SURVANTA(beractant)气管内悬液获FDA批准防止早产儿呼吸障碍 药物名称:Survanta气管内susp 8毫升，4毫升（Beractant)  外观标记:白色液体、透明玻璃瓶　　　　    廠牌 Manufactory 艾伯維　Ａｂｂｖｉｅ  臨床用途:治療呼吸窘迫症候群（需冷貯，勿冷凍）　　　　　　　　　　　　　　　　　 Clinical uses For respiratory distress syndrome 包裝規格 SURVANTA SUSP VIAL 8ML  BERACTANT  ABBVIE  00074-1040-08 SURVANTA SUSP VIAL 4ML  BERACTANT  ABBVIE  00074-1040-04 -------------------------------------------------------------- SURVANTA(beractant)suspension SURVANTA(beractant) (beractant) intratracheal suspension Sterile Suspension ForIntratracheal Administration Only DESCRIPTION SURVANTA ® (beractant) Intratracheal Suspension is a sterile, non-pyrogenicpulmonary surfactant intended for intratracheal use only. It is anatural bovine lung extract containing phospholipids, neutral lipids,fatty acids, and surfactant-associated proteins to which colfoscerilpalmitate (dipalmitoylphosphatidylcholine), palmitic acid, and tripalmitinare added to standardize the composition and to mimic surface-tensionlowering properties of natural lung surfactant. The resulting compositionprovides 25 mg/mL phospholipids (including 11.0-15.5 mg/mL disaturatedphosphatidylcholine), 0.5-1.75 mg/mL triglycerides, 1.4-3.5 mg/mLfree fatty acids, and less than 1.0 mg/mL protein. It is suspendedin 0.9% sodium chloride solution, and heat-sterilized. SURVANTA containsno preservatives. Its protein content consists of two hydrophobic,low molecular weight, surfactant-associated proteins commonly knownas SP-B and SP-C. It does not contain the hydrophilic, large molecularweight surfactant-associated protein known as SP-A. Each mL of SURVANTA contains 25 mg of phospholipids. It is an off-whiteto light brown liquid supplied in single-use glass vials containing4 mL (100 mg phospholipids) or 8 mL (200 mg phospholipids). CLINICAL PHARMACOLOGY Endogenous pulmonary surfactantlowers surface tension on alveolar surfaces during respiration andstabilizes the alveoli against collapse at resting transpulmonarypressures. Deficiency of pulmonary surfactant causes RespiratoryDistress Syndrome (RDS) in premature infants. SURVANTA replenishessurfactant and restores surface activity to the lungs of these infants. Activity In vitro, SURVANTA reproducibly lowersminimum surface tension to less than 8 dynes/cm as measured by thepulsating bubble surfactometer and Wilhelmy Surface Balance. In situ, SURVANTA restores pulmonarycompliance to excised rat lungs artificially made surfactant-deficient. In vivo, single SURVANTA dosesimprove lung pressure-volume measurements, lung compliance, and oxygenationin premature rabbits and sheep. Animal Metabolism SURVANTA is administereddirectly to the target organ, the lungs, where biophysical effectsoccur at the alveolar surface. In surfactant-deficient premature rabbitsand lambs, alveolar clearance of radio-labelled lipid components ofSURVANTA is rapid. Most of the dose becomes lung-associated withinhours of administration, and the lipids enter endogenous surfactantpathways of reutilization and recycling. In surfactant-sufficientadult animals, SURVANTA clearance is more rapid than in prematureand young animals. There is less reutilization and recycling of surfactantin adult animals. Limited animal experiments have not found effects of SURVANTA onendogenous surfactant metabolism. Precursor incorporation and subsequentsecretion of saturated phosphatidylcholine in premature sheep arenot changed by SURVANTA treatments. No information is available about the metabolicfate of the surfactant-associated proteins in SURVANTA. The metabolicdisposition in humans has not been studied. Clinical Studies Clinical effectsof SURVANTA were demonstrated in six single-dose and four multiple-doserandomized, multi-center, controlled clinical trials involving approximately1700 infants. Three open trials, including a Treatment IND, involvedmore than 8500 infants. Each dose of SURVANTA in all studies was 100mg phospholipids/kg birth weight and was based on published experiencewith Surfactant TA, a lyophilized powder dosage form of SURVANTA havingthe same composition. Prevention Studies Infants of 600-1250g birth weight and 23 to 29 weeks estimated gestational age were enrolledin two multiple-dose studies. A dose of SURVANTA was given