Esomeprazole Sodium for Injection
This product is white or white freeze-dried cake or powder.
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Esomeprazole Sodium for Injection Instructions
Please read the instructions carefully and use them under the guidance of a physician.
[Name of Drug]]
Common Name: Esomeprazole Sodium for Injection
English Name:Esomeprazole Sodium for Injection
Chinese Pinyin:ZhusheyongAisi'Aomeilazuone
[Dhis]]
The main ingredients are: esomeprazole sodium
The chemical name is:5-Methoxy-2-[(S)-[(4-methoxy-3,5-Dimethyl-2-pyridyl) methyl]sulfinyl]-1H-Benzimidazole sodium salt. The chemical structural formula is:
Molecular formula:C17H18N3O3SNa
Molecular weight:367.40
Excipients: Calcium sodium edetateSodium hydroxide
character]
This product is white or white freeze-dried cake or powder.
indications]
1.As an alternative therapy for gastroesophageal reflux disease when oral therapy is not applicable.
2. Low-risk patients with acute gastric or duodenal ulcer bleeding to whom oral therapy is not applicable (gastroscopicForrestGradingIIc-III)。
[specification]]
40mg(PressC17H19N3O3S)
Usage and dosage]
1.For patients with gastroesophageal reflux disease who cannot take oral medications, recommend daily1 intravenous injection or intravenous drip of this product20~40 mg. Patients with reflux esophagitis should use40mg, daily1times; for symptomatic treatment of reflux disease should be used20mg, daily1Times.This product should usually be used for a short period of time (not more7 days), once possible, should switch to oral treatment.
2.For those who cannot be taken orallyForrest gradingIIc-IIIIn patients with acute gastric or duodenal ulcer bleeding, intravenous infusion of this product is recommend.40mg, every12Once an hour, medication5Day.
method of administration
Medication by injection:The preparation of the solutionintravenous injection timeshould be at leastIn3More than minutes.
Instillation:Prepared solutionIntravenous drip timeShould be in30 minutesInside.
Use guidance
Injection is prepared by adding5ml.0.9% sodium chloride solution into vials for intravenous injection.
The preparation of the drip solution is by adding this product.1 branch dissolved0.9% sodium chloride solution100mlFor intravenous drip use.
The prepared liquid for injection or drip is a colorless to very yellowish clear solution and should be used immediately.
Compatibility taboo
The degradation of the formulated solution has a great impact onThe dependence of pH is very strong, so the drug must be applied in accordance with the instructions for use. This product can only be dissolved in0.9% sodium chloride for intravenous use. The prepared solution should not be mixed with other drugs or combined in the same infusion set.
adverse reaction]
In clinical trials with oral or intravenous administration of esomeprazole and in post-marketing studies with oral administration, the following adverse reactions have been established or suspected. These reactions are divided into the following categories according to their frequency of occurrence(Common>>1%,<10%; occasionally>>0.1%,<1%; rare>>0.01%,<0.1%; very rare<0.01%; frequency unknown(Unable to estimate based on available data)).
1. Eyes:
Occurred: Blurred vision.
2. Ear and lost:
Ocdental: Vertigo.
3. Skin and subcutaneous tissue:
Common: Reaction at the site of administration*
Ocdental: dermatitis, pruritus, rash, urticaria;
Rare: hair loss, photosensitivity;
Very rare: erythema multiform,Stevens-Johnson syndrome, toxic epidermal necrolysis(TEN).
4. Skeletal muscle, connective tissue and bone:
Ocular: hip, wrist, or spine fractures
Rare: arthralgia, myalgia;
Very rare: muscle weakness.
5. Respiration, chest, mediastinum:
Rare: bronchospasm.
6. The digestive system:
Common: Abdominal pain, constipation, diarrhea, bloating, nausea/Vomiting;
Ocdental: dry mouth;
Rare: stomatitis, gastrointestinal candidiasis.
Frequency unknown: microscopic colitis.
7. Hepatobiliary system:
Ocdental: elevated liver enzymes;
Rare: hepatitis with or without jaundice;
Very rare: Encephalopathy in patients with liver failure and previous liver disease.
8. Kidney and urinary system:
Very rare: Interstitial nephritis; renal failure has been reported in some patients.
