clavulanic acid (3 tablets), when prescribed as indicated below.
For children over 6 years of age weighing 25 to 40 kg, the maximum daily dose is 2400 mg amoxicillin / 600 mg clavulanic acid (4 tablets), when prescribed as indicated below.
If large doses of amoxicillin must be prescribed for treatment, other forms of the drug should be used to avoid the prescription of unnecessary high doses of clavulanic acid.
Adults and children weighing ≥ 40 kg
1 tablet Abiclava 500 mg / 125 mg 3 times a day.
Children aged 6 years and over weighing from 25 to 40 kg
Dose from 20 mg / 5 mg / kg / day to 60 mg / 15 mg / kg / day, divided into 3 doses.
Since the tablet cannot be divided, this form of the drug is not prescribed to children whose body weight is less than 25 kg.
Elderly patients
No dose adjustment is required in elderly patients. If necessary, the dose is adjusted depending on renal function.
Dosing for renal impairment
The dosage is based on the calculation of the maximum level of amoxicillin. There is no need to change the patient's dose if CC> 30 ml/min.
Adults and children weighing ≥ 40 kg
| CC 10-30 ml/min | 500 mg / 125 mg 2 times a day |
| Creatinine clearance | 500 mg / 125 mg 1 time per day |
| Hemodialysis | 500 mg/125 mg every 24 hours plus 500 mg/125 mg during dialysis (as plasma concentrations of amoxicillin and clavulanic acid decrease) |
Children aged 6 years and over weighing from 25 to 40 kg
Since the tablet cannot be divided, children over 6 years of age with a body weight of 25 to 40 kg, creatinine clearance less than 30 ml/min, or children on hemodialysis are not prescribed this form of Abiclava.
Dosing for liver dysfunction
Use with caution; liver function should be regularly monitored.
Tablets 875 mg / 125 mg
Overweight children
Dose from 25 mg / 3.6 mg / kg / day to 45 mg / 6.4 mg / kg / day, in 2 doses.
Elderly patients
No dose adjustment is required in elderly patients. If necessary, the dose is adjusted depending on renal function.
Dosing for liver dysfunction.
Use with caution and liver function must be monitored at regular intervals. There are insufficient data to make dosage recommendations.
Dosing for renal impairment
Abiclave 875/125 mg is prescribed only for the treatment of patients with a creatinine clearance of 30 ml/min. In case of renal failure with creatinine clearance less than 30 ml/min, Abiclave 875/125 mg is not used.
Use in elderly patients
It is advisable to determine vancomycin serum concentrations in patients with renal failure in patients over 60 years of age, since high, long-term concentrations of the drug in the blood may increase the risk of drug toxicity (maximum concentrations should not exceed 40 mcg/ml, and minimum concentrations should not exceed 10 mcg/ml). ml, concentrations above 80 µg/ml are considered toxic). For patients with renal failure, doses of vancomycin should be individualized.
Release form, composition and packagingConcentrate for the preparation of solution for infusion
in the form of a clear, colorless liquid.
| 4.264 mg, | |
| which corresponds to the content of anhydrous zoledronic acid | 4 mg |
Excipients:
mannitol, sodium citrate, water, nitrogen.
5 ml - colorless plastic bottles (1) - cardboard packs.
Clinical and pharmacological group:
Bone resorption inhibitor for bone metastases
Registration No.:
- concentrate for preparation. r-ra d/inf. 4 mg/5 ml: vial. 1 PC. — LS-001356, 03.03.06
Zoledronic acid is a highly potent bisphosphonate that has a selective effect on bone. The drug inhibits bone resorption by acting on osteoclasts.The selective effect of bisphosphonates on bone tissue is based on their high affinity for mineralized bone tissue. The exact molecular mechanism responsible for the inhibition of osteoclast activity still remains unclear. Zoledronic acid does not have undesirable effects on bone formation, mineralization, or mechanical properties.
In addition to the inhibitory effect on bone resorption, zoledronic acid has antitumor properties that ensure the effectiveness of the drug in bone metastases:
In vivo: inhibition of osteoclastic bone resorption, changing the microenvironment of the bone marrow, leading to a decrease in the growth of tumor cells; antiangiogenic activity. Suppression of bone resorption is clinically accompanied by a pronounced decrease in pain.
