Active material: Kaspofungin
When ATH: J02AX04
CCF: Antifungal agent
ICD-10 codes (testimony): B37.0, B37.1, B37.6, B37.7, B37.8, B44
When CSF: 08.01.04
Manufacturer: MERCK SHARP & DOHME B.V. (Netherlands)
Valium for solution for infusion in the form of dry, solid mass from white to almost white.
| 1 fl. | |
| kaspofungin | 50 mg |
Excipients: sucrose, mannitol, acetic acid glacial, Sodium hydroxide.
Colourless glass bottles with capacity 10 ml (1) – пачки картонные.
Valium for solution for infusion in the form of dry, solid mass from white to almost white.
| 1 fl. | |
| kaspofungin | 70 mg |
Excipients: sucrose, mannitol, acetic acid glacial, Sodium hydroxide.
Colourless glass bottles with capacity 10 ml (1) – пачки картонные.
Antifungal medication for systemic use. Is a semi-synthetic compound lipopeptidnoe (exinokandin), synthesized product of the fermentation Glarea lozoyensis. Ingibiruet synthesis of β-Kaspofungin(1,3)-D-глюкана – важнейшего компонента клеточной стенки многих рифомицетов и дрожжей.
In vitro caspofungin active against various pathogenic fungi of the genus Aspergillus (including Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Aspergillus nidulans, Aspergillus terreus and Aspergillus candidus) и Candida (including Candida albicans, Candida of Dublin, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lipolytica, Candida Lusitania, Candida parapsilosis, Candida tropicalis and Candida rugosa).
In vivo activity of kaspofungina is revealed when injecting animals with normal and reduced immunity, infected with Aspergillus and Candida. Application of kaspofungina in these cases, contributes to an increase in life expectancy of infected animals (Aspergillus and Candida) and eradication of pathogenic fungi (Candida) in the affected organs. Kaspofungin is also active in animals with immunodeficiency, infected by Candida glabrata, Candida krusei, Candida Lusitania, Candida parapsilosis, Candida tropicalis, which is achieved for pathogenic fungi (Candida) in the affected organs. Kaspofungin shows high activity in the prevention and treatment of pulmonary aspergillezov, What is revealed in the study on models of fatal lung infections in vivo.
Kaspofungin active against strains of fungi Candida, resistant to fluconazole, amfotericinu or flucitosinu, with a different mechanism of action.
Some patients during treatment with stand out varieties of fungi Candida with reduced sensitivity to kaspofunginu. Determination of the minimum majority of concentration (IGC) for kaspofungina is not performed, Since there is no correlation between the IPC and the clinical efficacy of the drug. Drug resistance to the drug in patients with invasive aspergillezom no.
Standardized methods for determining sensitivity to inhibitors of the synthesis of β-(1,3)-D-glucan content not created, and in vitro sensitivity studies may not correlate with clinical data.
Distribution
After a single on/in infusions for 1 h kaspofungina concentration in plasma reduced multiphase way. Immediately after the infusion comes short α-phase, followed by β-phase t1/2 from 9 to 11 no, which is the main characteristic of the profile and has a distinct log-linear relationship between 6 and 48 hours after infusion. During this period, the concentration of the drug in plasma is significantly reduced. There is also an additional γ-phase t1/2 from 40 to 50 no. The predominant mechanism, influence on plasma clearance, is the distribution, biotransformation or excretion than. Kaspofungin intensely binds to proteins (about 97%) with minimal penetration into erythrocytes. About 92% 3H-tags found in the tissues through the 36-48 hours after the single dose 70 mg labelled 3(H) kaspofungina acetate. For the first 30 hours after the excretion and biotransformation is insignificant kaspofungina.
Metabolism
Kaspofungin slowly metabolized by hydrolysis and N-acetylation and undergoes spontaneous chemical destruction to peptide compound with an open ring. At a later date (through 5 days or more after the introduction of a single dose of the labeled 3(H) kaspofungina acetate) plasma level is low (less 7 pmol/mg protein or 1.3% or less from the imposed dose) Covalent binding of radioactive tags, that may be due to the formation of two reactive intermediates chemical destruction kaspofungina. Supplementary metabolism involves hydrolysis to the constituent amino acids and their derivatives, including digidroksigomotirozin and N-acetyl-digidroksigomotirozin. These two tyrosine derivatives are found only in urine, that indicates their fast kidney klirens.
