部份中文SANDOSTATIN[善得定]处方（仅供参考 ） 分类名称 一级分类：内分泌系统药物 二级分类：下丘脑及影响内分泌的药物 三级分类：    药品英文名 Octreotide   药品别名 善得定、生长抑素八肽、善宁、益达生、施他宁[8肽]、Longastatina、Sandostatin、Sandostatine   药物剂型 1.善得定，注射剂：0.1mg(1ml)； 2.施他宁，注射剂：0.1mg(1ml)。   药理作用 本药是一种人工合成的八肽环状化合物，为天然生长抑素的同系物，具有与天然内源性生长抑素类似的作用，但作用较强且持久，血浆半衰期较天然生长抑素延长了30倍（1.5h)，天然生长抑素的半衰期仅为2～3min，因此本品效力更为显著。除了抑制生长激素外，还具有广泛的抑制内分泌和外分泌的作用。其具体作用如下：1.本药可抑制生长激素、促甲状腺激素、胃肠道和胰腺内分泌激素的病理性分泌过多，故可用于突眼性甲状腺肿、肢端肥大症的治疗；抑制胃肠道和胰内分泌胃泌素、血管活性肽、抑胃肽、神经降压素和和胰多肽等，可缓解由胃肠道和胰腺内分泌肿瘤(如胃泌素瘤、血管活性肠肽瘤、高血糖素瘤、胰岛素瘤、类癌综合征等)引起的症状；2.本药可选择性地减少门静脉及其侧支循环的血流量和压力，降低食管胃底曲张静脉的压力，抑制高血糖素的分泌和拮抗高血糖素对内脏血管的扩张作用，而对全身血流动力学影响小，对生长激素和胰升糖素的抑制有选择性的作用。因此本药已成为食管胃底曲张静脉破裂出血治疗的首选药物。3.本药可抑制胆囊排空，抑制缩胆囊素、促胰酶的分泌，减少胰酶分泌，减轻已激活胰酶的损害作用；对胰腺细胞膜有直接保护作用，有利于胰腺病变的恢复；可提高肝、脾、网状内皮系统的抗炎功能，减少胰腺疾病并发症的发生。因此可用于急性胰腺炎和胰腺损伤、胰腺手术期及围手术期的治疗，可预防胰腺术后并发症的发生率。同时，本药对缓解慢性胰腺炎的症状如疼痛亦有很好的疗效；4.本药能抑制胃酸、胃泌素和胃蛋白酶的分泌，对胃酸分泌的抑制作用与质子泵抑制剂相近。可改善胃黏膜的血液供应，对胃肠道黏膜有保护作用，可促进黏膜修复。因此可用于应激性溃疡和消化性溃疡引起的胃肠道大出血的治疗；5.本药可抑制胃肠蠕动，减少胃肠道分泌，增强肠道黏膜对水和钠和吸收。因此可用于一些难治性腹泻和慢性特发性假性肠梗阻的治疗。   药动学 皮下注射后吸收迅速且完全，生物利用度近100%，血浆药物浓度达峰时间为30min～1h，血浆半衰期为72～100min，血浆药物浓度峰值及浓度时间曲线下面积与本品剂量呈正相关。静脉注射后，其消除呈两相性，血浆分布半衰期为10min，消除半衰期为90min，血浆蛋白结合率为65%，与血细胞结合的量可忽略不计。表观分布容积为6L。本品广泛在肝脏代谢，健康受试者肝摄取率为30%～40%，从尿液中收回的原形药物为11%，粪便中为2%以下。血浆清除率为每分钟160ml。 适应证 本药具有多种生理活性，故应用范围广泛。 临床主要用于以下几个方面： 1.门脉高压引起的食管静脉曲张破裂出血； 2.应激性溃疡及消化道出血； 3.重型胰腺炎、胰腺损伤或手术后胰瘘。 4.缓解由胃、肠及胰内分泌系统肿瘤所起的症状。 5.毒性弥漫性甲状腺肿和肢端肥大症。 6.胃肠道瘘管。 7.预防胰腺手术后并发症。 禁忌证 1.对本品过敏者禁用。 2.孕妇及哺乳期妇女禁用。 3.14岁以下儿童禁用。 注意事项 1.慎用： (1)肾功能异常者； (2)胰腺功能异常者； (3)胆石症患者； (4)胰岛素瘤患者(因本药可能增加胰岛素瘤患者低血糖症的严重程度并延长其持续时间)； (5)糖尿病患者。 2.避免短期内同一部位重复注射本药。 不良反应 1.常见注射部位局部不适：表现为注射部位疼痛、红肿、针刺或烧灼感，一般可于15min后缓解。 2.常见胃肠道反应：如食欲缺乏，恶心、呕吐、痉挛性腹痛、腹胀、稀便、腹泻及脂肪泻。 3.由于本药可抑制缩胆囊素分泌，故能抑制胆囊收缩，使胆石症的发生率增高。 4.个别患者长期用药偶见持续高血糖、糖耐量异常(因本药可抑制胰岛素的释放，故可降低患者餐后的糖耐量)。 5.个别患者可发生肝胆功能障碍，如无胆汁淤滞的急性肝炎、血胆红素过多、伴碱性碱酸酶、γ-谷氨酰转移酶增高及肝脏氨基转移酶轻度增高。 6.罕见类似急性肠梗阻伴进行性腹胀、严重上腹痛、腹部触痛和肌紧张。 用法用量 1.皮下注射： (1)应激性溃疡及消化道出血：每次0.1mg，每8小时1次，疗程3～5天。 (2)消化道瘘：每次0.1～0.15mg，每8小时1次，疗程10～14天或直至瘘管闭合。胰瘘量可减少20%～50%。 (3)急性胰腺炎：每次0.1mg，每6小时1次，连用3～7天。 (4)重型胰腺炎：每次0.1mg，每天4次，疗程3～7天。 (5)用于肢端肥大症，初始每次0.05～0.1mg，每隔8～12小时给药1次，连续10～14天，维持量因人而异，特殊情况下可采用较大剂量。 (6)用于胃肠胰内分泌肿瘤，初始每次0.05mg，每天1～3次。 (7)用于突眼性甲亢症：每次0.1mg，隔8小时给药1次。2.静脉给药： (1)上消化道出血：每次0.25mg静脉滴注，并用雷尼替丁50mg静脉注射，每4小时1次。效果与神经垂体后叶素相同，但无不良反应。 (2)门脉高压引起的食管静脉曲张出血：先以0.1mg静脉注射，接着以每次0.5mg，每2小时1次静脉滴注，连用24～48h。肝硬化患者发生食管-胃静脉曲张出血：0.1mg缓慢静注(不少于5min)，随后每小时0.025～0.05mg静脉滴注至少48h。 (3)门静脉高压症：0.02～0.25mg静脉注射，继以每小时0.25mg持续静脉滴注，用药24～72h。效果优于血管紧张素胺。 (4)消化道瘘：每小时0.25mg持续静脉滴注，用药3～4天。 (5)非静脉曲张性消化道大出血：每次3mg静脉滴注，每12小时1次，用药3天。总有效率95%。 3.肌内注射： (1)消化道瘘：每次0.1～0.15mg，每8小时1次；胰瘘量可减少20%～50%。 (2)预防胰、十二指肠切除术肠瘘：0.1mg肌内注射，每8小时1次，用药7天。可预防术后胰腺肿胀，减轻腹痛和胰酶升高，可减少术后急性胰腺炎。 4.蛛网膜下隙注射：癌性疼痛：通过腰蛛网膜下隙导管注入本药0.12～0.48mg，对癌性疼痛和术后疼痛有效，与吗啡无交叉耐药性。 5.混合给药：胰腺外瘘：本药0.1mg加入生理盐水200ml静脉滴注，待每天引流量小于500ml时，改为每次0.1mg皮下注射。   药物相应作用 1.本品可减少环孢素的吸收，延缓对西咪替丁的吸收。 2.对口服降糖药或注射胰岛素的患者应用本品，可增加低血糖的程度，应密切监测血糖并调整降糖药的剂量。 3.本药与酮康唑合用产生协同作用，可降低泌尿系统的氢化可的松分泌。   专家点评 从1984年起，陆续有本品治疗肢端肥大症患者的报道，综合其观察结果，显示生长素/胰岛素样生长因子约有20%～50%恢复正常，但仍有20%使用高剂量仍没有效果。临床上约70%患者得到改善，20%～50%的患者脑垂体瘤变小，有50%患者较大的瘤变小。对48例食管静脉曲张破裂出血者随机分为2组，应用本品组静脉注射每次0.1mg，以后1h静脉滴注0.025mg；垂体后叶素组静脉滴注每分钟0.4U。在6h内的最初控制止血率，应用本品组为88%，垂体后叶素组为50%，有明显差异。24h的完全止血率，两组分别为60%和44%。无论在止血速度、止血量等方面，本品均优于后者。但两组的存活率无明显差别。本品的止血机制在于能选择性减少门静脉及肝脏血流，降低门静脉压力，并能减少曲张食管静脉内血流，降低其压力。 对不能手术治疗的肢端肥大症及肿瘤等有较好的抑制作用，目前在临床广泛应用，对消化道出血也有良好疗效。另有大量临床资料已证实：奥曲肽对急性胰腺炎有治疗作用。由于重症急性胰腺炎时往往存在周围循环不良，故静脉用药较皮下注射更有效。 近年来，生长抑素与生长激素联合应用，对于出血坏死型胰腺炎的治疗在动物试验中已证实有效。 