In vitro: inhibition of osteoblast proliferation, direct cytotoxic and proapoptotic activity, synergistic cytostatic effect with antitumor drugs; anti-adhesive/invasive activity.
Zoledronic acid, by inhibiting proliferation and inducing apoptosis, has a direct antitumor effect against human myeloma cells and breast cancer, and also reduces the penetration of breast cancer cells through the extracellular matrix, which indicates the presence of antimetastatic properties. In addition, zoledronic acid inhibits the proliferation of human endothelial cells and has an antiangiogenic effect in animals.
In patients with breast cancer, prostate cancer and other solid tumors with metastatic bone lesions, Zometa prevents the development of pathological fractures, spinal cord compression, reduces the need for radiation therapy and surgical interventions, and reduces tumor hypercalcemia. The drug is able to inhibit the progression of pain. The therapeutic effect is less pronounced in patients with osteoblastic lesions than in patients with osteolytic lesions. In patients with multiple myeloma and breast cancer with at least one bone lesion, the effectiveness of Zometa at a dose of 4 mg is comparable to pamidronate at a dose of 90 mg.
In patients with tumor hypercalcemia, the effect of Zometa is characterized by a decrease in the level of calcium in the blood serum and calcium excretion in the urine. The average time for calcium levels to normalize is about 4 days. By the 10th day, calcium concentration is normalized in 87-88% of patients. The average time to relapse (albumin-corrected serum calcium level of at least 2.9 mmol/L) is 30-40 days. There are no significant differences between the effectiveness of Zometa in doses of 4 and 8 mg in the treatment of hypercalcemia.
The studies did not reveal significant differences in the incidence or severity of adverse events observed in patients receiving Zometa 4 mg, 8 mg, pamidronate 90 mg, or placebo for the treatment of either bone metastases or hypercalcemia.
Pharmacokinetics
Pharmacokinetic data for bone metastases were obtained after single and repeated 5- and 15-minute infusions of 2, 4, 8 and 16 mg of zoledronic acid in 64 patients. Pharmacokinetic parameters do not depend on the dose of the drug.After initiation of Zometa infusion, serum concentrations increase rapidly, reaching a peak at the end of the infusion, followed by a rapid decrease in concentrations of 10% after 4 hours and by less than 1% after 24 hours, with a successively prolonged period of low concentrations not exceeding 0.1% of the maximum to repeated infusion on day 28.
Zoledronic acid administered intravenously is excreted by the kidneys in 3 stages: rapid two-phase elimination of the drug from the systemic circulation with T1/2 of 0.24 hours and 1.87 hours and a long phase with a final T1/2 of 146 hours. No accumulation of the drug was noted with repeated administrations every 28 days.
Zoledronic acid does not undergo systemic metabolism and is excreted unchanged by the kidneys. During the first 24 hours, 39±16% of the administered dose is found in the urine. The remaining amount of the drug is mainly associated with bone tissue. Zoledronic acid is then slowly released back from bone tissue into the systemic circulation and excreted by the kidneys. The total plasma clearance of the drug is 5.04±2.5 l/h and does not depend on the dose of the drug, gender, age, race and body weight of the patient. Increasing the infusion time from 5 to 15 minutes resulted in a 30% decrease in zoledronic acid concentration at the end of infusion but had no effect on AUC.
Pharmacokinetic studies have not been conducted in patients with hypercalcemia or liver failure. Based on in vitro data, zoledronic acid does not inhibit the human P450 enzyme and is not biotransformed, suggesting that liver function does not significantly influence the pharmacokinetics of zoledronic acid. Less than 3% of the drug dose is excreted in feces.
Renal clearance of zoledronic acid correlates positively with creatinine clearance and accounts for 75±33% of the creatinine clearance, reaching an average of 84±29% (range 22-143 ml/min) in 64 patients included in the study. A population analysis showed that in patients with CC 20 ml/min (severe renal failure) or 50 ml/min (moderate renal failure), the calculated clearance of zoledronic acid was 37% and 72%, respectively, of the clearance value of zoledronate in patients with CC 84 ml/min. Limited pharmacokinetic data have been obtained for patients with severe renal failure (creatinine clearance less than 30 ml/min).