Deduction
The organism appears around 75% product (Pharmacokinetic studies with radioactive mečennym kaspofunginom): 41% – с мочой и 34% – с калом. Plasma concentrations of tags and kaspofungina for the first 24-48 hours after the dose did not differ, then drug levels dropping faster, and decrease its concentration is below the level of quantification is a 6-8 day after doses, and radioactive tags-through 22.3 of the week. A small amount of kaspofungina is highlighted in an unmodified form with urine (about 1.4% dose). Kidney klirens original drug low and approximately 0.15 ml / min.
Pharmacokinetics in special clinical situations
Kaspofungina concentration in the plasma of healthy men and women in the 1-th day after injection of a single dose of 70 mg equal. After 13 daily introductions to 50 kaspofungina mg concentration in plasma in some women approximately 20% higher, than men.
The content of kaspofungina in plasma of healthy men and older women (65 and older), compared with healthy young men, several improved on 28% (AUC). In patients older c invasive or invasive when conducting empirical therapy observed the same moderate changes in the concentration of the drug in plasma, as in a group of healthy elderly patients compared to healthy patients of young age. Correction mode for older (65 and older) patients are not required to.
Kaspofungina concentration in plasma of patients with mild hepatic insufficiency (5-6 points on the Child-Pugh) After the introduction of the single dose 70 mg increases by approximately 55% (AUC), compared with healthy volunteers. The introduction of the drug for these patients 14 days (70 mg in 1-St day followed by daily introduction by 50 mg) accompanied by a moderate increase in its concentration in the plasma and is 19-25% (AUC) on 7-th and 14th day, compared with healthy volunteers.
Held 5 long-term clinical studies with the study drug Kansidas® patients to 18 years, including research pharmacokinetics of the drug (initially a study among adolescents (12-17 years) and children (2-11 years), затем – у детей младшего возраста (3-23 Months), and in infants and children, the first three months of life).
Adolescents (12-17 years), received kaspofungin dose 50 mg / m2 (The maximum daily dose - 70 mg), concentration in blood plasma ( AUC0-24 no) in General corresponded to concentrations in adults, taking kaspofungina dose 50 mg / day. All teens have gotten kaspofungin dose above 50 mg, and 6 from 8 the patients were receiving the maximum daily dose 70 mg. Kaspofungina concentration in the blood plasma in these patients was lower compared to concentrations in adults, receiving the drug in a daily dose of 70 mg, the dose of, that is most often applied to adolescents.
In children 2-11 years, received kaspofungin dose 50 mg / m2 per day (the maximum daily dose 70 mg), its concentration in the blood plasma (AUC0-24) was comparable with the analogous indicator in adult patients, which was administered at a dose of kaspofungin 50 mg / day. On the first day of application of the concentration of the drug in plasma (AUC0-24) was slightly higher in children compared to adults (on 37% When comparable dosages 50 mg / m2 and 50 mg 1 time / day). But, it must be emphasized, that concentration in plasma ( AUC0-24) the children on the first day was still below, than adults in long-term care.
In children 3-23 months, which prescribed a daily dose of kaspofungin 50 mg / m2 (the maximum dose - 70 mg), kaspofungina concentration in plasma with long-term use was comparable with concentrations in adults, which imposed dose 50 mg / day. As for older children, children in this age group, received kaspofungin dose 50 mg / m2, the concentration of the drug in plasma was higher on the first day of treatment, compared with older, those who received a standard dose of kaspofungina 50 mg. Pharmacokinetic parameters kaspofungina the dose 50 mg / m2 in children younger age group (3-23 of the month) and more senior group (2-11 years) the same dosing regime were comparable.
Infants and children up to 3 Months, which kaspofungin prescribed dose 25 mg / m2, the maximum concentration of kaspofungina (FROM1no) and its threshold concentration (FROM24no) After repeated introductions are consistent with similar indicators in adults, receiving drug dose 50 mg / day. On the first day of the peak concentration c1no was comparable with older, a threshold concentration with24no was moderately increased in neonates and infants compared with adults. Determination of the concentration of the drug in plasma ( AUC0-24) This study has not been carried out because of the difficulties of sampling. Note, that study of efficacy and safety during adequate prospective clinical trials of the drug Kansidas® infants and children up to 3 months has not been.