SANDOSTATIN (octreotide acetate) injection, solution [Novartis Pharmaceuticals Corporation] DESCRIPTION Sandostatin® (octreotide acetate) Injection, a cyclic octapeptide prepared as a clear sterile solution of octreotide, acetate salt, in a buffered lactic acid solution for administration by deep subcutaneous (intrafat) or intravenous injection. Octreotide acetate, known chemically as L-Cysteinamide, D-phenylalanyl-L-cysteinyl-L-phenylalanyl-D-tryptophyl-L-lysyl-L-threonyl-N-[2-hydroxy-1-(hydroxymethyl)propyl]-, cyclic (2→7)-disulfide; [R-(R*, R*)] acetate salt, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin. Sandostatin Injection is available as: sterile 1-mL ampuls in 3 strengths, containing 50, 100, or 500 mcg octreotide (as acetate), and sterile 5-mL multi-dose vials in 2 strengths, containing 200 and 1000 mcg/mL of octreotide (as acetate). Each ampul also contains: lactic acid, USP       3.4 mg mannitol, USP       45 mg sodium bicarbonate, USP       qs to pH 4.2 ± 0.3 water for injection, USP       qs to 1 mL Each mL of the multi-dose vials also contains: lactic acid, USP       3.4 mg mannitol, USP       45 mg phenol, USP       5.0 mg sodium bicarbonate, USP       qs to pH 4.2 ± 0.3 water for injection, USP       qs to 1 mL Lactic acid and sodium bicarbonate are added to provide a buffered solution, pH to 4.2 ± 0.3. The molecular weight of octreotide acetate is 1019.3 (free peptide, C49H66N10O10S2) and its amino acid sequence is: CLINICAL PHARMACOLOGY Sandostatin® (octreotide acetate) exerts pharmacologic actions similar to the natural hormone, somatostatin. It is an even more potent inhibitor of growth hormone, glucagon, and insulin than somatostatin. Like somatostatin, it also suppresses LH response to GnRH, decreases splanchnic blood flow, and inhibits release of serotonin, gastrin, vasoactive intestinal peptide, secretin, motilin, and pancreatic polypeptide. By virtue of these pharmacological actions, Sandostatin has been used to treat the symptoms associated with metastatic carcinoid tumors (flushing and diarrhea), and Vasoactive Intestinal Peptide (VIP) secreting adenomas (watery diarrhea). Sandostatin substantially reduces growth hormone and/or IGF-I (somatomedin C) levels in patients with acromegaly. Single doses of Sandostatin have been shown to inhibit gallbladder contractility and to decrease bile secretion in normal volunteers. In controlled clinical trials the incidence of gallstone or biliary sludge formation was markedly increased (see WARNINGS). Sandostatin suppresses secretion of thyroid stimulating hormone (TSH). Pharmacokinetics After subcutaneous injection, octreotide is absorbed rapidly and completely from the injection site. Peak concentrations of 5.2 ng/mL (100-mcg dose) were reached 0.4 hours after dosing. Using a specific radioimmunoassay, intravenous and subcutaneous doses were found to be bioequivalent. Peak concentrations and area under the curve values were dose proportional after intravenous single doses up to 200 mcg and subcutaneous single doses up to 500 mcg and after subcutaneous multiple doses up to 500 mcg t.i.d. (1500 mcg/day). In healthy volunteers the distribution of octreotide from plasma was rapid (tα1/2 = 0.2 h), the volume of distribution (Vdss) was estimated to be 13.6 L, and the total body clearance ranged from 7 L/hr to 10 L/hr. In blood, the distribution into the erythrocytes was found to be negligible and about 65% was bound in the plasma in a concentration-independent manner. Binding was mainly to lipoprotein and, to a lesser extent, to albumin. The elimination of octreotide from plasma had an apparent half-life of 1.7 to 1.9 hours compared with 1-3 minutes with the natural hormone. The duration of action of Sandostatin is variable but extends up to 12 hours depending upon the type of tumor. About 32% of the dose is excreted unchanged into the urine. In an elderly population, dose adjustments may be necessary due to a significant increase in the half-life (46%) and a significant decrease in the clearance (26%) of the drug. In patients with acromegaly, the pharmacokinetics differ somewhat from those in healthy volunteers. A mean peak concentration