英文药名: Solu-Cortef(hydrocortisone sodium succinate Act-O-Vials)

中文药名: 氢化可的松琥珀酸钠注射剂

生产厂家: Pfizer

药品名称

中文通用名称：氢化可的松琥珀酸钠
英文通用名称：Hydrocortisone Sodium Succinate
中文其它名称：氢可琥钠, 琥珀酸钠皮质醇, 琥珀酸钠氢化可的松, 注射用氢化可的松琥珀酸钠, 琥钠氢可松
英文其它名称：Solu-Cortef, Hydrocortisone Sodium Succinate for Injection
产品所属分类：代谢及内分泌系统用药\肾上腺皮质激素\糖皮质激素
规格

注射剂 100mg, 250mg, 500mg, 1000mg
适应症

糖皮质激素类药在临床应用非常广泛，主要包括：
1.原发性或继发性(垂体性)肾上腺皮质功能减退症的替代治疗。
2.用于治疗合成糖皮质激素所需酶系缺陷所致的各型肾上腺皮质增生症(包括21-羟化酶缺陷、17-羟化酶缺陷、11-羟化酶缺陷等)。
3.利用激素的抗炎、抗风湿、免疫抑制及抗休克作用治疗多种疾病：
(1)自身免疫性疾病，如系统性红斑狼疮、皮肌炎、风湿性关节炎、自身免疫性溶血、血小板减少性紫癜、重症肌无力等。
(2)过敏性疾病，如严重支气管哮喘、血清病、血管性水肿、过敏性鼻炎等。
(3)器官移植排斥反应，如肾、肝、心、肺等组织移植。
(4)中毒性感染，如中毒性细菌性痢疾、中毒性肺炎、重症伤寒、结核性脑膜炎、胸膜炎等。
(5)炎症性疾患，如节段性回肠炎、溃疡性结肠炎、损伤性关节炎等。
(6)血液病，如急性白血病、淋巴瘤等。
(7)抗休克及危重病例的抢救等。
(8)外用制剂可局部用于皮肤及眼科等炎症性或过敏性疾病等，如过敏性皮炎、神经性皮炎、虹膜睫状体炎等。
本药主要用于肾上腺皮质功能减退症及垂体功能减退症的替代治疗，也可用于过敏性和炎症性疾病等。
用法用量

成人
•常规剂量
•口服给药
1.肾上腺皮质功能减退：一日20-25mg(清晨服用2/3，午餐后服1/3)。有应激状况时，应适当加量，可增至一日80mg，分次服用。有严重应激时改用本药静脉滴注。
2.类风湿关节炎、支气管哮喘等：一日20-40mg，清晨顿服。
•静脉注射
肾上腺皮质功能减退及腺垂体功能减退危象、严重过敏反应、哮喘持续状态及休克：氢化可的松注射液一次100mg(或氢化可的松琥珀酸钠135mg)，最大日剂量可达300mg，疗程不超过3-5日。
•静脉滴注
各种危重病例的抢救：一次100-200mg(特殊危重病例一日可用至1000-2000mg)，稀释于生理盐水或葡萄糖注射液(5%或10%)500ml中，混匀后滴注，可并用维生素C 500-1000mg。
•肌内注射
醋酸氢化可的松注射液一日20-40mg。
•关节腔内注射
关节炎、腱鞘炎、急慢性扭伤及肌腱劳损等：一次12.5-50mg，加适量盐酸普鲁卡因注射液，摇匀后注射于关节腔中肌腱处。
•鞘内注射
结核性脑膜炎、脑膜炎：使用醋酸氢化可的松注射液，一次25mg(1ml)。
•局部给药
1.痔疮顽固并发症：将一薄层油膏涂于患处，用手抹匀，早晚各1次。
2.对皮质激素治疗有效的皮肤病：本药霜剂涂于患处，一日1-3次，待症状改善后，改为一日1次或者一周2-3次。
3.神经性皮炎：用气雾膜，用量根据皮损面积酌定，可一日或隔日喷涂1次。病程短的患者见效较快，痊愈率也较高，但痊愈后有复发。
4.各种炎性眼病：用滴眼液或眼膏，一日3-4次。
儿童
•常规剂量
•口服给药
肾上腺皮质功能减退：一日20-25mg/m☆2☆，分为每8小时服用1次。
[国外用法用量参考]
除国内用法用量外，国外尚有以下用法可供参考：
成人
•常规剂量
•肌内注射
用氢化可的松磷酸钠，一日15-240mg，根据具体疾病和病人的反应调整剂量。
•直肠给药
溃疡性结肠炎：一次100mg，睡前保留灌肠，需保留1小时以上，一日1次，连用21日。
儿童
•常规剂量
•口服给药
1.抗炎和抑制免疫：一日2.5-10mg/kg，分为每6-8小时给药1次。
2.生理替代治疗：一日20-25mg/m☆2☆(或0.5-0.75mg/kg)，分为每8小时给药1次。
3.先天性肾上腺皮质增生症：开始剂量为一日30-36mg/m☆2☆(早晨服用1/3，晚上服用2/3)，维持量为一日25-30mg/m☆2☆。
•肌内注射
1.抗炎和抑制免疫：一日1-5mg/kg(或30-150mg/m☆2☆)，分为每12-24小时注射1次。 2.生理替代治疗：一次0.25-0.35mg/kg(或12-15mg/m☆2☆)，一日1次。
•静脉给药
1.抗炎和抑制免疫：一日1-5mg/kg(或30-150mg/m☆2☆)，分为每12-24小时注射1次。
2.急性肾上腺皮质功能不全：
(1)婴幼儿和较小儿童：首次负荷剂量为1-2mg/kg，然后一日25-150mg，分为每6-8小时给药1次。
(2)较大儿童：首次负荷剂量为1-2mg/kg，然后一日150-250mg，分为每6-8小时给药1次。
任何疑问, 请遵医嘱!
给药说明