-empirical therapy for febrile neutropenic patients with suspected fungal infection;
is invasive candidiasis (incl. kandidemija) in patients with neutropenia or without;
-invasive aspergillosis (patients, refractory to other therapies or not tolerate her);
— èzofageal′nyj candidiasis;
— orofaringealny candidiasis.
The daily dose Kansidasa® administered by slow in/in infusion (≥1) 1 time / day.
At empirical therapy on the first day, introducing a single loading dose 70 mg, in the second and subsequent days of treatment daily dose is 50 mg / day. Duration of treatment depends on the clinical and microbiological efficacy. Empirical therapy should be carried out to the full resolution of neutropenia. Upon confirmation of a fungal infection, patients should receive the drug at least 14 Nights; Kansidasom therapy should continue for at least 7 days after the disappearance of clinical manifestations as fungal infection, and neutropenia. The existing data on the safety and tolerability of Kansidasa® to increase the daily dose of up to 70 mg, If the daily dose 50 mg is well tolerated by the patient, but it does not give the desired clinical effect.
At invasive candidiasis in 1-St day therapy administered a single loading dose 70 mg, in the 2nd and subsequent days of treatment daily dose is 50 mg / day. The treatment of invasive candidiasis is determined by the clinical effect and microbiological effectiveness. The general rule is the continuation of antifungal therapy is not less 14 days after the last receipt of blood culture. Patients with persistent neutropenia may require longer treatment before allowing neutropenia.
At invasive aspergilleze in 1-St day introduces a single loading dose 70 mg, in the 2nd and subsequent days of treatment daily dose is 50 mg / day. Duration of treatment depends on the severity of the disease, degree of recovery of the patient from the immunosuppression, clinical and microbiological effects of therapy.
The existing data on the safety and tolerability of Kansidasa® to increase the daily dose of up to 70 mg, If the daily dose 50 mg is well tolerated by the patient, but it does not give the desired clinical effect.
At ezofagealnom and orofaringeal′nom 4-8 daily dose is 50 mg/day every day treatment.
Elderly patients (65 and older) dose adjustment is not required.
Correction mode is not required in the appointment of the drug patients with decreased renal function, as well as sexual and racial differences.
Patients with mild hepatic insufficiency (5-6 points on the Child-Pugh) dose adjustment is required. At moderate hepatic insufficiency (from 7 to 9 points on the Child-Pugh) maintaining daily intake Kansidasa® is reduced to 35 mg / day, but when the relevant testimony saved loading dose 70 mg on the first day of therapy. Clinical experience with the drug in patients with severe liver failure (more 9 points on the Child-Pugh) no.
Daily dose of the drug Kansidas®introduced children (from 3 months before 17 years) by slow I / Infusion (≥ 1 no) 1 time / day.
Dose based on body surface area of the patient by the formula Mostellera.
For all the evidence on the first day you enter single loading dose 70 mg / m2 (shall not exceed the permissible dose 70 mg), в последующие дни – 50 mg / m2 per day (shall not exceed the permissible dose 70 mg). Duration of therapy is determined individually and depends on the indication for the designation of.
Daily dose of the drug Kansidas®can be increased to 70 mg / m2 in that case, If the daily dose 50 mg / m2 well tolerated by the patient, but it does not give the desired clinical effect (shall not exceed the permissible dose 70 mg).
While appointing the drug Kansidas® with inducers of clearance of drugs (rifampicin, EFV, nevirapine, phenytoin, dexamethasone or carbamazepine) should be considered the possibility of increasing the daily dose of the drug Kansidas® to 70 mg / m2 for this group of patients (but not exceeding the permissible dose 70 mg).
Clinical experience in the application of the drug in children with any degree of hepatic insufficiency no.
Preparation of solution of the drug Kansidas® for on/in infusions for adults
You cannot use solutions, dextrose (A-D-glucose), tk. in infusion solutions, dextrose, Kansidas® unstable.
Kansidas® not mixed and not enter simultaneously with any other drugs, because no data on its compatibility with other drugs for the on/in the introduction.
View the ready infusion solution, to make sure that it is free from particulate matter or discoloration.