9. Blood and lymphatic system:
Rare: leukopenia, thrombocytopenia;
Very rare: agranulocytosis, pancytopenia.
10. The immune system:
Rare: Hypersensitivity reactions such as fever, angioedema, and anaphylaxis/shock.
11. Metabolic and nutritional disorders:
Ocular: peripheral edema;
Rare: hyponatremia;
Frequency unknown: hypomagnesemia. Severe hypomagnesemia may be associated with hypocalcemia.
12. Nervous system:
Common: headache;
Ocdental: dizziness, abnormal sensation, drowsiness;
Rare: taste disorders.
13. Mental State:
Ocdental: insomnia;
Rare: agitation, confusion, depression;
Very rare: attacks, hallucinations.
14. Reproductive system and breasts:
Very rare: gynecomastia.
15. Site of administration and general discomfort:
Rare: malaise, sweating.
* Site of administration reactions are mainly seen in a3Day(72Hours)High-dose exposure studies.
Receiving racemic omeprazole(especially high doses)Irreversible visual impairment has been reported in critically ill patients given intravenously, but a causal relationship has not been established.
taboo]
It is contraindicated in persons with known hypersensitivity to esomeprazole, other benzimidazoles or any other component of this product.
This product is prohibited from being used with Nefenavir.(nelfinavir) in combination; not recommend with atazanavir(Atazanavir)Saquinavirin combined use(See [Drug Interactions] for details]).
[Note]]
1.When a patient is suspected of having a stomach ulcer or has already had a stomach ulcer, if abnormal symptoms occur(Such as obvious unintentional weight loss, repeated vomiting, difficulty swallowing, hematemesis or melena)The possibility of malignant tumors should be ruled out first.Sex. Because the use of this product treatment can reduce symptoms, delay diagnosis.
Proton pump inhibitors may slightly increase the risk of gastrointestinal infections (eg, Salmonella and Campylobacter) (see Pharmacology and Toxicology).
It is not recommended to use this product in combination with atazanavir (see Drug Interactions). If atazanavir must be used in combination with a proton pump inhibitor, the dose of atazanavir should be increased400mg(also supplemented with ritonavir100mg); It is recommended to cooperate with close clinical monitoring, and the dose of this product should not exceed20mg.
4.EsomeprazoleAs with all acid-suppressing drugs, vitamins may be reduced due to reduced or deficient stomach acid.B12Absorption of (cyanocobalamin). Vitamins in the body should be considered for patients with long-term medicationB12Reduced storage orVitaminsB12Risk factors for reduced absorption.
5.Esomeprazole is aCYP2C19 inhibitors,When starting or discontinuing treatment with esomeprazole,Consideration should be given to its relationship with otherPotential interactions between drugs that CYP2C19 metabolism.Interactions between clopidogrel and omeprazole have been observed(See No.Section 4.5),The clinical relevance of this interaction is unclear.. As a precaution, it is not recommendedOmeprazole combined with clopidogrel.
6. Accept at least3months as well as the vast majority in one year of acceptancePPI(such as esomeprazole)Cases of severe hypomagnesaemia have been reported in treated patients. Severe clinical manifestations of hypomagnesemia, such as fatigue, tetany, delirium, convulsions, dizziness, and ventricular arrhythmias, may occur, but they are often cryptic at first and thus ignored. In most patients, after magnesium supplementation therapy and discontinuationPPIAfter that, hypomagnesemia improved.
Expected need to extendPPI therapy or concomitant medications such as digoxin may cause hypomagnesemia(For example, diuretics)of the drugs that medical professionals may consider in the beginningPPIBlood magnesium concentrations were monitored prior to treatment and at regular intervals.
7. Proton pump inhibitors, especially when using high doses and long-term medication(>1Year)May increase the risk of hip, wrist and spine fractures, primarily in the elderly or in patients with other known risk factors. Observational studies suggest that proton pump inhibitors increase the overall risk of fracture10~40%. Some of these may also be due to other risk factors. Patients at risk of osteoporosis should be treated according to current clinical guidelines and take appropriate amounts of vitaminsDand calcium.