1.本药可直接静脉注射，常用于各种危重病人的抢救。
2.本药混悬液(酯型)可供关节腔内注射。局部给药也可用于眼科、皮肤科疾病。
3.因本药注射剂(醇型)中含有50%乙醇，故必须充分稀释至0.2mg/ml后供静脉滴注用，需大剂量用药时应改用氢化可的松琥珀酸钠。
4.本药可直接发挥药理作用，与醋酸可的松不同(需经肝脏活化)，故现已逐渐替代可的松。
5.为避免发生肾上腺皮质功能减退及原有疾病症状复燃，在长程糖皮质激素治疗后应逐渐缓慢减量，并由原来的一日用药数次改为一日上午用药1次，或隔日上午用药1次。
6.糖皮质激素与感染的关系：生理剂量的糖皮质激素可提高病人对感染的抵抗力；非肾上腺皮质功能减退患者接受药理剂量糖皮质激素后易发生感染，但某些感染时应用糖皮质激素可减轻组织的破坏、减少渗出、减轻感染中毒症状，但必须同时使用有效的抗生素治疗、密切观察病情变化，在短期用药后，即应迅速减量、停药。
7.长期使用糖皮质激素可发生失钾、缺钙、负氮平衡和垂体肾上腺皮质轴功能的抑制，应补充钾和钙、高蛋白饮食，必要时配合蛋白同化激素等，并限制糖摄入，同时及早采用保护肾上腺皮质功能的措施，如隔日疗法和定期ACTH兴奋等。
8.肾上腺以外的疾病，利用糖皮质激素的药理作用，大致可分为以下三类情况。
(1)急症：如过敏性休克、感染性休克、严重哮喘持续状态、器官移植抗排斥反应，往往需静脉给予大剂量糖皮质激素，疗程限于3-5日，必须同时应用有关的其它有效治疗，如感染性休克应用有效抗生素，过敏性休克时用肾上腺素、抗组胺药等。停药时不需严格递减。
(2)中程治疗：对一些较严重的疾病，如肾病综合征、狼疮性肾炎、恶性浸润性突眼，应采用药理剂量的人工合成制剂，生效后减至维持量，疗程为4-8周。用药剂量和疗程需根据病情的程度和治疗效果而予以调整。停药时须逐渐递减。
(3)长程治疗：慢性疾病，如类风湿性关节炎、血小板减少性紫癜、系统性红斑狼疮，应尽量采用其它治疗方法，必要时用糖皮质激素，采用尽可能小的剂量，病情有好转时即减量，宜每日上午用药1次或隔日上午用1次中效制剂，以尽可能减轻对下丘脑-垂体-肾上腺轴的抑制作用。对于病情较重者，在隔日疗法的不用激素日，可加用其它治疗措施。
不良反应