The low affinity of zoledronic acid for blood components has been shown.
Plasma protein binding is low (about 50%) and does not depend on the concentration of Zometa. Indications
: bone metastases of common malignant tumors (prostate cancer, breast cancer) and multiple myeloma, incl. to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery;- hypercalcemia caused by a malignant tumor.
Dosage regimen
For bone metastases of common malignant tumors and multiple myeloma
in adults and elderly patients,
the recommended dose of the drug is 4 mg. Before administering the drug, dilute the concentrate (contents of 1 bottle) in 100 ml of solution for infusion that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution). Zometa is administered intravenously; infusion duration is at least 15 minutes. Frequency of appointment - every 3-4 weeks.Patients should also be additionally prescribed calcium orally at a dose of 500 mg/day and vitamin D orally at a dose of 400 IU/day.
For hypercalcemia caused by a malignant tumor
(albumin-corrected calcium concentration >= 12 mg/dL or 3 mmol/L),
for adults and elderly patients
the recommended dose of the drug is 4 mg. Before administering the drug, dilute the concentrate (contents of 1 bottle) in 100 ml of solution for infusion that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution). Zometa is administered intravenously; infusion duration is at least 15 minutes. To ensure adequate hydration of the patient, it is recommended that saline be administered before, concurrently, or after Zometa infusion.The decision to treat hypercalcemia due to malignancy with
in
patients with severe renal impairment,
it should be taken only after a careful assessment of the risks of using the drug and the expected benefits of therapy. Patients whose serum creatinine concentration is <400 µmol/L or <4.5 mg/dL do not require dosage adjustment.For bone metastases of common malignant tumors and multiple myeloma
The dose of Zometa depends on the initial QC level, calculated using the Cockcroft-Gault formula. It is not recommended to use Zometa in patients with severely impaired renal function (creatinine clearance <30 ml/min).
Recommended doses in patients with mild or moderate renal impairment (creatinine clearance 30-60 ml/min) are given below.
| Initial CC value (ml/min) | Recommended dose of Zometa |
| >60 | 4 mg (5 ml concentrate) |
| 50 — 60 | 3.5 mg (4.4 ml concentrate) |
| 40 — 49 | 3.3 mg (4.1 ml concentrate) |
| 30 — 39 | 3.0 mg (3.8 ml concentrate) |
After initiating Zometa therapy, serum creatinine concentrations should be determined before each dose of the drug. If renal dysfunction is detected, the next administration of Zometa should be postponed. Renal dysfunction is determined by the following parameters:
- for patients with normal initial creatinine values (<1.4 mg/dl) - an increase in serum creatinine concentration by 0.5 mg/dl.
- for patients with deviations in the initial level of creatinine (>1.4 mg/dl) - an increase in serum creatinine concentration by 1 mg/dl.
Zometa therapy is resumed only after creatinine levels reach values within 10% of the initial value, at the same dose that was used before treatment was interrupted.
Rules for preparing a solution for infusion
A solution for infusion is prepared from a 4 mg/5 ml concentrate (contents of 1 bottle). The solution should be prepared under aseptic conditions. Before administering the drug, dilute the concentrate (the contents of 1 bottle or a smaller volume, if required) with 100 ml of a solution for infusion that does not contain calcium (0.9% sodium chloride solution or 5% dextrose solution). It is advisable to use the prepared Zometa solution immediately after preparation. The solution not used immediately can be stored in the refrigerator at a temperature of 2°-8°C for no more than 24 hours. Before administration, the solution should be kept indoors until it reaches room temperature.
The total time between diluting the concentrate, storing the prepared solution in the refrigerator at a temperature of 2°-8°C and the end of the drug administration should not exceed 24 hours.
Zometa solution should not be mixed with any other medications.