8. Interference with laboratory tests
Interfering with the examination of neuroendocrine tumors. During treatment with antacid drugs, decreased gastric acid secretion leads to increased serum gastrin. Decreased gastric acidity can also cause chromograninA(CgA) increased.CgAElevated levels may interfere with the examination of neuroendocrine tumors, which has been reported in the literature.CgABefore level detection, at least pausePPITreatment5Day. If5days laterCgAand gastrin levels do not return to normal and should be stopped after treatment with esomeprazole14Day review.
9.No dose adjustment is required in patients with impaired renal function. Due to the limited experience of using this product in patients with severe renal insufficiency, treatment should be cautious(See【pharmacokinetics]]).
10.Patients with impaired liver function during high-dose esomeprazole after endoscopic hemostasis for peptic ulcer bleeding80mg IV bolus dose does not need to be adjusted,with mild to moderate hepatic impairment (Child-Pugh A和Blevel), the maximum continuous drip rate does not exceed6mg/h; Patients with severe liver damage(Child-Pugh Class C) maximum sustained drip rate not exceeding4mg/h. Treatment of adultsDose adjustment is not required in patients with mild to moderate hepatic impairment in GERD. The daily dose in patients with severe hepatic impairment should not exceed20mg(See Pharmacokinetics]).
11.Impact on the ability to drive and use machines: This has not been observed.
Medication for pregnant and lactating women]
Clinical data on the use of esomeprazole in pregnant women are limited. Animal experiments have not shown that esomeprazole has a direct or indirect impairment of the animal embryo or fetal development. with the racemic mixture(Omeprazole)Animal experiments have also not shown any direct or indirect harmful effects on animal pregnancy, parturition, or postnatal development. However, the use of esomeprazole in pregnant women should be cautious.
It is not known whether esomeprazole is excreted in human milk. It has also not been studied in lactating women and should not be used during lactation.
children's medication]
Esomeprazole should not be used in children as data are not available.
elderly medication]
No dose adjustment is required in elderly patients.
drug interaction]
1, EssoEffect of Meprazole on the Pharmacokinetics of Other Drugs
absorptionDrugs affected by pH:
(1)Absorption of drugs whose absorption process is affected by gastric acid may be increased or decreased due to a decrease in gastric acid during treatment with RETIN. As with other acid secretion inhibitors or antacids, the absorption of ketoconazole, itraconazole and erlotinib decreases and the absorption of digoxin increases during treatment. Healthy subjects receiving omeprazole(20mg/day)and digoxin increase the bioavailability of digoxin10%(10Example subjects have2cases increased30%). Rare reports of digoxin toxicity. However, caution should be exercised in elderly patients treated with high doses of esomeprazole, and monitoring of therapeutic digoxin levels should be enhanced.
(2)Omeprazole has been reported to interact with some protease inhibitors, but the clinical significance and mechanism of these drug interactions are not very clear. Increased gastrointestinal tract during omeprazole treatmentpH, may change the absorption of other protease inhibitors, and other possible mechanisms are through inhibitionCYP2C19Enzymes cause drug interactions. It has also been reported that the serum concentrations of atazanavir and nelfenavir are reduced when given in combination with omeprazole, so the combined use is not recommended. Concomitantly taking omeprazole in healthy volunteers40mgOnce daily and atazanavir300mg/Ritonavir(ritonavir)100mg, can reduce the drug exposure of atazanavir(AUC, CmaxandCminapproximately reduced75%). The dose of atazanavir was increased400mgNor does it compensate for the effects of omeprazole. proton pump inhibitor(Including this product)Concomitant administration with atazanavir is not recommend.
Healthy volunteers Omeprazole(20mg once daily)with atazanavir400mg/Ritonavir100mgExposure to atazanavir due to combination versus non-combination(Azzanavir300mg/Ritonavir100mgOnce-daily monotherapy)When the exposure is reduced compared to approx.30%. Combined use of omeprazole(40mg, daily1Times)make nelferavir'sAUC, CmaxandCmindown.36~39%its pharmacologically active metabolitesM8the averageAUC, CmaxandCminDescent75~92%. For saquinavir(Saquinavir) (concomitant with ritonavir), has been reported in combination with omeprazole(40mg, daily1Times)when the serum concentration increases(80~100%). Omeprazole20mgOnce-daily treatment for dirunavir(darunavir)(concomitant with ritonavir)and Aminavir(Amprenavir) (concomitant with ritonavir)The exposure had no effect. Use of esomeprazole20mg, once daily to Ampriavir(With or without ritonavir)The exposure had no effect. Use of omeprazole40mg, once a day against Lopinavir(lopinavir)(concomitant with ritonavir)The exposure had no effect. Since omeprazole and esomeprazole have similar pharmacodynamic and pharmacodynamic properties, the combination of this product with atazanavir is not recommend, and the combination of this product with nelfenavir is prohibited.