of 2.8 ng/mL (100-mcg dose) was reached in 0.7 hours after subcutaneous dosing. The volume of distribution (Vdss) was estimated to be 21.6 ± 8.5 L and the total body clearance was increased to 18 L/h. The mean percent of the drug bound was 41.2%. The disposition and elimination half-lives were similar to normals. In patients with renal impairment the elimination of octreotide from plasma was prolonged and total body clearance reduced. In mild renal impairment (ClCR 40-60 mL/min) octreotide t1/2 was 2.4 hours and total body clearance was 8.8 L/hr, in moderate impairment (ClCR 10-39 mL/min) t1/2 was 3.0 hours and total body clearance 7.3 L/hr, and in severely renally impaired patients not requiring dialysis (ClCR <10 mL/min) t1/2 was 3.1 hours and total body clearance was 7.6 L/hr. In patients with severe renal failure requiring dialysis, total body clearance was reduced to about half that found in healthy subjects (from approximately 10 L/hr to 4.5 L/hr). Patients with liver cirrhosis showed prolonged elimination of drug, with octreotide t1/2 increasing to 3.7 hr and total body clearance decreasing to 5.9 L/hr, whereas patients with fatty liver disease showed t1/2 increased to 3.4 hr and total body clearance of 8.2 L/hr. INDICATIONS AND USAGE Acromegaly Sandostatin® (octreotide acetate) is indicated to reduce blood levels of growth hormone and IGF-I (somatomedin C) in acromegaly patients who have had inadequate response to or cannot be treated with surgical resection, pituitary irradiation, and bromocriptine mesylate at maximally tolerated doses. The goal is to achieve normalization of growth hormone and IGF-I (somatomedin C) levels (see DOSAGE AND ADMINISTRATION). In patients with acromegaly, Sandostatin reduces growth hormone to within normal ranges in 50% of patients and reduces IGF-I (somatomedin C) to within normal ranges in 50%-60% of patients. Since the effects of pituitary irradiation may not become maximal for several years, adjunctive therapy with Sandostatin to reduce blood levels of growth hormone and IGF-I (somatomedin C) offers potential benefit before the effects of irradiation are manifested. Improvement in clinical signs and symptoms or reduction in tumor size or rate of growth were not shown in clinical trials performed with Sandostatin; these trials were not optimally designed to detect such effects. Carcinoid Tumors Sandostatin is indicated for the symptomatic treatment of patients with metastatic carcinoid tumors where it suppresses or inhibits the severe diarrhea and flushing episodes associated with the disease. Sandostatin studies were not designed to show an effect on the size, rate of growth or development of metastases. Vasoactive Intestinal Peptide Tumors (VIPomas) Sandostatin is indicated for the treatment of the profuse watery diarrhea associated with VIP-secreting tumors. Sandostatin studies were not designed to show an effect on the size, rate of growth or development of metastases. CONTRAINDICATIONS Sensitivity to this drug or any of its components. WARNINGS Single doses of Sandostatin® (octreotide acetate) have been shown to inhibit gallbladder contractility and decrease bile secretion in normal volunteers. In clinical trials (primarily patients with acromegaly or psoriasis), the incidence of biliary tract abnormalities was 63% (27% gallstones, 24% sludge without stones, 12% biliary duct dilatation). The incidence of stones or sludge in patients who received Sandostatin for 12 months or longer was 52%. Less than 2% of patients treated with Sandostatin for 1 month or less developed gallstones. The incidence of gallstones did not appear related to age, sex or dose. Like patients without gallbladder abnormalities, the majority of patients developing gallbladder abnormalities