within15 minutes of birth to prevent the development of RDS. Up to threeadditional doses in the first 48 hours, as often as every 6 hours,were given if RDS subsequently developed and infants required mechanicalventilation with an FiO2 ≥ 0.30. Results of thestudies at 28 days of age are shown in Table 1. Table 1. Study 1 SURVANTA Control P-Value Number infants studied 119 124 Incidence of RDS (%) 27.6 63.5 < 0.001 Death due to RDS (%) 2.5 19.5 < 0.001 Death or BPD due to RDS (%) 48.7 52.8 0.536 Death due to any cause (%) 7.6 22.8 0.001 Air Leaksa (%) 5.9 21.7 0.001 Pulmonary interstitial emphysema (%) 20.8 40.0 0.001 Study 2b SURVANTA Control P-Value aPneumothorax or pneumopericardiumbStudy discontinued when Treatment IND initiated cNocause of death in the SURVANTA group was significantly increased;the higher number of deaths in this group was due to the sum of allcauses. Number infants studied 91 96 Incidence of RDS (%) 28.6 48.3 0.007 Death due to RDS (%) 1.1 10.5 0.006 Death or BPD due to RDS (%) 27.5 44.2 0.018 Death due to any cause C(%) 16.5 13.7 0.633 Air Leaks a(%) 14.5 19.6 0.374 Pulmonary interstitial emphysema (%) 26.5 33.2 0.298 Rescue Studies Infants of 600-1750g birth weight with RDS requiring mechanical ventilation and an FiO2 ≥ 0.40 were enrolled in two multiple-dose rescue studies. The initial dose of SURVANTAwas given after RDS developed and before 8 hours of age. Infants couldreceive up to three additional doses in the first 48 hours, as oftenas every 6 hours, if they required mechanical ventilation and an FiO2 ≥ 0.30. Results of the studies at 28 days of age areshown in Table 2. Table 2. Study 3a SURVANTA Control P-Value Number infants studied 198 193 Death due to RDS (%) 11.6 18.1 0.071 Death or BPD due to RDS (%) 59.1 66.8 0.102 Death due to any cause (%) 21.7 26.4 0.285 Air Leaksb (%) 11.8 29.5 <0.001 Pulmonary interstitial emphysema (%) 16.3 34.0 <0.001 Study 4 SURVANTA Control P-Value aStudy discontinued when Treatment IND initiatedbPneumothoraxor pneumopericardium Number infants studied 204 203 Death due to RDS (%) 6.4 22.3 < 0.001 Death or BPD due to RDS (%) 43.6 63.4 < 0.001 Death due to any cause (%) 15.2 28.2 0.001 Air Leaksb (%) 11.2 22.2 0.005 Pulmonary interstitial emphysema (%) 20.8 44.4 < 0.001 Acute Clinical Effects Marked improvementsin oxygenation may occur within minutes of administration of SURVANTA. All controlled clinicalstudies with SURVANTA provided information regarding the acute effectsof SURVANTA on the arterial-alveolar oxygen ratio (a/APO2), FiO2, and mean airway pressure (MAP) during the first48 to 72 hours of life. Significant improvements in these variableswere sustained for 48-72 hours in SURVANTA-treated infants in foursingle-dose and two multiple-dose rescue studies and in two multiple-doseprevention studies. In the single-dose prevention studies, the FiO2 improved significantly. Indications and Usage SURVANTA is indicated forprevention and treatment (“rescue”) of Respiratory DistressSyndrome (RDS) (hyaline membrane disease) in premature infants. SURVANTAsignificantly reduces the incidence of RDS, mortality due to RDS andair leak complications. Prevention In premature infantsless than 1250 g birth weight or with evidence of surfactant deficiency,give SURVANTA as soon as possible, preferably within 15 minutes ofbirth. Rescue To treat infantswith RDS confirmed by x-ray and requiring mechanical ventilation,give SURVANTA as soon as possible, preferably by 8 hours of age. Contraindications None known. Warnings SURVANTA is intended forintratracheal use only. SURVANTA can rapidly affect oxygenation and lung compliance. Therefore,its use should be restricted to a highly supervised clinical settingwith immediate availability of clinicians experienced with intubation,ventilator management, and general care of premature infants. Infantsreceiving SURVANTA should be frequently monitored with arterial ortranscutaneous measurement of systemic oxygen and carbon dioxide. During the dosing procedure,transient episodes of bradycardia and decreased oxygen saturationhave been reported. If these occur, stop the dosing procedure andinitiate appropriate measures to alleviate the condition. After stabilization,resume the