ByCYP2C19 Metabolized Drugs:
(3)CYP2C19 is the main metabolic enzyme of esomeprazole, so when this product is related toCYP2C19Metabolic drugs(Such as diazepam, citalopram, imipramine, clomipramine, phenytoin and so on)When combined, the plasma concentrations of these drugs may be elevated, and dose reductions may be required. Concomitant oral esomeprazole30mgCan makeCYP2C19Decreased clearance of metabolic diazepam45%. coadministration of oral esomeprazole40mgCan increase the trough concentration of plasma phenytoin in patients with epilepsy13%. Therefore, monitoring of phenytoin plasma levels during phenytoin therapy is recommended when conotherapy is initiated or discontinued. Omeprazole40mgOnce-daily use increased voriconazole(Voriconazolea kindCYP2C19substrate) CmaxandAUCτ, respectively.15%and41%.
(4)Clinical trials have shown that oral esomeprazole is used in patients treated with warfarin40mg, the clotting time is within the acceptable range. However, esomeprazole oral formulations have been reported post-marketing, and individual cases have clinically significantINR(International Normalized Ratio)Rising. Therefore, it is recommended to monitor the blood concentration of warfarin during treatment with warfarin or other coumarin derivatives when starting conotherapy or discontinuation of this product.
Omeprazole and esomeprazole areCYP2C19inhibitors, in a crossover study, healthy subjects receivedAfter administration of 40mg omeprazole, cilostazolCmaxandAUCIncrease separately18% and26%An active metabolite of cilostazolCmaxandAUCIncrease separately29% and69%.
(5)In healthy volunteers, co-administered oralAsiOMeprazole40 mg, which can increase the blood concentration of cisapride-Area under the time curve(AUC)Increase32%, elimination half-life(t1/2)Extension31%, but did not significantly increase the plasma peak concentration of cisapride. The combination of this product will not aggravate the effect caused by cisapride alone.QTcSlight prolongation of the interval.
(6) The study showed no clinically relevant effect on the pharmacokinetics of amoxicillin or quinidine.
(7)No response to high-dose intravenous regimens(80mg 8mg/h) conducted an in vivo interaction study, under which esomeprazole was administeredCYP2C19Metabolic effects of drugs may be more pronounced,During the periodDuring the 3-day intravenous administration, patients should be closely monitored for adverse reactions.
(8) The results of studies in healthy subjects showed that clopidogrel(300mgloading dose/75mgdaily maintenance dose)and esomeprazole(40mg p.o.daily dose)between which pharmacokinetics will occur(PK)/pharmacodynamics(PD)interaction, resulting in an average decrease in exposure to the active metabolite of clopidogrel40%, which ultimately leads to maximal inhibition of platelet aggregation(ADPinduction)Average decline14%.
(9) Clopidogrel versus esomeprazole in healthy subjects20mg Aspirin(ASA) 81mgThe exposure to the active metabolite of clopidogrel decreased by almost40%. However, the clopidogrel group and the clopidogrel+compound preparation(EsomeprazoleASA)Maximum inhibition level of platelet aggregation in subjects in the group(ADPinduction)Same.
(10) In both observational and clinical studies, esomeprazole was reported.PK/PDSignificant cardiovascular events resulting from the interaction resulted in data inconsistent with clinical effects. Therefore, among the precautions, it is proposed that simultaneous use with clopidogrel is not encouraged.
Unknown mechanism of action
(11) Concomitant administration with esomeprazole has been reported to increase serum levels of tacrolimus.
(12) has been reported, in some patients,PPIThe level of methotrexate was elevated at the time of concomitant medication. In the case of high-dose methotrexate, suspension of esomeprazole therapy may be considered.