Zometa should not be mixed with any solutions containing calcium or any other divalent cations, such as lactated Ringer's solution. The prepared zoledronic acid solution must be administered using a separate IV infusion system. Side effects
Information on the frequency of adverse reactions when using Zometa at a dose of 4 mg is based mainly on data obtained during long-term therapy. Adverse reactions associated with the use of Zometa are usually mild and transient; similar to those reported with other bisphosphonates.
With intravenous administration, the development of a flu-like syndrome was usually observed in almost 9% of patients, with bone pain, fever, general malaise, and chills.
Cases of arthralgia and myalgia have been reported occasionally (in approximately 3% of patients).
Often (in approximately 20% of patients), a decrease in renal calcium excretion was accompanied by a sharp decrease in phosphorus concentration, which was asymptomatic and did not require treatment. In approximately 3% of patients, serum calcium concentrations decreased to hypocalcemia (without clinical manifestations).
There are reports of gastrointestinal reactions, such as nausea (5.8%) and vomiting (2.6%), after intravenous infusion of Zometa.
Local reactions at the infusion site, such as redness or swelling and/or pain, were observed in less than 1% of patients.
Anorexia was observed in 1.5% of patients receiving Zometa 4 mg.
A few cases of rash or itching have been observed (less than 1%).
As with other bisphosphonates, cases of conjunctivitis have been reported in approximately 1%.
There are reports of renal dysfunction (2.3%); however, other risk factors in this group of patients may also be important.
Based on a pooled analysis of controlled studies, severe anemia (hemoglobin <8.0 g/dL) was reported in 5.2% of patients receiving Zometa 4 mg compared with 4.2% receiving placebo.
Adverse reactions are listed below by organ and system, indicating the frequency of their occurrence. Frequency criteria: very often (>=;1/10), often ((>=;1/100, <1/10), sometimes ((>=;1/1000, <1/100), rarely - (> =;1/10000, <1/1000), very rarely (<1/10000), including isolated reports.
From the hematopoietic organs:
often - anemia, sometimes - thrombocytopenia, leukopenia; rarely - pancytopenia.
From the peripheral nervous system and central nervous system:
often - headache; sometimes - dizziness, paresthesia, taste disturbances, hypoesthesia, hyperesthesia, tremor, anxiety, sleep disorders; rarely - confusion.
From the organs of vision:
often - conjunctivitis; sometimes blurred vision; very rarely - uveitis, episcleritis.
From the digestive system:
often - nausea, vomiting, anorexia; sometimes - diarrhea, constipation, abdominal pain, dyspepsia, stomatitis, dry mouth.
From the respiratory system:
sometimes - shortness of breath, cough.
Dermatological reactions:
sometimes - itching, rash (including erythematous and macular), increased sweating.
From the musculoskeletal system:
often - bone pain, myalgia, arthralgia, generalized pain; sometimes - muscle cramps.
From the cardiovascular system:
sometimes - a pronounced increase or decrease in blood pressure; rarely - bradycardia.
From the urinary system:
often - renal dysfunction; sometimes - acute renal failure, hematuria, proteinuria.
From the immune system:
sometimes - hypersensitivity reactions; rarely - angioedema.
From the laboratory parameters:
very often - hypophosphatemia; often - increased serum concentrations of creatinine and urea, hypocalcemia; sometimes - hypomagnesemia, hypokalemia; rarely - hyperkalemia, hypernatremia.
Local reactions:
pain, irritation, swelling, formation of infiltration at the injection site.
Other:
often - fever, flu-like syndrome (including general malaise, chills, pain, fever), sometimes - asthenia, peripheral edema; chest pain, weight gain.
It should be borne in mind that when using other bisphosphonates in patients with bronchial asthma who are sensitive to acetylsalicylic acid, cases of bronchospasm were observed, but this phenomenon was not observed when using Zometa.
In one clinical trial of zoledronic acid administered for 3 years to patients with postmenopausal osteoporosis (at a dose of 5 mg once a year), the overall incidence of atrial fibrillation was 2.5% (96 of 3862 people) compared with 1.9% (75 of 3862 people). 3852) in the placebo group. The incidence of atrial fibrillation accompanied by severe hemodynamic disturbances was 1.3% (51 of 3862 people) and 0.6% (22 of 3852 people) for zoledronic acid and placebo, respectively. The reason for the increased incidence of atrial fibrillation during therapy with zoledronic acid in patients with postmenopausal osteoporosis has not been established.