on ultrasound had gastrointestinal symptoms. The symptoms were not specific for gallbladder disease. A few patients developed acute cholecystitis, ascending cholangitis, biliary obstruction, cholestatic hepatitis, or pancreatitis during Sandostatin therapy or following its withdrawal. One patient developed ascending cholangitis during Sandostatin therapy and died. PRECAUTIONS General Sandostatin® (octreotide acetate) alters the balance between the counter-regulatory hormones, insulin, glucagon and growth hormone, which may result in hypoglycemia or hyperglycemia. Sandostatin also suppresses secretion of thyroid stimulating hormone, which may result in hypothyroidism. Cardiac conduction abnormalities have also occurred during treatment with Sandostatin. However, the incidence of these adverse events during long-term therapy was determined vigorously only in acromegaly patients who, due to their underlying disease and/or the subsequent treatment they receive, are at an increased risk for the development of diabetes mellitus, hypothyroidism, and cardiovascular disease. Although the degree to which these abnormalities are related to Sandostatin therapy is not clear, new abnormalities of glycemic control, thyroid function and ECG developed during Sandostatin therapy as described below. Risk of Pregnancy with Normalization of IGF-1 and GH Although acromegaly may lead to infertility, there are reports of pregnancy in acromegalic women. In women with active acromegaly who have been unable to become pregnant, normalization of GH and IGF-1 may restore fertility. Female patients of childbearing potential should be advised to use adequate contraception during treatment with octreotide. The hypoglycemia or hyperglycemia which occurs during Sandostatin therapy is usually mild, but may result in overt diabetes mellitus or necessitate dose changes in insulin or other hypoglycemic agents. Hypoglycemia and hyperglycemia occurred on Sandostatin in 3% and 16% of acromegalic patients, respectively. Severe hyperglycemia, subsequent pneumonia, and death following initiation of Sandostatin therapy was reported in one patient with no history of hyperglycemia. In patients with concomitant Type I diabetes mellitus, Sandostatin Injection and Sandostatin LAR® Depot (octreotide acetate for injectable suspension) are likely to affect glucose regulation, and insulin requirements may be reduced. Symptomatic hypoglycemia, which may be severe, has been reported in these patients. In non-diabetics and Type II diabetics with partially intact insulin reserves, Sandostatin Injection or Sandostatin LAR Depot administration may result in decreases in plasma insulin levels and hyperglycemia. It is therefore recommended that glucose tolerance and antidiabetic treatment be periodically monitored during therapy with these drugs. In acromegalic patients, 12% developed biochemical hypothyroidism only, 8% developed goiter, and 4% required initiation of thyroid replacement therapy while receiving Sandostatin. Baseline and periodic assessment of thyroid function (TSH, total and/or free T4) is recommended during chronic therapy. In acromegalics, bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias occurred in 9% of patients during Sandostatin therapy. Other EKG changes observed included QT prolongation, axis shifts, early repolarization, low voltage, R/S transition, and early R wave progression. These ECG changes are not uncommon in acromegalic patients. Dose adjustments in drugs such as beta-blockers that have bradycardia effects may be necessary. In one acromegalic patient with severe congestive heart failure, initiation of Sandostatin therapy resulted in worsening of CHF with improvement when drug was discontinued. Confirmation of a drug effect