Phase 1. Primary preparation of the solution in a bottle
Before breeding of cold orange powder must be brought to room temperature and aseptic respecting add 10.5 ml of sterile water for injection (bacteriostatic water for injection, methyl paraben, propilparabena or bacteriostatic water for injection with benzilovym alcohol). The concentration of the drug in the primary solution will be 7 mg / ml (bottle 70 mg) or 5 mg / ml (bottle 50 mg).
White or almost white residue completely dissolved. Gently mix the contents of the vial before obtaining a transparent solution. Inspect the primary solution, to ensure no balanced draught or color changes. Cooked this way the primary solution can be stored in a bottle to 24 h at a temperature below 25° c.
Phase 2. Final preparation infuzing solution
Solution for the infusions are prepared in compliance with the conditions of asepsis. As solvents use sterile saline solution for infusions or solution periods with lactatom. For the final preparation infuzing solution, designed to introduce the patient, plastic infusion bag or bottle infusion solvent (sterile saline solution for infusions or solution periods with lactatom) capacity 250 ml add appropriate amount of prepared on 1 primary stage of solution Kansidasa® (as shown in table 1). If you type the daily dose 50 mg or 35 mg, You can reduce the amount of the infusion to 100 ml.
You cannot use the muddy or containing precipitate solution.
The final infusion solution should be used within 24 no, if it is stored at room temperature (below 25° c); during 48 h when stored in the refrigerator (2-8°C).
Kansidas® Enter through slow (≥1) in / Infusion.
Table 1. Preparation of final preparation infuzing solution Kansidas®
| Dose * preparation | Primary volume r-RA to add into the bowl with the solvent for the on/in infusion | Standard breeding(250 mL of solvent); concentration target infusion r-RA | Breeding in a reduced amount (100 mL of solvent); concentration target infusion r-RA |
| 70 mg | 10 ml | 0.27 mg / ml | not recommended |
| 70 mg (from 2 fl. by 50 mg)** | 14 ml | 0.27 mg / ml | not recommended |
| 50 mg | 10 ml | 0.19 mg / ml | 0.45 mg / ml |
| 35 mg (from 1 bottle 70 mg) moderate hepatic insufficiency | 5 ml | 0.14 mg / ml | 0.33 mg / ml |
| 35 mg (from 1 bottle 50 mg) moderate hepatic insufficiency | 7 ml | 0.14 mg / ml | 0.33 mg / ml |
* – во флакон с порошком Кансидаса® always added 10.5 ml of solvent, regardless of dose (50 mg or 70 mg).
** – при отсутствии флакона по 70 mg dose can be prepared from 2 vials 50 mg.
Preparation of solution of the drug Kansidas® for on/in infusions for children
Process for preparation of a solution of the drug Kansidas® for in/infusion in children is similar to the preparation of solution for the infusions for adults. It includes the activities described above 2 phase — cooking primary and final solution.
The main difference consists in determining dosage, which is calculated by the formula, following, and takes into account the value of the patient's body surface area.
Determination of the surface area of the body (PPT) to calculate the dose in children
Before preparation infuzing solution it is necessary to calculate body surface area (PPT) the child according to the following formula (formula Mostellera):
PPT (m2)= the square root of: Growth(cm) × Body weight (kg)/3600
Preparation preparation for introducing children to the age of 3 months (using a bottle 70 mg)
Determine necessary for this child loading dose, using PPT (calculated, as described above) and the following equation:
PPT (m2) × 70 mg / m2 = Loading dose
Maximum loading dose on the first day of treatment should not exceed 70 mg, regardless of the estimated dose for a given patient.
Bottle selection is determined by the dose in mg, you plan to enter the child. For, to ensure the accuracy of dosing in children, requiring dose, not to exceed 50 mg, It is recommended to use a bottle with a product, contains 50 mg (kaspofungina concentration 5.2 mg / ml). Vials with the contents of kaspofungina 70 mg is recommended for children, requiring dose, exceeding 50 mg.
Preparation of a solution for infusions 2 этапа – см. section solution preparation drug Kansidas® for on/in infusions for adults
Remove the vial from the amount of the drug, equal to the calculated loading dose. In aseptic conditions move this volume (ml) a recovered drug Kansidas in a container for on/in infusions, contains 250 ml 0.9%, 0.45% or 0.225% sodium chloride solution for injection, either solution periods with lactatom for injection. If necessary, the final solution may be reduced so, to the total concentration of the drug does not exceed the 0.5 mg / ml.