dosing procedure. Precautions General Rales and moistbreath sounds can occur transiently after administration. Endotrachealsuctioning or other remedial action is not necessary unless clear-cutsigns of airway obstruction are present. Increased probability of post-treatment nosocomial sepsis in SURVANTA-treatedinfants was observed in the controlled clinical trials (Table 3). The increased risk for sepsis among SURVANTA-treated infants wasnot associated with increased mortality among these infants. The causativeorganisms were similar in treated and control infants. There wasno significant difference between groups in the rate of post-treatmentinfections other than sepsis. Use of SURVANTA in infants less than 600 g birth weight or greaterthan 1750 g birth weight has not been eva luated in controlled trials. There is no controlled experience with use of SURVANTA in conjunctionwith experimental therapies for RDS (eg, high-frequency ventilationor extracorporeal membrane oxygenation). No information is available on the effects of doses other than 100mg phospholipids/kg, more than four doses, dosing more frequentlythan every 6 hours, or administration after 48 hours of age. Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicitystudies have not been performed with SURVANTA. SURVANTA was negativewhen tested in the Ames test for mutagenicity. Using the maximumfeasible dose volume, SURVANTA up to 500 mg phospholipids/kg/day (approximatelyone-third the premature infant dose based on mg/m2/day)was administered subcutaneously to newborn rats for 5 days. The ratsreproduced normally and there were no observable adverse effects intheir offspring. Adverse Reactions The most commonly reportedadverse experiences were associated with the dosing procedure. Inthe multiple-dose controlled clinical trials, each dose of SURVANTAwas divided into four quarter-doses which were instilled through acatheter inserted into the endotracheal tube by briefly disconnectingthe endotracheal tube from the ventilator. Transient bradycardia occurredwith 11.9% of doses. Oxygendesaturation occurred with 9.8% of doses. Other reactions duringthe dosing procedure occurred with fewer than 1% of doses and includedendotracheal tube reflux, pallor, vasoconstriction, hypotension, endotrachealtube blockage, hypertension, hypocarbia, hypercarbia, and apnea. No deaths occurred during the dosing procedure, and all reactionsresolved with symptomatic treatment. The occurrence of concurrent illnesses common in premature infantswas eva luated in the controlled trials. The rates in all controlledstudies are in Table 3. Table 3. All Controlled Studies Concurrent Event SURVANTA (%) Control (%) P-Valuea aP-value comparing groups in controlled studies Patent ductus arteriosus 46.9 47.1 0.814 Intracranial hemorrhage 48.1 45.2 0.241 Severe intracranial hemorrhage 24.1 23.3 0.693 Pulmonary air leaks 10.9 24.7 < 0.001 Pulmonary interstitial emphysema 20.2 38.4 < 0.001 Necrotizing enterocolitis 6.1 5.3 0.427 Apnea 65.4 59.6 0.283 Severe apnea 46.1 42.5 0.114 Post-treatment sepsis 20.7 16.1 0.019 Post-treatment infection 10.2 9.1 0.345 Pulmonary hemorrhage 7.2 5.3 0.166 When all controlled studieswere pooled, there was no difference in intracranial hemorrhage. However, in one of the single-dose rescue studies and one of the multiple-doseprevention studies, the rate of intracranial hemorrhage was significantlyhigher in SURVANTA patients than control patients (63.3% v 30.8%, P = 0.001; and 48.8% v 34.2%, P = 0.047, respectively). The rate in a Treatment IND involving approximately 8100 infantswas lower than in the controlled trials. In the controlled clinical trials, there was no effect of SURVANTAon results of common laboratory tests: white blood cell count andserum sodium, potassium, bilirubin, and creatinine. More than 4300 pretreatment and post-treatment serum samples fromapproximately 1500 patients were tested by Western Blot Immunoassayfor antibodies to surfactant-associated proteins SP-B and SP-C. NoIgG or IgM antibodies were detected. Several other complications are known to occur in premature infants. The following conditions were reported in the controlled clinicalstudies. The rates of the complications were not