1.不良反应与疗程、剂量、用药种类、用法及给药途径等有密切关系，但应用生理剂量替代治疗时未见明显不良反应。
2.大剂量或长期应用本类药物，可引起医源性库欣综合征，表现为满月脸、向心性肥胖、紫纹、出血倾向、痤疮、糖尿病倾向(血糖升高)、高血压、骨质疏松或骨折(包括脊椎压缩性骨折、长骨病理性骨折)等。还可见血钙、血钾降低、广泛小动脉粥样硬化、下肢浮肿、创口愈合不良、月经紊乱、股骨头缺血性坏死、儿童生长发育受抑制以及精神症状(如欣快感、激动、不安、谵妄、定向力障碍等)等。其它不良反应还包括肌无力、肌萎缩、胃肠道刺激(恶心、呕吐)、消化性溃疡或肠穿孔、胰腺炎、水钠潴留(血钠升高)、水肿、青光眼、白内障、眼压增高、良性颅内压升高综合征等。另外，使用糖皮质激素还可并发(或加重)感染。
3.静脉迅速给予大剂量时可能发生全身性的过敏反应，表现为面部、鼻粘膜及眼睑肿胀，荨麻疹、气短、胸闷、喘鸣等。
4.外用偶可出现局部烧灼感、瘙痒、刺激以及干燥感。若较长时间或大面积使用，可能导致皮肤萎缩、毛细血管扩张、皮肤条纹及痤疮等，甚至出现全身性不良反应。
5.用药后可见血胆固醇、血脂肪酸升高，淋巴细胞、单核细胞、嗜酸粒细胞和嗜碱粒细胞计数下降，多形核白细胞计数增加，血小板计数增加或下降。
6.糖皮质激素停药后综合征可有以下各种不同的情况：
(1)下丘脑-垂体-肾上腺轴功能减退，可表现为乏力、食欲减退、恶心、呕吐、血压偏低。长期治疗后该轴功能的恢复一般需要9-12个月。
(2)已被控制的疾病症状可于停药后重新出现。
(3)有的患者在停药后出现头晕、头痛、昏厥倾向、腹痛或背痛、低热、食欲减退、恶心、呕吐、肌肉或关节疼痛、乏力等，经仔细检查如能排除肾上腺皮质功能减退和原来疾病的复发，则可考虑为对糖皮质激素的依赖综合征。
注意事项