The ready infusion solution should be used within 24 h when stored at a temperature of no higher than 25° c or over 48 h when stored in a refrigerator at 2-8° c. If defined by the formula, the above, the magnitude of loading dose is less than 50 mg, then you can prepare recovery solution from the vial 50 mg (cm. drug Preparation section below for an introduction to children over the age of 3 months (using a bottle 50 mg). When using the bottle 50 mg concentration of the drug in the primary solution will be 5.2 mg / ml.
Preparation preparation for introducing children to the age of 3 months (using a bottle 50 mg)
Determine necessary for this child, the daily dose, using PPT (calculated, as described above) and the following equation:
PPT (m2) x 50 mg / m2 = Daily supports dose
Daily dose should not exceed 70 mg, regardless of the estimated dose for a given patient.
Preparation of a solution for infusions 2 этапа – см. see section. section rastvorapreparata Cooking Kansidas®for on/in infusions for adults.
Remove the vial from the amount of the drug, equal to the calculated daily maintenance dose. In aseptic conditions move this volume (ml) a recovered drug Kansidas® in a container for on/in infusions, contains 250 ml 0.9%, 0.45% or 0.225% sodium chloride solution for injection, either solution periods with lactatom for injection. If necessary, the final solution may be reduced so, to the total concentration of the drug does not exceed the 0.5 mg / ml.
The ready infusion solution should be used within 24 h when stored at a temperature of no higher than 25° c or over 48 h when stored in a refrigerator at 2-8° c.
If the calculated daily dose supporting more 50 mg, You can use the bottle 70 mg, as described above, the concentration of the solution will be restored 7.2 mg / ml.
Identified adverse reactions, associated with drug, usually have a light period and rarely required preparation as in adults, and children.
Common side effects: Often (≥ 1/10), often (≥ 1/100, but <1/10) and infrequently (≥ 1/1000, but <1/100).
In Adult:
From the body as a whole: часто – лихорадка, headache, feeling the chill.
From the digestive system: often - nausea, diarrhea, vomiting, abdominal pain, increase in serum activity of ACT, GOLD, Alkaline phosphatase, direct and total bilirubin.
From the hematopoietic system: часто – анемия.
Cardio-vascular system: часто – тахикардия, flebit / tromboflebit, peripheral edema, venous complications postinfuzionnye, tides.
On the part of the respiratory system: часто – одышка.
Skin and subcutaneous fat: rash, itch (incl. at the site of injection), increased sweating.
From the laboratory parameters: often- hypoalbuminemia, hypoproteinemia, kaliopenia, giponatriemiya, gipomagniemiya, hypocalcemia, leukopenia, neutropenia, thrombocytopenia, eozinofilija, decrease in hemoglobin and hematocrit, increase in partial thromboplastin and prothrombin time, proteinuria, leucocyturia, mikrogematuriâ, increase in serum creatinine concentration; нечасто – гиперкальциемия.
Имеются отдельные сообщения о редких случаях дисфункции печени и аллергических реакциях – сыпи, facial edema, zude, the sense of heat or of bronchospasm, as well as anaphylaxis. In the postmarketingovom period identified rare cases liver dysfunction, as well as peripheral edema, hypercalcemia. У пациентов с инвазивным аспергиллезом – отек легких, respiratory distress syndrome in adults, infiltrates on x-ray.
Children:
From the body as a whole: очень часто – fever, often - headache, feeling the chill, gistaminoposredovannye reaction (ie. allergic and anaphylactic reactions).
Cardio-vascular system: часто – тахикардия, decrease in blood pressure, tides, peripheral edema.
From the digestive system: often- abnormal liver function, increase in serum activity of ACT, GOLD.
Skin and subcutaneous fat: often – rash, itch (incl. at the site of injection).
From the laboratory parameters: often-hypokalemia, gipomagniemiya, hypercalcemia, eozinofilija, increase in the serum concentrations of glucose and phosphorus, reduction of phosphorus concentration in the serum.
Local reactions: often- pain at the site of catheter, гистаминопосредованные реакции в месте введения – припухлость.