different in treatedand control infants, and none of the complications were attributedto SURVANTA. Respiratory lung consolidation, blood from the endotracheal tube,deterioration after weaning, respiratory decompensation, subglotticstenosis, paralyzed diaphragm, respiratory failure. Cardiovascular hypotension, hypertension, tachycardia, ventriculartachycardia, aortic thrombosis, cardiac failure, cardio-respiratoryarrest, increased apical pulse, persistent fetal circulation, airembolism, total anomalous pulmonary venous return. Gastrointestinal abdominal distention, hemorrhage, intestinal perforations,volvulus, bowel infarct, feeding intolerance, hepatic failure, stressulcer. Renal renal failure, hematuria. Hematologic coagulopathy, thrombocytopenia, disseminated intravascularcoagulation. Central Nervous System seizures Endocrine/Metabolic adrenal hemorrhage, inappropriate ADH secretion,hyperphosphatemia. Musculoskeletal inguinal hernia. Systemic fever, deterioration. Follow-Up eva luations To date, no long-termcomplications or sequelae of SURVANTA therapy have been found. Single-Dose Studies Six-month adjusted-agefollow-up eva luations of 232 infants (115 treated) demonstrated noclinically important differences between treatment groups in pulmonaryand neurologic sequelae, incidence or severity of retinopathy of prematurity,rehospitalizations, growth, or allergic manifestations. Multiple-Dose Studies Six-month adjustedage follow-up eva luations have been completed in 631 (345 treated)of 916 surviving infants. There were significantly less cerebralpalsy and need for supplemental oxygen in SURVANTA infants than controls.Wheezing at the time of examination was significantly more frequentamong SURVANTA infants, although there was no difference in bronchodilatortherapy. Finaltwelve-month follow-up data from the multiple-dose studies are availablefrom 521 (272 treated) of 909 surviving infants. There was significantlyless wheezing in SURVANTA infants than controls, in contrast to thesix-month results. There was no difference in the incidence of cerebralpalsy at twelve months. Twenty-four month adjusted age eva luations were completed in 429(226 treated) of 906 surviving infants. There were significantlyfewer SURVANTA infants with rhonchi, wheezing, and tachypnea at thetime of examination. No other differences were found. Overdosage Overdosage with SURVANTAhas not been reported. Based on animal data, overdosage might resultin acute airway obstruction. Treatment should be symptomatic andsupportive. Rales andmoist breath sounds can transiently occur after SURVANTA is given,and do not indicate overdosage. Endotracheal suctioning or other remedialaction is not required unless clear-cut signs of airway obstructionare present. Dosage and Administration For intratracheal administrationonly. SURVANTA shouldbe administered by or under the supervision of clinicians experiencedin intubation, ventilator management, and general care of prematureinfants. Marked improvementsin oxygenation may occur within minutes of administration of SURVANTA. Therefore, frequent and careful clinical observation and monitoringof systemic oxygenation are essential to avoid hyperoxia. Review of audiovisual instructionalmaterials describing dosage and administration procedures is recommendedbefore using SURVANTA. Materials are available upon request from AbbottNutrition. Dosage Each dose of SURVANTAis 100 mg of phospholipids/kg birth weight (4 mL/kg). The SURVANTADosing Chart shows the total dosage for a range of birth weights. SURVANTA DOSING CHART Weight (grams) Total Dose (mL) Weight (grams) Total Dose (mL) 600-650 2.6 1301-1350 5.4 651-700 2.8 1351-1400 5.6 701-750 3.0 1401-1450 5.8 751-800 3.2 1451-1500 6.0 801-850 3.4 1501-1550 6.2 851-900 3.6 1551-1600 6.4 901-950 3.8 1601-1650 6.6 951-1000 4.0 1651-1700 6.8 1001-1050 4.2 1701-1750 7.0 1051-1100 4.4 1751-1800 7.2 1101-1150 4.6 1801-1850 7.4 1151-1200 4.8 1851-1900 7.6 1201-1250 5.0 1901-1950 7.8 1251-1300 5.2 1951-2000 8.0 Four doses ofSURVANTA can be administered in the first 48 hours of life. Dosesshould be given no more frequently than every 6 hours. Directions for Use SURVANTA shouldbe inspected visually for discoloration prior to