In clinical studies with the use of zoledronic acid (at a dose of 4 mg every 3-4 weeks) in patients with cancer, no increase in the frequency of fibrillations was observed.
During therapy with Zometa, the following adverse events were observed in clinical practice, regardless of the presence of a cause-and-effect relationship with the use of the drug: when treating patients with bisphosphonates (including Zometa), rare cases of the development of osteonecrosis of the jaw have been described in clinical practice (usually after tooth extraction or other dental intervention).
In very rare cases, with the use of Zometa, a decrease in blood pressure has been observed, leading to fainting or circulatory collapse, mainly in patients with risk factors for the development of drowsiness, bronchoconstriction, atrial fibrillation, anaphylactic reactions/shock and urticaria.
Contraindications
: pregnancy;
- lactation (breastfeeding);
- hypersensitivity to zoledronic acid, other bisphosphonates and other components of the drug.
Use during pregnancy and breastfeeding
Zometa for use during pregnancy and lactation (breastfeeding).
Use for liver dysfunction
Since there are limited clinical data on the use of the drug in patients with severe liver failure, it is not possible to give specific recommendations for this category of patients.
Use for impaired renal function
When deciding on the use of Zometa in patients with hypercalcemia caused by a malignant tumor, against the background of impaired renal function, it is necessary to assess the patient’s condition and make a conclusion about whether the potential benefit of administering the drug outweighs the possible risk.
Before each administration of Zometa, the serum creatinine concentration should be determined. At the beginning of treatment with the drug in patients with bone metastases and with mild to moderate renal dysfunction, it is recommended to use Zometa in reduced doses. In patients who develop renal impairment during Zometa therapy, therapy with the drug can be continued only after the creatinine concentration returns to values that are within 10% of the initial value.
Considering the possibility of renal dysfunction when using bisphosphonates, incl.
Zometa, as well as due to the lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration >=;400 µmol/l or >=;4.5 mg/dl in patients with hypercalcemia caused by a malignant tumor and >= ;265 µmol/l or >=;3.0 mg/dl in patients with malignant tumors with bone metastases) and the presence of very limited pharmacokinetic data in patients with initial severe renal impairment (CC<=;30 ml/min), the use of Zometa It is not recommended for this group of patients. Special instructions
When deciding on the use of Zometa in patients with hypercalcemia caused by a malignant tumor, against the background of impaired renal function, it is necessary to assess the patient’s condition and make a conclusion about whether the potential benefit of administering the drug outweighs the possible risk.
Before each administration of Zometa, the serum creatinine concentration should be determined. At the beginning of treatment with the drug in patients with bone metastases and with mild to moderate renal dysfunction, it is recommended to use Zometa in reduced doses. In patients who develop renal impairment during Zometa therapy, therapy with the drug can be continued only after the creatinine concentration returns to values that are within 10% of the initial value.
Considering the possibility of renal dysfunction when using bisphosphonates, incl. Zometa, as well as due to the lack of comprehensive data on the clinical safety of the drug in patients with severely impaired renal function (serum creatinine concentration >=;400 µmol/l or >=;4.5 mg/dl in patients with hypercalcemia caused by a malignant tumor and >= ;265 µmol/l or >=;3.0 mg/dl in patients with malignant tumors with bone metastases) and the presence of very limited pharmacokinetic data in patients with initial severe renal impairment (creatinine clearance <=; 30 ml/min), the use of Zometa It is not recommended for this group of patients.
Before infusion, ensure that the patient is adequately hydrated. If necessary, it is recommended to administer saline before, in parallel or after the infusion of Zometa. Overhydration of the patient should be avoided due to the risk of cardiovascular complications.
After administration of Zometa, constant monitoring of the concentrations of calcium, phosphorus, magnesium and creatinine in the blood serum is necessary. If hypocalcemia, hypophosphatemia or hypomagnesemia develops, short-term additional administration of the corresponding substances may be necessary. Patients with untreated hypercalcemia usually have impaired renal function, so careful monitoring of renal function in this category of patients is necessary.