1.交叉过敏
对其它肾上腺皮质激素类药物过敏者也可能对本药过敏。
2.禁忌症
(1)对肾上腺皮质激素类药物过敏。
(2)下列疾病患者一般不宜使用：严重的精神病(过去或现在)和癫痫、活动性消化性溃疡、新近胃肠吻合手术、骨折、创伤修复期、角膜溃疡、肾上腺皮质功能亢进症、高血压、糖尿病、孕妇、未能控制的感染(如水痘、麻疹、真菌感染)、较重的骨质疏松等。
(3)以下患者应避免使用：动脉粥样硬化、心力衰竭或慢性营养不良。
3.慎用
(1)心脏病患者。
(2)憩室炎患者。
(3)情绪不稳定和有精神病倾向患者。
(4)肝功能不全。
(5)眼单纯疱疹。
(6)高脂蛋白血症。
(7)甲状腺功能减退症(此时糖皮质激素作用增强)。
(8)重症肌无力。
(9)骨质疏松。
(10)胃溃疡、胃炎或食管炎等。
(11)肾功能损害或结石。
(12)结核病患者。
(13)全身性真菌感染。
(14)青光眼。
4.药物对儿童的影响
(1)小儿如长期使用本药及其它糖皮质激素，需十分慎重，因糖皮质激素可抑制患儿的生长和发育。
(2)儿童或青少年长期使用本药及其它糖皮质激素必须密切观察，因长期使用糖皮质激素后，患儿发生骨质疏松症、股骨头缺血性坏死、青光眼、白内障的危险性增加。
(3)儿童使用本药及其它糖皮质激素药的剂量除了一般的按年龄或体重而定外，更应当按疾病的严重程度和患儿对治疗的反应而定。对于有肾上腺皮质功能减退患儿的治疗，其用量应根据体表面积而定，如果按体重而定，则易发生过量，尤其是婴幼儿和矮小或肥胖的患儿。
5.药物对老人的影响
老年患者用本药及其它糖皮质激素易发生高血压和骨质疏松，更年期后的女性发生骨质疏松的可能性更大。
6.药物对妊娠的影响
本药及其它糖皮质激素类药物可透过胎盘。动物实验证实孕期给药可增加胚胎腭裂、胎盘功能不全、自发性流产和胎儿宫内生长发育迟缓的发生率。人类使用药理剂量的糖皮质激素可增加胎盘功能不全、新生儿体重减轻或死胎的发生率。孕妇不宜使用。美国药品和食品管理局(FDA)对本药的妊娠安全性分级为D级。
7.药物对哺乳的影响
糖皮质激素的生理剂量或低药理剂量对婴儿一般无不良影响，但哺乳妇女如接受药理性大剂量的糖皮质激素，则不应哺乳，因为糖皮质激素可由乳汁中分泌，可对婴儿造成不良影响(如抑制生长及肾上腺皮质功能等)。
8.药物对检验值或诊断的影响
(1)长期大剂量使用可使皮肤试验结果呈假阴性，如结核菌素试验、组织胞质菌素试验和过敏反应皮试(如青霉素皮试)等。
(2)可使甲状腺☆131☆I摄取率下降，减弱促甲状腺素(TSH)对促甲状腺素释放素(TRH)刺激的反应，使TRH兴奋试验结果呈假阳性，干扰促性腺素释放激素(LHRH)兴奋试验的结果。
(3)使放射性核素脑和骨显像减弱或稀疏。
9.用药前后及用药时应当检查或监测
(1)血糖、尿糖或糖耐量试验，尤其糖尿病患者或有患糖尿病倾向者。
(2)小儿应定期监测生长和发育情况。
(3)眼科检查，注意白内障、青光眼或眼部感染的发生。
(4)血电解质和大便隐血。
(5)血压和骨密度检查(尤其老年人)。
 
包装规格：
·1000mg 5 盒 
·100mg 10支 x 2ml
·250mg 10支 x 2ml
·500mg 5支 x 4ml 

Solu-Cortef
Generic Name: hydrocortisone sodium succinate
Dosage Form: injection, powder, for solution
Solu-Cortef® (hydrocortisone sodium succinate for injection, USP)
For Intravenous or Intramuscular Administration
Solu-Cortef Description
Solu-Cortef Sterile Powder is an anti-inflammatory glucocorticoid, which contains hydrocortisone sodium succinate as the active ingredient. Solu-Cortef Sterile Powder is available in several packages for intravenous or intramuscular administration.
100 mg Plain—Vials containing hydrocortisone sodium succinate equivalent to 100 mg hydrocortisone, also 0.8 mg monobasic sodium phosphate anhydrous, 8.73 mg dibasic sodium phosphate dried. Solu-Cortef 100 mg plain does not contain diluent (see DOSAGE AND ADMINISTRATION, Preparation of Solutions).

ACT-O-VIAL® System (Single-Dose Vial) in four strengths:
	100 mg ACT-O-VIAL	250 mg ACT-O-VIAL	500 mg ACT-O-VIAL	1000 mg ACT-O-VIAL
	Each 2 mL contains: (when mixed)	Each 2 mL contains: (when mixed)	Each 4 mL contains: (when mixed)	Each 8 mL contains: (when mixed)
Hydrocortisone   sodium succinate	equiv. to 100 mg Hydrocortisone	equiv. to 250 mg Hydrocortisone	equiv. to 500 mg Hydrocortisone	equiv. to 1000 mg Hydrocortisone
Monobasic sodium   phosphate anhydrous	0.8 mg	2 mg	4 mg	8 mg
Dibasic sodium   phosphate dried	8.73 mg	21.8 mg	44 mg	87.32 mg

The diluent, as part of the packaging presentation for the ACT-O-VIAL® system, is comprised of Water for Injection only, and does not contain any preservative.