administration. The color of SURVANTA is off-white to light brown. If settling occursduring storage, swirl the vial gently (DO NOT SHAKE) to redisperse.Some foaming at the surface may occur during handling and is inherentin the nature of the product. SURVANTA is stored refrigerated (2-8°C). Date and time needto be recorded in the box on front of the carton or vial, wheneverSURVANTA is removed from the refrigerator. Before administration,SURVANTA should be warmed by standing at room temperature for at least20 minutes or warmed in the hand for at least 8 minutes. Artificialwarming methods should not be used. If a prevention dose is to begiven, preparation of SURVANTA should begin before the infant’sbirth. Unopened,unused vials of SURVANTA that have been warmed to room temperaturemay be returned to the refrigerator within 24 hours of warming, andstored for future use. SURVANTA SHOULD NOT BE REMOVED FROM THE REFRIGERATORFOR MORE THAN 24 HOURS. SURVANTA SHOULD NOT BE WARMED AND RETURNEDTO THE REFRIGERATOR MORE THAN ONCE. Each single-use vial of SURVANTAshould be entered only once. Used vials with residual drug shouldbe discarded. SURVANTA does not require reconstitution or sonication before use. Dosing Procedures General SURVANTA is administeredintratracheally by instillation through a 5 French end-hole catheter. The catheter can be inserted into the infant’s endotrachealtube without interrupting ventilation by passing the catheter througha neonatal suction valve attached to the endotracheal tube. Alternatively,SURVANTA can be instilled through the catheter by briefly disconnectingthe endotracheal tube from the ventilator. The neonatal suction valve used for administeringSURVANTA should be a type that allows entry of the catheter into theendotracheal tube without interrupting ventilation and also maintainsa closed airway circuit system by sealing the valve around the catheter. If the neonatal suctionvalve is used, the catheter should be rigid enough to pass easilyinto the endotracheal tube. A very soft and pliable catheter maytwist or curl within the neonatal suction valve. The length of thecatheter should be shortened so that the tip of the catheter protrudesjust beyond the end of the endotracheal tube above the infant’scarina. SURVANTA should not be instilled into a mainstem bronchus. To ensure homogenousdistribution of SURVANTA throughout the lungs, each dose is dividedinto four quarter-doses. Each quarter-dose is administeredwith the infant in a different position. The recommended positionsare: Head and body inclined 5-10° down, head turned to the right Head and body inclined 5-10° down, head turned to the left Head and body inclined 5-10° up, head turned to the right Head and body inclined 5-10° up, head turned to the left The dosing procedureis facilitated if one person administers the dose while another personpositions and monitors the infant. First Dose Determine the totaldose of SURVANTA from the SURVANTA dosing chart based on the infant’sbirth weight. Slowly withdraw the entire contents of the vial intoa plastic syringe through a large-gauge needle (eg, at least 20 gauge).Do not filter SURVANTA and avoid shaking. Attach the premeasured 5 French end-hole catheter to the syringe. Fill the catheter with SURVANTA. Discard excess SURVANTA throughthe catheter so that only the total dose to be given remains in thesyringe. Beforeadministering SURVANTA, assure proper placement and patency of theendotracheal tube. At the discretion of the clinician, the endotrachealtube may be suctioned before administering SURVANTA. The infant shouldbe allowed to stabilize before proceeding with dosing. In the prevention strategy,weigh, intubate and stabilize the infant. Administer the dose assoon as possible after birth, preferably within 15 minutes. Positionthe infant appropriately and gently inject the first quarter-dosethrough the catheter over 2-3 seconds. After administration of the first quarter-dose, remove the catheterfrom the endotracheal tube. Manually ventilate with a hand-bag withsufficient oxygen to prevent cyanosis, at a rate of 60 breaths/minute,and sufficient positive pressure to provide adequate air exchangeand chest wall excursion. In the rescue strategy, the