When deciding whether to treat patients with bone metastases with Zometa in order to reduce the risk of pathological fractures, spinal cord compression, tumor-related hypercalcemia, and reduce the need for radiation therapy or bone surgery, it should be taken into account that the therapeutic effect occurs after 2 -3 months after starting treatment with Zometa.
There are isolated reports of renal dysfunction associated with the use of bisphosphonates. Risk factors for such complications include dehydration, previous renal failure, repeated administration of Zometa or other bisphosphonates, as well as the use of nephrotoxic drugs, and too rapid administration of the drug. Despite the fact that the risk of the above-described complications is reduced if Zometa is administered at a dose of 4 mg for at least 15 minutes, the possibility of impaired renal function remains.
There have been cases of deterioration in renal function, progression of renal failure and the need for hemodialysis with the first or single use of Zometa.
Increases in serum creatinine concentrations have also been observed in some patients with long-term use of Zometa at recommended doses, although less frequently.
Since there are limited clinical data on the use of the drug in patients with severe liver failure, it is not possible to make specific recommendations for this category of patients.
Cases of osteonecrosis of the jaw have been described in cancer patients during antitumor treatment, including bisphosphonates (including Zometa). Many patients had signs of a local infectious and inflammatory process, including osteomyelitis.
In clinical practice, the development of osteonecrosis of the jaw was most often observed in patients with advanced breast cancer and myeloma, as well as in the presence of dental diseases (including after tooth extraction, periodontal diseases, unsatisfactory fixation of dentures). Known risk factors for osteonecrosis of the jaw are: cancer, cancer-related treatment (including chemotherapy, radiation therapy, corticosteroids), concomitant diseases (including anemia, coagulopathy, infection, pre-existing oral disease).
Before prescribing bisphosphonates, patients with cancer should undergo a dental examination and appropriate preventive procedures, and recommend strict adherence to good oral hygiene.
Dental surgery should be avoided if possible during treatment of these patients. There is no evidence that interrupting bisphosphonate treatment before dental procedures reduces the risk of osteonecrosis of the jaw. The treatment plan for a particular patient should be based on an individual assessment of the risk/benefit ratio.
In clinical practice, rare cases of severe and in some cases disabling pain in bones, joints and muscles have been reported with the use of bisphosphonates, which include zoledronic acid.
These symptoms developed over a period of 1 day to several months from the start of treatment. Symptoms resolved in most patients after treatment was stopped. In several patients, symptoms recurred when therapy was restarted or another bisphosphonate was prescribed.
Zometa contains the same active ingredient as Aklasta - zoledronic acid. Patients receiving Zometa therapy should not receive Aklasta at the same time.
Use in pediatrics
The effectiveness and safety of Zometa in pediatric practice have not yet been established.
Impact on the ability to drive vehicles and operate machinery
The effect of Zometa on the ability to drive vehicles and operate machinery has not been studied.
Overdose
Symptoms:
in case of acute overdose of the drug (limited data), renal dysfunction (including renal failure), changes in electrolyte composition (including concentrations of calcium, phosphate and magnesium in the blood plasma) were noted. A patient who has received the drug in a dose exceeding the recommended one should be under constant supervision.
Treatment:
If hypocalcemia occurs with clinically significant manifestations, an infusion of calcium gluconate is indicated.
Drug interactions
When used simultaneously with Zometa other commonly used drugs (antitumor drugs, diuretics, antibiotics, analgesics), no clinically significant interactions were observed.
According to data obtained in in vitro studies, zoledronic acid does not have significant binding to plasma proteins and does not inhibit enzymes of the cytochrome P450 system. However, specific clinical studies to study drug interactions have not been conducted.
Caution is recommended when using bisphosphonates and aminoglycosides concomitantly, since the simultaneous effect of these drugs is manifested by an increase in the duration of the decrease in plasma calcium concentrations.
Caution is necessary when using Zometa simultaneously with drugs that have a potentially nephrotoxic effect.
The possibility of developing hypomagnesemia should also be kept in mind.
Zometa are administered intravenously in combination with thalidomide.