was obtained with a positive rechallenge. Several cases of pancreatitis have been reported in patients receiving Sandostatin therapy. Sandostatin may alter absorption of dietary fats in some patients. In patients with severe renal failure requiring dialysis, the half-life of Sandostatin may be increased, necessitating adjustment of the maintenance dosage. Depressed vitamin B12 levels and abnormal Schilling’s tests have been observed in some patients receiving Sandostatin therapy, and monitoring of vitamin B12 levels is recommended during chronic Sandostatin therapy. Information for Patients Careful instruction in sterile subcutaneous injection technique should be given to the patients and to other persons who may administer Sandostatin Injection. Laboratory Tests Laboratory tests that may be helpful as biochemical markers in determining and following patient response depend on the specific tumor. Based on diagnosis, measurement of the following substances may be useful in monitoring the progress of therapy: Acromegaly: Growth Hormone, IGF-I (somatomedin C) Responsiveness to Sandostatin may be evaluated by determining growth hormone levels at 1-4 hour intervals for 8-12 hours post dose. Alternatively, a single measurement of IGF-I (somatomedin C) level may be made two weeks after drug initiation or dosage change. Carcinoid: 5-HIAA (urinary 5-hydroxyindole acetic acid), plasma serotonin, plasma Substance P VIPoma: VIP (plasma vasoactive intestinal peptide) Baseline and periodic total and/or free T4 measurements should be performed during chronic therapy (see PRECAUTIONS – General). Drug Interactions Sandostatin has been associated with alterations in nutrient absorption, so it may have an effect on absorption of orally administered drugs. Concomitant administration of Sandostatin with cyclosporine may decrease blood levels of cyclosporine and result in transplant rejection. Patients receiving insulin, oral hypoglycemic agents, beta blockers, calcium channel blockers, or agents to control fluid and electrolyte balance, may require dose adjustments of these therapeutic agents. Concomitant administration of octreotide and bromocriptine increases the availability of bromocriptine. Limited published data indicate that somatostatin analogs might decrease the metabolic clearance of compounds known to be metabolized by cytochrome P450 enzymes, which may be due to the suppression of growth hormones. Since it cannot be excluded that octreotide may have this effect, other drugs mainly metabolized by CYP3A4 and which have a low therapeutic index (e.g., quinidine, terfenadine) should therefore be used with caution. Drug Laboratory Test Interactions No known interference exists with clinical laboratory tests, including amine or peptide determinations. Carcinogenesis/Mutagenesis/Impairment of Fertility Studies in laboratory animals have demonstrated no mutagenic potential of Sandostatin. No carcinogenic potential was demonstrated in mice treated subcutaneously for 85-99 weeks at doses up to 2000 mcg/kg/day (8x the human exposure based on body surface area). In a 116-week subcutaneous study in rats, a 27% and 12% incidence of injection site sarcomas or squamous cell carcinomas was observed in males and females, respectively, at the highest dose level of 1250 mcg/kg/day (10x the human exposure based on body surface area) compared to an incidence of 8%-10% in the vehicle-control groups. The increased incidence of injection site tumors was most probably caused by irritation and the high sensitivity of the rat to repeated subcutaneous injections at the same site. Rotating injection sites would prevent chronic irritation in humans. There have been no reports of injection site tumors in patients treated with Sandostatin for