When necessary, the pH of each formula was adjusted with sodium hydroxide so that the pH of the reconstituted solution is within the USP specified range of 7 to 8.

The chemical name for hydrocortisone sodium succinate is pregn-4-ene-3,20-dione,21-(3-carboxy-1-oxopropoxy)-11,17-dihydroxy-, monosodium salt, (11β)- and its molecular weight is 484.52.

The structural formula is represented below:

Hydrocortisone sodium succinate is a white or nearly white, odorless, hygroscopic amorphous solid. It is very soluble in water and in alcohol, very slightly soluble in acetone and insoluble in chloroform.

Solu-Cortef - Clinical Pharmacology

Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract.

Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their anti-inflammatory effects in disorders of many organ systems.

Hydrocortisone sodium succinate has the same metabolic and anti-inflammatory actions as hydrocortisone. When given parenterally and in equimolar quantities, the two compounds are equivalent in biologic activity. The highly water-soluble sodium succinate ester of hydrocortisone permits the immediate intravenous administration of high doses of hydrocortisone in a small volume of diluent and is particularly useful where high blood levels of hydrocortisone are required rapidly. Following the intravenous injection of hydrocortisone sodium succinate, demonstrable effects are evident within one hour and persist for a variable period. Excretion of the administered dose is nearly complete within 12 hours. Thus, if constantly high blood levels are required, injections should be made every 4 to 6 hours. This preparation is also rapidly absorbed when administered intramuscularly and is excreted in a pattern similar to that observed after intravenous injection.

Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune response to diverse stimuli.

Indications and Usage for Solu-Cortef

When oral therapy is not feasible, and the strength, dosage form, and route of administration of the drug reasonably lend the preparation to the treatment of the condition, the intravenous or intramusculat use of Solu-Cortef Sterile Powder is indicated as follows:

Allergic states

Control of severe or incapacitating allergic conditions intractable to adequate trials of conventional treatment in asthma, atopic dermatitis, contact dermatitis, drug hypersensitivity reactions, perennial or seasonal allergic rhinitis, serum sickness, transfusion reactions.

Dermatologic diseases

Bullous dermatitis herpetiformis, exfoliative erythroderma, mycosis fungoides, pemphigus, severe erythema multiforme (Stevens-Johnson syndrome).

Endocrine disorders

Primary or secondary adrenocortical insufficiency (hydrocortisone or cortisone is the drug of choice; synthetic analogs may be used in conjunction with mineralocorticoids where applicable; in infancy, mineralocorticoid supplementation is of particular importance), congenital adrenal hyperplasia, hypercalcemia associated with cancer, nonsuppurative thyroiditis.

Gastrointestinal diseases

To tide the patient over a critical period of the disease in regional enteritis (systemic therapy) and ulcerative colitis.

Hematologic disorders

Acquired (autoimmune) hemolytic anemia, congenital (erythroid) hypoplastic anemia (Diamond-Blackfan anemia), idiopathic thrombocytopenic purpura in adults (intravenous administration only; intramuscular administration is contraindicated), pure red cell aplasia, selected cases of secondary thrombocytopenia.

Miscellaneous

Trichinosis with neurologic or myocardial involvement, tuberculous meningitis with subarachnoid block or impending block when used concurrently with appropriate antituberculous chemotherapy.

Neoplastic diseases

For the palliative management of leukemias and lymphomas.

Nervous System

Acute exacerbations of multiple sclerosis; cerebral edema associated with primary or metastatic brain tumor, or craniotomy.

Ophthalmic diseases

Sympathetic ophthalmia, uveitis and ocular inflammatory conditions unresponsive to topical corticosteroids.

Renal diseases

To induce diuresis or remission of proteinuria in idiopathic nephrotic syndrome or that due to lupus erythematosus.

Respiratory diseases

Berylliosis, fulminating or disseminated pulmonary tuberculosis when used concurrently with appropriate antituberculous chemotherapy, idiopathic eosinophilic pneumonias, symptomatic sarcoidosis.