Pharmaceutical interactions
A diluted Zometa solution should not be mixed with infusion solutions containing calcium ions (for example, Ringer's solution).
When using glass vials, infusion systems and bags of various types made of polyvinyl chloride, polyethylene and polypropylene (pre-filled with 0.9% sodium chloride solution or 5% dextrose solution) for the administration of Zometa, no signs of incompatibility with Zometa were found.
Conditions for dispensing from pharmacies
The drug is dispensed with a prescription.
Conditions and periods of storage
The drug should be stored out of the reach of children at a temperature not exceeding 30°C. Shelf life: 3 years. The drug should not be used after the expiration date.
special instructions
The drug is intended for use only in a hospital setting.
When using the drug in infants and premature newborns, the concentration of vancomycin in the blood plasma should be regularly monitored.
The drug should be administered slowly by infusion (at least 60 minutes). Rapid administration (eg, within a few minutes) of vancomycin may be accompanied by a marked decrease in blood pressure and, in rare cases, cardiac arrest.
The incidence and severity of thrombophlebitis can be reduced by properly diluting the original solution and alternating the sites of drug administration.
With long-term use of vancomycin, it is necessary to conduct an audiogram, monitor the peripheral blood picture, kidney function (general urinalysis, creatinine and blood urea nitrogen levels).
It is advisable to determine vancomycin serum concentrations in patients with renal failure in patients over 60 years of age, since high, long-term vancomycin blood concentrations may increase the risk of drug toxicity (maximum concentrations should not exceed 40 mcg/ml, and minimum concentrations should not exceed 10 mcg/ml). ml, concentrations above 80 µg/ml are considered toxic). For patients with renal failure, doses of vancomycin should be individualized.
Features of application:
Before starting treatment, you should carefully check for a history of hypersensitivity reactions to penicillins, cephalosporins or other allergens.
Serious and sometimes even fatal cases of hypersensitivity (anaphylactic reactions) have been observed in patients during penicillin therapy. These reactions are reliable in individuals with similar reactions to penicillin in the past. If allergic reactions occur, Abiclav therapy should be discontinued and alternative therapy should be started.
If it is proven that the infection is caused by microorganisms sensitive to amoxicillin, it is necessary to weigh the possibility of switching from the amoxicillin/clavulanic acid combination to amoxicillin according to official recommendations.
The drug should not be used in cases where there is a high risk that the pathogens are resistant to β-lactams, and is not used to treat pneumonia caused by penicillin-resistant strains of S. pneumoniae.
Abiclav should not be prescribed if infectious mononucleosis is suspected, since cases of morbilliform rash have been reported with the use of amoxicillin for this pathology.
Long-term use of the drug can cause excessive growth of microflora insensitive to it.
The development of polymorphic erythema associated with pustules at the beginning of treatment may be a symptom of acute generalized exanthematous pustulosis. In this case, it is necessary to stop treatment and further use of amoxicillin is contraindicated.
The drug should be prescribed with caution to patients with signs of liver failure. Adverse reactions from the liver occurred mainly in men and elderly patients and were associated with long-term treatment. Such events have been reported very rarely in children. In all patient groups, symptoms and signs usually occurred during or immediately after treatment, but in some cases they appeared several months after stopping treatment. In general, these phenomena were the opposite. Liver side effects can be severe and very rarely fatal. They always occurred in patients with severe concomitant diseases or during concomitant use of drugs known to have potential negative effects on the liver.
Antibiotic-associated colitis has been reported with almost all antibacterial drugs, which can range from mild to life-threatening. Therefore, it is important to keep this in mind if patients experience diarrhea during or after antibiotic use. If antibiotic-associated colitis occurs, treatment with Abiclave should be stopped immediately, consult a doctor and begin appropriate treatment.
Rarely, patients taking Abiklav and oral anticoagulants may experience an increase in prothrombin time (increase in INR level). When taking anticoagulants simultaneously, appropriate monitoring of laboratory parameters is necessary. Dosage adjustment of oral anticoagulants may be required to maintain the required level of coagulation.
In patients with impaired renal function, the dose must be adjusted according to the degree of renal impairment.