up to 5 years. There was also a 15% incidence of uterine adenocarcinomas in the 1250 mcg/kg/day females compared to 7% in the saline-control females and 0% in the vehicle-control females. The presence of endometritis coupled with the absence of corpora lutea, the reduction in mammary fibroadenomas, and the presence of uterine dilatation suggest that the uterine tumors were associated with estrogen dominance in the aged female rats which does not occur in humans. Sandostatin did not impair fertility in rats at doses up to 1000 mcg/kg/day, which represents 7x the human exposure based on body surface area. Pregnancy Category B There are no adequate and well-controlled studies of octreotide use in pregnant women. Reproduction studies have been performed in rats and rabbits at doses up to 16 times the highest recommended human dose based on body surface area and revealed no evidence of harm to the fetus due to octreotide. However, because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. In postmarketing data, a limited number of exposed pregnancies have been reported in patients with acromegaly. Most women were exposed to octreotide during the first trimester of pregnancy at doses ranging from 100-300 mcg/day of Sandostatin s.c. or 20-30 mg/month of Sandostatin LAR, however some women elected to continue octreotide therapy throughout pregnancy. In cases with a known outcome, no congenital malformations were reported. Nursing Mothers It is not known whether octreotide is excreted into human milk. Because many drugs are excreted in human milk, caution should be exercised when octreotide is administered to a nursing woman. Pediatric Use Safety and efficacy of Sandostatin Injection in the pediatric population have not been demonstrated. No formal controlled clinical trials have been performed to evaluate the safety and effectiveness of Sandostatin in pediatric patients under age 6 years. In post-marketing reports, serious adverse events, including hypoxia, necrotizing enterocolitis, and death, have been reported with Sandostatin use in children, most notably in children under 2 years of age. The relationship of these events to octreotide has not been established as the majority of these pediatric patients had serious underlying co-morbid conditions. The efficacy and safety of Sandostatin using the Sandostatin LAR Depot formulation was examined in a single randomized, double-blind, placebo-controlled, six–month pharmacokinetics study in 60 pediatric patients age 6-17 years with hypothalamic obesity resulting from cranial insult. The mean octreotide concentration after 6 doses of 40 mg Sandostatin LAR Depot administered by IM injection every four weeks was approximately 3 ng/ml. Steady-state concentrations was achieved after 3 injections of a 40 mg dose. Mean BMI increased 0.1 kg/m2 in Sandostatin LAR Depot-treated subjects compared to 0.0 kg/m2 in saline control-treated subjects. Efficacy was not demonstrated. Diarrhea occurred in 11 of 30 (37%) patients treated with Sandostatin LAR Depot. No unexpected adverse events were observed. However, with Sandostatin LAR Depot 40 mg once a month, the incidence of new cholelithiasis in this pediatric population (33%) was higher than that seen in other adults indications such as acromegaly (22%) or malignant carcinoid syndrome (24%), where Sandostatin LAR Depot was 10 to 30 mg once a month. Geriatric Use Clinical studies of Sandostatin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. ADVERSE REACTIONS Gallbladder Abnormalities Gallbladder abnormalities, especially stones and/or biliary sludge, frequently develop in patients on chronic Sandostatin® (octreotide acetate) therapy (see WARNINGS). Cardiac In acromegalics, sinus bradycardia (<50 bpm) developed in 