first dose should be given as soon aspossible after the infant is placed on a ventilator for managementof RDS. In the clinical trials, immediately before instilling thefirst quarter-dose, the infant’s ventilator settings were changedto rate 60/minute, inspiratory time 0.5 second, and FiO2 1.0. Positionthe infant appropriately and gently inject the first quarter-dosethrough the catheter over 2-3 seconds. After administration of thefirst quarter-dose, remove the catheter from the endotracheal tubeand continue mechanical ventilation. In both strategies, ventilate the infant for at least 30 secondsor until stable. Reposition the infant for instillation of the nextquarter-dose. Instill the remaining quarter-doses using the same procedures. Afterinstillation of each quarter-dose, remove the catheter and ventilatefor at least 30 seconds or until the infant is stabilized. After instillationof the final quarter-dose, remove the catheter without flushing it.Do not suction the infant for 1 hour after dosing unless signs ofsignificant airway obstruction occur. After completion of the dosing procedure, resume usual ventilatormanagement and clinical care. Repeat Doses The dosage of SURVANTAfor repeat doses is also 100 mg phospholipids/kg and is based on theinfant’s birth weight. The infant should not be reweighedfor determination of the SURVANTA dosage. Use the SURVANTA DosingChart to determine the total dosage. The need for additional doses of SURVANTA is determined by evidenceof continuing respiratory distress. Using the following criteriafor redosing, significant reductions in mortality due to RDS wereobserved in the multiple-dose clinical trials with SURVANTA. Dose no sooner than 6hours after the preceding dose if the infant remains intubated andrequires at least 30% inspired oxygen to maintain a PaO2 less than or equal to 80 torr. Radiographic confirmation of RDS should be obtained before administeringadditional doses to those who received a prevention dose. Prepare SURVANTA andposition the infant for administration of each quarter-dose as previouslydescribed. After instillation of each quarter-dose, remove the dosingcatheter from the endotracheal tube and ventilate the infant for atleast 30 seconds or until stable. In the clinical studies, ventilator settings used to administer repeatdoses were different than those used for the first dose. For repeatdoses, the FiO2 was increased by 0.20 or an amount sufficientto prevent cyanosis. The ventilator delivered a rate of 30/minutewith an inspiratory time less than 1.0 second. If the infant’s pretreatment rate was 30 or greater,it was left unchanged during SURVANTA instillation. Manual hand-bag ventilation should not be used to administer repeatdoses. During the dosing procedure, ventilator settings may be adjustedat the discretion of the clinician to maintain appropriate oxygenationand ventilation. After completion of the dosing procedure, resume usual ventilatormanagement and clinical care. Dosing Precautions If an infant experiencesbradycardia or oxygen desaturation during the dosing procedure, stopthe dosing procedure and initiate appropriate measures to alleviatethe condition. After the infant has stabilized, resume the dosingprocedure. Rales and moist breath sounds can occur transiently after administrationof SURVANTA. Endotracheal suctioning or other remedial action is unnecessaryunless clear-cut signs of airway obstruction are present. How Supplied SURVANTA (beractant) IntratrachealSuspension is supplied in single-use glass vials containing 4 mL (NDC0074-1040-04) or 8 mL of SURVANTA (NDC 0074-1040-08). Each millilitercontains 25 mg of phospholipids suspended in 0.9% sodium chloridesolution. ——surfaxin是在美国批准用于治疗早产儿呼吸障碍的第五种药物 早产儿的肺部无法产生足够的表面活性剂，如果不能及时使保持他们呼吸通畅。大多数婴儿会在在出生时或出生后的头几个小时内的缺氧导致严重的不良后果。 surfaxin是在美国批准用于治疗早产儿呼吸障碍的第五种药物。美国食品与药品监督管理局（FDA）批准的其他表面活性剂包括Survanta（beractant），固尔苏（poractant阿尔法），Infasurf（calfactant），Exosurf（colfosceril棕榈酸酯）已不再销售。 这次获得批准是基于一个单一的随机，主动控制，多剂量的研究，涉及1294早产儿表现的Surfaxin的安全性和有效性。研究中的婴儿出生后30分钟内使用Surfaxin，Exosurf或Survanta。surfaxin和Exosurf担任本研究主要比较；Survanta作为担任另一个比较。 surfaxin证明在24小时内对早产儿呼吸障碍着的改善，通过两个星期的策略相关的死亡率和出生后，与Exosurf相比，Surfaxin最常见的副作用有关其管理下早产儿的呼吸管（气管插管），包括气管插管回流，皮肤苍白，气管内管阻塞，需要剂量中断。