In patients with reduced urine excretion, crystalluria can very rarely be observed, mainly with parenteral administration of the drug. Therefore, to reduce the risk of occurrence during treatment with high doses, it is recommended to ensure a balance between the fluid drunk and urine excreted.
When treating with amoxicillin, enzymatic reactions with glucose oxidase should be used to determine the level of glucose in urine, since other methods may give false-positive results.
The presence of clavulanic acid in the drug can cause nonspecific binding of IgG and albumin on red blood cell membranes, resulting in a false positive result when performing the Coombs test.
There have been reports of false-positive test results for the presence of Aspergillus in patients receiving amoxicillin/clavulanic acid (using the Bio-Rad Laboratories Platelis Aspergillus EIA test). Therefore, such positive results in patients receiving amoxicillin/clavulanic acid should be interpreted with caution and confirmed by other diagnostic methods.
Overdose
Symptoms: increased severity of side effects from the urinary system and sensory organs.
Treatment: carry out symptomatic therapy. Fluid administration and monitoring of vancomycin plasma concentrations is recommended. To quickly remove excess vancomycin from the body, hemofiltration is more effective than hemodialysis.
Side effect
With simultaneous intravenous administration of vancomycin and local anesthetics, erythematous rashes and hyperemia of the skin of the face may appear; in adults, intracardiac conduction disturbances may occur.
With simultaneous and/or sequential systemic or local use of other potentially ototoxic and/or nephrotoxic drugs (aminoglycosides, amphotericin B, aminosalicylic acid or other salicylates, capreomycin, carmustine, cyclosporine, loop diuretics, including ethacrynic acid, polymyxin B, cisplatin) requires careful monitoring of the possible development of these symptoms.
Cholestyramine reduces the activity of vancomycin when taken orally.
Antihistamines, meclozine, phenothiazines, thioxanthenes can mask the symptoms of vancomycin ototoxicity (tinnitus, vertigo).
Pharmaceutical interactions
Vancomycin solution has a low pH, which may cause physical or chemical instability when mixed with other solutions. Mixing with alkaline solutions should be avoided.
Solutions of vancomycin and beta-lactam antibiotics are physically incompatible when mixed.
The likelihood of precipitation increases with increasing concentrations of vancomycin. The IV system should be adequately flushed between uses of these antibiotics. In addition, it is recommended to reduce vancomycin concentrations to 5 mg/ml or less.
Side effects:
Infections and invasions: candidiasis of the skin and mucous membranes.
From the blood: reversible leukopenia (including neutropenia) and thrombocytopenia, reversible agranulocytosis and hemolytic anemia, increased bleeding time and prothrombin index.
From a block of the immune system: angioedema, anaphylaxis, serum syndrome, allergic vasculitis.
From the nervous system: dizziness, headache, reversible hyperactivity and convulsions. Seizures may occur in patients with impaired kidney function or in those receiving high doses of the drug.
From the digestive tract: diarrhea, nausea, vomiting, indigestion, antibiotic-associated colitis (including pseudomembranous and hemorrhagic colitis), black “hairy” tongue.
Nausea is more often associated with high doses of the drug. The above mentioned gastrointestinal symptoms can be reduced by taking the drug at the beginning of meals.
From the digestive system: a moderate increase in AST and/or ALT levels was observed in patients treated with β-lactam antibiotics, but the clinical significance of this has not been established; hepatitis and cholestatic jaundice. These phenomena have occurred with the use of other penicillins and cephalosporins.
Hepatitis occurred mainly in men and elderly patients, and its occurrence may be associated with long-term treatment.
In children, such phenomena occurred very rarely.
Signs and symptoms of the disease occur during or immediately after treatment, but in some cases may occur several weeks after treatment ends. These phenomena are usually reversible. Very rarely (less than 1 report in approximately 4 million prescriptions) deaths occur, which always occur in patients with a severe underlying disease or in patients simultaneously receiving drugs that negatively affect the liver.
From the skin and subcutaneous tissue: skin rash, itching and urticaria, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, bullous exfoliative dermatitis, acute generalized exanthematous pustulosis.
If any allergic dermatitis occurs, treatment should be discontinued.
From the urinary system: interstitial nephritis, crystalluria.