2,Other drugsIsoEffect of Meprazole on Pharmacokinetics:
EsomeprazoleCYP2C19 andCYP3A4Metabolism. Simultaneous oral esomeprazole andCYP3A4Inhibitor Clarithromycin(500mgTwice daily), can make the body's exposure to esomeprazole(AUC)Double it. Esomeprazole.CYP2C19,CYP3A4Co-inhibitor co-administration increased esomeprazole exposure more than twofold.CYP2C19andCYP3A4The inhibitor of voriconazole increases omeprazoleAUCτ280%. In both cases the dose of esomeprazole need not be adjusted regular. However, for patients with severe liver damage and requiring long-term treatment, consideration should be given to adjusting the dose of this product.
Known inducibleCYP2C19 orCYP3A4or drugs that induce both(such as rifampicin and hypericum perforatum) can be enhancedAsiOMetabolism of merprazole resulting inAsiOReduced serum levels of meprazole.
drug overdose]
Experience with excessive use of this product is very limited. patient oral esomeprazoleAfter 280mg, the symptoms were mainly gastrointestinal symptoms and weakness. patient a single oral dose of esomeprazole80mgand24Intravenous administration of esomeprazole within hours308mgAfter no abnormal reaction. There is no known specific antidote for esomeprazole. Esomeprazole binds extensively to plasma proteins and is therefore difficult to dialyze. Treatment of any overdose-induced intoxication should be symptomatic and supportive.
pharmacology and toxicology]
Pharmacological effects:
This product is a specific inhibitor of proton pump in gastric parietal cells.AsiOmeprazole is omeprazole'sS-isomer, through specific proton pump inhibition, reduces gastric acid secretion, omeprazoleR-isomers andS-The isomers have similar pharmacodynamic properties.
AsiOmeprazole is a weakly basic drug that is concentrated in the high acid environment of parietal cell acid-secreting microtubules and converted to an active form, thereby inhibitingH+/K+-ATPEnzymes (proton pumps) that inhibit both basal and stimulated gastric acid secretion.
gastroesophageal reflux disease(GERD) patients daily oralAsiOmeprazole20 mg and40 mg,5day after its24Within hours to maintain the stomachpH>4The average time is13hours and17Hours.AsiThe effect of oral or intravenous administration of omeprazole was similar.
UseAUC (blood drug concentration-Area under the time curve)The relationship between inhibition of gastric acid secretion and drug exposure after oral administration can also be shown.
Healthy Subjects Receiving80mg esomeprazole (30minute IV bolus administration) followed by continuous IV infusion23.5Hours (8mg/h), in24Within hours, inside the stomachpH>4, andpH>6The average duration21hours and11~13Hours.
Oral administration in patients with reflux esophagitisAsiOmeprazole40 mg for 4 weeks, the healing rate was approximately78%,8Weeks later93%.
Enterochromaffin-like patterns were observed in some children and adults treated with esomeprazole for a long time(ECL) cells, which may be related to the increase of serum gastrin levels. These findings were not considered clinically significant.
Some increase in the incidence of gastric gland cysts has been reported during long-term antacid therapy. These reactions are physiological responses following significant inhibition of acid secretion, which are benign and reversible.
Use of any means including proton pump inhibitors to reduce gastric acidity,increases the bacteria in the stomach(usually present in the gastrointestinal tract). UseProton pump inhibitor therapy may cause gastrointestinal infections(such as Salmonella and Campylobacter) slightly increased risk. There may also be a slightly increased risk of gastrointestinal infections caused by C. difficile in hospitalized patients.
PoisonSexResearch:
rat oral racemic mixture(Omeprazole)Carcinogenicity study finds gastric enterochromaffin-like(ECL)Cell hyperplasia and carcinoid. These effects are secondary to a sustained decrease in gastric acid production and marked hypergastrinemia in rats after long-term use of inhibitors of gastric acid secretion. In a non-clinical study on intravenous esomeprazole, subcutaneous(paravenous)There was no evidence of vascular irritation after injection, but a slight tissue inflammatory reaction was noted at the injection site.
pharmacokinetics]
1.absorption andDistribution
The apparent volume of distribution at steady state in healthy subjects is approximately0.22L/kg body weight. The plasma protein binding rate of this product is97%.
2.metabolism and excretion
This product is completely cytochromeP450 enzyme system(CYP)Metabolism. Most of the metabolism of this product depends on specific isozymesCYP2C19to produce the hydroxylates and demethylated metabolites of esomeprazole. The remainder relies on another specific isozymeCYP3A4Metabolized to produce esomeprazole sulfone, which is the main metabolite in plasma.