- Children up to age 3 months;
- Hypersensitivity to the drug.
FROM caution shall mean the combined application with ziklosporinom, as well as in patients with moderate hepatic insufficiency (from 7 to 9 points on the Child-Pugh).
Clinical experience on the use of drugs in pregnancy and lactation (breast-feeding) no. Animals kaspofungin penetrates through the placental barrier. Caspofungin should not be administered to women during pregnancy, except in cases, when use of the drug is essential.
Since there is no kaspofungina allocation data with breast milk, if necessary, the appointment during lactation should stop breastfeeding.
Use in Pediatrics
Effectiveness and safety of drug Kansidas® in children with 3 months before 17 years confirms sufficient clinical research data, on the basis of which the drug is successfully applied in this category of patients for the same reasons, that and in adult patients.
No data on the safety and efficacy of Kansidas® in infants and children under 3 months.
No data on drug overdose. В клинических исследованиях хорошо переносилась самая высокая из испытанных доз – однократная разовая доза 210 mg (6 Healthy volunteers).
It was also shown good tolerability of the drug in his introduction to the daily dose 100 mg for 21 day (15 Healthy volunteers).
In overdose caspofungin dialysis is not carried out.
Caspofungin acetate is not an inhibitor of an enzyme of the cytochrome P450 (CYP), and is not an inducer of CYP3A4-mediated metabolism of other drugs. Caspofungin is not a substrate for P-glycoprotein enzymes and represents a poor substrate for cytochrome P450 enzymes.
The farmakokinetiku Kansidasa® influence itraconazole, Amphotericin B, Mycophenolate Mofetil;, nelfinavir or Tacrolimus.
In turn, Kansidas® does not affect the pharmacokinetic performance of itraconazole, Amphotericin B, rifampina or active metabolites Mycophenolate.
Kansidas® lowers rate of 12-hour concentration in the blood of Tacrolimus 26%. Patients, receiving both drugs, recommended standard monitoring of Tacrolimus blood and, if necessary, correction dosage.
If you are applying to Kansidasa® and Cyclosporine perhaps tranzithornoe (disappear after drug withdrawal) increased activity of AST and ALT (not more than 3 times, compared with the top rules), as well as the increase in AUC of approximately kaspofungina 35% without changing the concentration of cyclosporin. The joint appointment of these drugs (for up to 290 d) There were no serious adverse events from the liver. The simultaneous appointment Kansidasa® and Cyclosporine can be considered a reasonable, the potential benefit of such appointment exceeds the potential risk.
Rifampin can accelerate, and slow down the distribution of caspofungin. While joint appointment with rifampicin for 14 days noted a transient increase in the concentration of plasma kaspofungina in first day (increase in AUC of about 60%). At the same time, this was not observed ingibiruty effect, when the appointment took place against caspofungin held for 14 days monotherapy rifampicin, on the background of the sustainable effect rifampina inductor noted a slight decrease in AUC and kaspofungina concentration towards the end of infusion, а пороговой концентрации – приблизительно на 30%.
The combined application with Kansidasom® inductors clearance of drugs (efavirenz, Nevirapine, phenytoin, dexamethasone or carbamazepine) may result in a clinically significant decrease in the concentration of caspofungin. Available evidence suggests that, that induced by these drugs decrease the concentration of caspofungin happening soon due to the acceleration of elimination, rather than metabolism. Therefore, when combined with the application of Kansidasa® with èfavirenzem, nelfinavirom, nevirapine, rifampicin, deksametazonom, phenytoin or carbamazepine should consider increasing the daily dose Kansidasa® to 70 mg after application of usual loading dose 70 mg.
Children combined application of dexamethasone and kaspofungina may be accompanied by a clinically significant reductions in concentration threshold kaspofungina.
The drug is released under the prescription.
The drug should be stored out of reach of children at a temperature of 2 ° to 8 ° C. Shelf life - 2 year.
The prepared vial primary solution Kansidasa® can be stored at a temperature below 25° c 24 hours before preparation infuzing solution, designed for the introduction of a patient.
Prepared final recovery solution Kansidasa® in a plastic bag or infuzionnom vial for on/in infusions can be stored at a temperature below 25° c 24 h or refrigerated at a temperature from 2° to 8° c for 48 no.
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