25%; conduction abnormalities occurred in 10% and arrhythmias developed in 9% of patients during Sandostatin therapy (see PRECAUTIONS – General). Gastrointestinal Diarrhea, loose stools, nausea and abdominal discomfort were each seen in 34%-61% of acromegalic patients in U.S. studies although only 2.6% of the patients discontinued therapy due to these symptoms. These symptoms were seen in 5%-10% of patients with other disorders. The frequency of these symptoms was not dose-related, but diarrhea and abdominal discomfort generally resolved more quickly in patients treated with 300 mcg/day than in those treated with 750 mcg/day. Vomiting, flatulence, abnormal stools, abdominal distention, and constipation were each seen in less than 10% of patients. In rare instances, gastrointestinal side effects may resemble acute intestinal obstruction, with progressive abdominal distension, severe epigastric pain, abdominal tenderness and guarding. Hypo/Hyperglycemia Hypoglycemia and hyperglycemia occurred in 3% and 16% of acromegalic patients, respectively, but only in about 1.5% of other patients. Symptoms of hypoglycemia were noted in approximately 2% of patients. Hypothyroidism In acromegalics, biochemical hypothyroidism alone occurred in 12% while goiter occurred in 6% during Sandostatin therapy (see PRECAUTIONS – General). In patients without acromegaly, hypothyroidism has only been reported in several isolated patients and goiter has not been reported. Other Adverse Events Pain on injection was reported in 7.7%, headache in 6% and dizziness in 5%. Pancreatitis was also observed (see WARNINGS and PRECAUTIONS). Other Adverse Events 1%-4% Other events (relationship to drug not established), each observed in 1%-4% of patients, included fatigue, weakness, pruritus, joint pain, backache, urinary tract infection, cold symptoms, flu symptoms, injection site hematoma, bruise, edema, flushing, blurred vision, pollakiuria, fat malabsorption, hair loss, visual disturbance and depression. Other Adverse Events <1% Events reported in less than 1% of patients and for which relationship to drug is not established are listed: Gastrointestinal: hepatitis, jaundice, increase in liver enzymes, GI bleeding, hemorrhoids, appendicitis, gastric/peptic ulcer, gallbladder polyp; Integumentary: rash, cellulitis, petechiae, urticaria, basal cell carcinoma; Musculoskeletal: arthritis, joint effusion, muscle pain, Raynaud’s phenomenon; Cardiovascular: chest pain, shortness of breath, thrombophlebitis, ischemia, congestive heart failure, hypertension, hypertensive reaction, palpitations, orthostatic BP decrease, tachycardia; CNS: anxiety, libido decrease, syncope, tremor, seizure, vertigo, Bell’s Palsy, paranoia, pituitary apoplexy, increased intraocular pressure, amnesia, hearing loss, neuritis; Respiratory: pneumonia, pulmonary nodule, status asthmaticus; Endocrine: galactorrhea, hypoadrenalism, diabetes insipidus, gynecomastia, amenorrhea, polymenorrhea, oligomenorrhea, vaginitis; Urogenital: nephrolithiasis, hematuria; Hematologic: anemia, iron deficiency, epistaxis; Miscellaneous: otitis, allergic reaction, increased CK, weight loss. Evaluation of 20 patients treated for at least 6 months has failed to demonstrate titers of antibodies exceeding background levels. However, antibody titers to Sandostatin were subsequently reported in three patients and resulted in prolonged duration of drug action in two patients. Anaphylactoid reactions, including anaphylactic shock, have been reported in several patients receiving Sandostatin. Postmarketing Experience The following adverse reactions have been identified during the postapproval use of Sandostatin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal: intestinal obstruction Hematologic: thrombocytopenia