Rheumatic disorders

As adjunctive therapy for short-term administration (to tide the patient over an acute episode or exacerbation) in acute gouty arthritis; acute rheumatic carditis; ankylosing spondylitis; psoriatic arthritis; rheumatoid arthritis, including juvenile rheumatoid arthritis (selected cases may require low-dose maintenance therapy). For the treatment of dermatomyositis, temporal arteritis, polymyositis, and systemic lupus erythematosus.

Contraindications

Solu-Cortef Sterile Powder is contraindicated in systemic fungal infections and patients with known hypersensitivity to the product and its constituents.

Intramuscular corticosteroid preparations are contraindicated for idiopathic thrombocytopenic purpura.

Solu-Cortef Sterile Powder is contraindicated for intrathecal administration. Reports of severe medical events have been associated with this route of administration.

Warnings

General

Injection of Solu-Cortef may result in dermal and/or subdermal changes forming depressions in the skin at the injection site. In order to minimize the incidence of dermal and subdermal atrophy, care must be exercised not to exceed recommended doses in injections. Injection into the deltoid muscle should be avoided because of a high incidence of subcutaneous atrophy.

Rare instances of anaphylactoid reactions have occurred in patients receiving corticosteroid therapy (see ADVERSE REACTIONS).

Increased dosage of rapidly acting corticosteroids is indicated in patients on corticosteroid therapy subjected to any unusual stress before, during, and after the stressful situation.

Results from one multicenter, randomized, placebo-controlled study with methylprednisolone hemisuccinate, an IV corticosteroid, showed an increase in early (at 2 weeks) and late (at 6 months) mortality in patients with cranial trauma who were determined not to have other clear indications for corticosteroid treatment. High doses of systemic corticosteroids, including Solu-Cortef, should not be used for the treatment of traumatic brain injury.

Cardio-renal

Average and large doses of corticosteroids can cause elevation of blood pressure, salt and water retention, and increased excretion of potassium. These effects are less likely to occur with the synthetic derivatives except when used in large doses. Dietary salt restriction and potassium supplementation may be necessary. All corticosteroids increase calcium excretion.

Literature reports suggest an apparent association between use of corticosteroids and left ventricular free wall rupture after a recent myocardial infarction; therefore, therapy with corticosteroids should be used with great caution in these patients.

Endocrine

Hypothalamic-pituitary adrenal (HPA) axis suppression. Cushing's syndrome, and hyperglycemia. Monitor patients for these conditions with chronic use. Corticosteroids can produce reversible HPA axis suppression with the potential for glucocorticosteroid insufficiency after withdrawal of treatment. Drug induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted.

Infections

General

Patients who are on corticosteroids are more susceptible to infections than are healthy individuals. There may be decreased resistance and inability to localize infection when corticosteroids are used. Infection with any pathogen (viral, bacterial, fungal, protozoan or helminthic) in any location of the body may be associated with the use of corticosteroids alone or in combination with other immunosuppressive agents.

These infections may be mild, but can be severe and at times fatal. With increasing doses of corticosteroids, the rate of occurrence of infectious complications increases. Corticosteroids may also mask some signs of current infection. Do not use intra-articularly, intrabursally or for intratendinous administration for local effect in the presence of acute local infection.

Fungal infections

Corticosteroids may exacerbate systemic fungal infections and therefore should not be used in the presence of such infections unless they are needed to control drug reactions. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure (see CONTRAINDICATIONS and PRECAUTIONS, Drug Interactions, Amphotericin B injection and potassium-depleting agents).

Special pathogens

Latent disease may be activated or there may be an exacerbation of intercurrent infections due to pathogens, including those caused by Amoeba, Candida, Cryptococus, Mycobacterium, Nocardia, Pneumocystis, Toxoplasma.

It is recommended that latent amebiasis or active amebiasis be ruled out before initiating corticosteroid therapy in any patient who has spent time in the tropics or in any patient with unexplained diarrhea.

Similarly, corticosteroids should be used with great care in patients with known or suspected Strongyloides (threadworm) infestation. In such patients, corticosteroid-induced immunosuppression may lead to Strongyloides hyperinfection and dissemination with widespread larval migration, often accompanied by severe enterocolitis and potentially fatal gram-negative septicemia.

Corticosteroids should not be used in cerebral malaria. There is currently no evidence of benefit from steroids in this condition.