The following parameters mainly reflectPharmacokinetic profiles of individuals with normal CYP2C19 function, I .e., fast metabolizers.
Total plasma clearance after a single dose of about17L/h, after many times of medication is about9L/h. Plasma elimination half-life after repeated daily dosing is approximately1.3Hours. Increased exposure to esomeprazole after repeated dosing, dose-dependent, but can lead to non-linear dosing after repeated dosing/Exposure relationships. This time and dose dependence is due to a decrease in first pass metabolism and total body clearance, which may be caused by esomeprazole and(or)Its metabolite esomeprazole sulfone inhibitsCYP2C19.
When dosed once a day, the product is completely eliminated from the plasma during the two doses, with no tendency to accumulate. Multiple intravenous injectionsAfter 40mg, the mean peak plasma concentration was approximately13.6mmol/L. The mean peak plasma concentration after oral administration of the corresponding dose was approximately4.6mmol/L. A small increase in total exposure after intravenous administration compared to oral administration(About30%). Esomeprazole30minute intravenous infusion administration(40mg,80mgor120mg)After continuous infusion administration(4mg/hor8mg/h)up23.5hours, the total exposure increased linearly with dose.
The main metabolites of this product have no effect on gastric acid secretion. After a single oral dose, nearly80% of esomeprazole is excreted in the urine in the form of metabolites, the rest is excreted in the feces. The original drug in the urine is less1%.
3.Special patient groups
About in the Western crowd.1 ~3%The individual lacks an activeCYP2C19enzymes, called slow metabolizers; and the proportion of slow metabolizers in the Asian population is about13~23%. This part of the individual may be mainly through.CYP3A4Metabolized esomeprazole. Oral esomeprazole once daily40mgMean total exposure of slow metabolizers after repeated administration(AUC)than having activityCYP2C19the individual(Fast metabolizer)high near100%, mean peak plasma concentrations increased by about60%. Similar differences were observed with intravenous administration of this product. These findings were not related to the dose of esomeprazole.
This product in the elderly(71~80year old)There was no significant change in metabolism.
Single oral administration of esomeprazoleAfter 40mg, the average total exposure of women exceeds that of men by about30%. No gender differences were observed after repeated once-daily dosing. Similar differences were observed with intravenous esomeprazole. These findings were independent of the dose of esomeprazole.
In patients with mild to moderate hepatic impairment, the metabolism of esomeprazole may be impaired. Increased exposure to esomeprazole due to decreased metabolic rate in patients with severe hepatic impairment1 times. Therefore, severe liver damageGERDThe maximum dose used by the patient should not exceed20mg.
There is no tendency for the product or its major metabolites to accumulate when administered once daily.
Patients with impaired liver function during high-dose esomeprazole after endoscopic hemostasis for peptic ulcer bleeding80mg IV bolus dose without adjustment with mild to moderate hepatic impairment (Child-Pugh AandBlevel), the maximum continuous drip rate does not exceed6mg/h; Patients with severe liver damage (Child-Pugh Clevel) the maximum continuous drip rate does not exceed4mg/h.
Similar studies have not been conducted in patients with reduced renal function. Since the kidneys are responsible only for the excretion of metabolites of this product and not the original drug, the metabolism of this product is not expected to change in patients with renal impairment.
storage]
Shading,sealed preservation.
[packaging]]
Medium borosilicate glass regulated injection bottle/Halogenated butyl rubber stopper (brominated) with partially coated polytetrafluoroethylene membrane for freeze-dried injectionCarton packaging,1/Box or 10 p/ box.
[validity period]]
24 months
[executive standard] YBH03162020
[Approval No.] Chinese Medicine H20203449
【Drug marketing authorization holder]]
Name: Zhejiang Jianfeng Pharmaceutical Co., Ltd.
Registered Address:Gao Fan Section of Baitang Downline in Wucheng District, Jinhua City, Zhejiang Province58No.X02 Office Quality Inspection Building, 2nd Floor
production enterprise]
Company: Zhejiang Jianfeng Pharmaceutical Co., Ltd.
Production Address: Gaofan Section of Baitang Lower Line, Wucheng District, Jinhua City, Zhejiang Province58No.
Postal Code:321075
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