OVERDOSAGE A limited number of accidental overdoses of Sandostatin® in adults have been reported. In adults, the doses ranged from 2,400–6,000 micrograms/day administered by continuous infusion (100-250 micrograms/hour) or subcutaneously (1,500 micrograms t.i.d.). Adverse events in some patients included arrhythmia, hypotension, cardiac arrest, brain hypoxia, pancreatitis, hepatitis steatosis, hepatomegaly, lactic acidosis, flushing, diarrhea, lethargy, weakness, and weight loss. Sandostatin Injection given in intravenous boluses of 1 mg (1000 mcg) to healthy volunteers did not result in serious ill effects, nor did doses of 30 mg (30,000 mcg) given intravenously over 20 minutes and of 120 mg (120,000 mcg) given intravenously over 8 hours to research patients. If overdose occurs, symptomatic management is indicated. Up-to-date information about the treatment of overdose can often be obtained from the National Poison Control Center at 1-800-222-1222. Drug Abuse and Dependence There is no indication that Sandostatin has potential for drug abuse or dependence. Sandostatin levels in the central nervous system are negligible, even after doses up to 30,000 mcg. DOSAGE AND ADMINISTRATION Sandostatin® (octreotide acetate) may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of Sandostatin for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination. Sandostatin is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product. Sandostatin is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50-200 mL and infused intravenously over 15-30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis) it may be given by rapid bolus. The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows. Acromegaly Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses. IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone levels at 0-8 hours after Sandostatin® (octreotide acetate) administration permit more rapid titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females. The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be re-evaluated at 6-month intervals. Sandostatin should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, Sandostatin therapy may be resumed. Carcinoid Tumors The suggested daily dosage of Sandostatin during the first 2 weeks of therapy ranges from 100-600 mcg/day in 2-4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day. However, experience with doses above 750 mcg/day is limited. VIPomas Daily dosages of 200-300 mcg in 2-4 divided doses are recommended during the initial 2 weeks of therapy (range 150-750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required. HOW SUPPLIED Sandostatin® (octreotide acetate) Injection is available in 1-mL ampuls and 5-mL multi-dose vials as follows: Ampuls 50 mcg/mL octreotide (as acetate) Package of 10 ampuls       NDC 0078-0180-01 100 mcg/mL octreotide (as acetate) Package of 10 ampuls       NDC 0078-0181-01 500 mcg/mL octreotide (as acetate) Package of 10 ampuls       NDC 0078-0182-01 Multi-Dose Vials 200 mcg/mL octreotide (as acetate) Box of one       NDC 0078-0183-25 1000 mcg/mL octreotide (as acetate) Box of one       NDC 0078-0184-25 Storage For prolonged storage, Sandostatin ampuls and multi-dose vials should be stored at refrigerated temperatures 2ºC-8ºC (36ºF-46ºF) and store in outer carton in order to protect from light. At room temperature, (20ºC-30ºC or 70ºF-86ºF), Sandostatin is stable for 14 days if protected from light. The solution can be allowed to come to room temperature prior to administration. Do not warm artificially. After initial use, multiple-dose vials should be discarded within 14 days. Ampuls should be opened just prior to administration and the unused portion discarded. Dispose unused product or waste properly.