Tuberculosis

The use of corticosteroids in active tuberculosis should be restricted to those cases of fulminating or disseminated tuberculosis in which the corticosteroid is used for the management of the disease in conjunction with an appropriate antituberculous regimen.

If corticosteroids are indicated in patients with latent tuberculosis or tuberculin reactivity, close observation is necessary as reactivation of the disease may occur. During prolonged corticosteroid therapy, these patients should receive chemoprophylaxis.

Vaccination

Administration of live or live, attenuated vaccines is contraindicated in patients receiving immunosuppressive doses of corticosteroids. Killed or inactivated vaccines may be administered. However, the reponse to such vaccines cannot be predicted. Immunization procedures may be undertaken in patients who are receiving corticosteroids as replacement therapy, e.g., for Addison's disease.

Viral infections

Chicken pox and measles can have a more serious or even fatal course in pediatric and adult patients on corticosteroids. In pediatric and adult patients who have not had these diseases, particular care should be taken to avoid exposure. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chicken pox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chicken pox develops, treatment with antiviral agents should be considered.

Neurologic

Reports of severe medical events have been associated with the intrathecal route of administration (see ADVERSE REACTIONS, Neurologic/Psychiatric).

Ophthalmic

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma with possible damage to the optic nerves, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. The use of oral corticosteroids is not recommended in the treatment of optic neuritis and may lead to an increase in the risk of new episodes. Corticosteroids should be used cautiously in patients with ocular herpes simplex because of corneal perforation. Corticosteroids should not be used in active ocular herpes simplex.

Precautions

General

This product, like many other steroid formulations, is sensitive to heat. Therefore, it should not be autoclaved when it is desirable to sterilize the exterior of the vial. The lowest possible dose of corticosteroid should be used to control the condition under treatment. When reduction in dosage is possible, the reduction should be gradual.

Since complications of treatment with glucocorticoids are dependent on the size of the dose and the duration of treatment, a risk/benefit decision must be made in each individual case as to dose and duration of treatment and as to whether daily or intermittent therapy should be used.

Kaposi's sarcoma has been reported to occur in patients receiving corticosteroid therapy, most often for chronic conditions. Discontinuation of corticosteroids may result in clinical improvement.

Cardio-renal

As sodium retention with resultant edema and potassium loss may occur in patients receiving corticosteroids, these agents should be used with caution in patients with congestive heart failure, hypertension, or renal insufficiency.

Endocrine

Drug-induced secondary adrenocortical insufficiency may be minimized by gradual reduction of dosage. This type of relative insufficiency may persist for months after discontinuation of therapy; therefore, in any situation of stress occurring during that period, hormone therapy should be reinstituted. Since mineralocorticoid secretion may be impaired, salt and/or a mineralocorticoid should be administered concurrently. Metabolic clearance of corticosteroids is decreased in hypothyroid patients and increased in hyperthyroid patients. Changes in thyroid status of the patient may necessitate adjustment in dosage.

Gastrointestinal

Steroids should be used with caution in active or latent peptic ulcers, diverticulitis, fresh intestinal anastomoses, and nonspecific ulcerative colitis, since they may increase the risk of a perforation. Signs of peritoneal irritation following gastrointestinal perforation in patients receiving corticosteroids may be minimal or absent.

There is an enhanced effect due to increased metabolism of corticosteroids in patients with cirrhosis.

Musculoskeletal

Corticosteroids decrease bone formation and increase bone resorption both through their effect on calcium regulation (i.e., decreasing absorption and increasing excretion) and inhibition of osteoblast function. This, together with a decrease in the protein matrix of the bone secondary to an increase in protein catabolism, and reduced sex hormone production, may lead to inhibition of bone growth in pediatric patients and the development of osteoporosis at any age. Special consideration should be given to patients at increased risk of osteoporosis (i.e., postmenopausal women) before initiating corticosteroid therapy.

Local injection of a steroid into a previously infected site is not usually recommended.

Neurologic-psychiatric

Although controlled clinical trials have shown corticosteroids to be effective in speeding the resolution of acute exacerbations of multiple sclerosis, they do not show that they affect the ultimate outcome or natural history of the disease. The studies do show that relatively high doses of corticosteroids are necessary to demonstrate a significant effect. (See DOSAGE AND ADMINISTRATION.)

An acute myopathy has been observed with the use of high doses of corticosteroids, most often occurring in patients with disorders of neuromuscular transmission (e.g., myasthenia gravis), or in patients receiving concomitant therapy with neuromuscular blocking drugs (e.g., pancuronium). This acute myopathy is generalized, may involve ocular and respiratory muscles, and may result in quadriparesis. Elevation of creatinine kinase may occur. Clinical improvement or recovery after stopping corticosteroids may require weeks to years.

Psychic derangements may appear when corticosteroids are used, ranging from euphoria, insomnia, mood swings, personality changes, and severe depression to frank psychotic manifestations. Also, existing emotional instability or psychotic tendencies may be aggravated by corticosteroids.

Ophthalmic

Intraocular pressure may become elevated in some individuals. If steroid therapy is continued for more than 6 weeks, intraocular pressure should be monitored.

Information for Patients

Patients should be warned not to discontinue the use of corticosteroids abruptly or without medical supervision, to advise any medical attendants that they are taking corticosteroids and to seek medical advice at once should they develop fever or other signs of infection.

Persons who are on corticosteroids should be warned to avoid exposure to chicken pox or measles. Patients should also be advised that if they are exposed, medical advice should be sought without delay.

Drug Interactions

Aminoglutethimide

Aminoglutethimide may lead to a loss of corticosteroid-induced adrenal suppression.

Amphotericin B injection and potassium-depleting agents

When corticosteroids are administered concomitantly with potassium-depleting agents (i.e., amphotericin-B, diuretics), patients should be observed closely for development of hypokalemia. There have been cases reported in which concomitant use of amphotericin B and hydrocortisone was followed by cardiac enlargement and congestive heart failure.

Antibiotics

Macrolide antibiotics have been reported to cause a significant decrease in corticosteroid clearance (see Drug Interactions, Hepatic Enzyme Inhibitors).

Anticholinesterases

Concomitant use of anticholinesterase agents and corticosteroids may produce severe weakness in patients with myasthenia gravis. If possible, anticholinesterase agents should be withdrawn at least 24 hours before initiating corticosteroid therapy.

Anticoagulants, oral

Coadministration of corticosteroids and warfarin usually results in inhibition of response to warfarin, although there have been some conflicting reports. Therefore, coagulation indices should be monitored frequently to maintain the desired anticoagulant effect.

Antidiabetics

Because corticosteroids may increase blood glucose concentrations, dosage adjustments of antidiabetic agents may be required.

Antitubercular drugs

Serum concentrations of isoniazid may be decreased.

Cholestyramine

Cholestyramine may increase the clearance of corticosteroids.

Cyclosporine

Increased activity of both cyclosporine and corticosteroids may occur when the two are used concurrently. Convulsions have been reported with this concurrent use.

Digitalis glycosides

Patients on digitalis glycosides may be at increased risk of arrhythmias due to hypokalemia.

Estrogens, including oral contraceptives

Estrogens may decrease the hepatic metabolism of certain corticosteroids, thereby increasing their effect.

Hepatic Enzyme Inducers (e.g., barbiturates, phenytoin, carbamazepine, rifampin)

Drugs which induce cytochrome P450 3A4 enzyme activity may enhance the metabolism of corticosteroids and require that the dosage of the corticosteroid be increased.

Hepatic Enzyme Inhibitors (e.g., ketoconazole, macrolide antibiotics such as erythromycin and troleandomycin)

Drugs which inhibit cytochrome P450 3A4 have the potential to result in increased plasma concentrations of corticosteroids.

Ketoconazole

Ketoconazole has been reported to significantly decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased risk of corticosteroid side effects.

Nonsteroidal anti-inflammatory agents (NSAIDs)

Concomitant use of aspirin (or other nonsteroidal anti-inflammatory agents) and corticosteroids increases the risk of gastrointestinal side effects. Aspirin should be used cautiously in conjunction with corticosteroids in hypoprothrombinemia. The clearance of salicylates may be increased with concurrent use of corticosteroids.

Skin tests

Corticosteroids may suppress reactions to skin tests.

Vaccines

Patients on prolonged corticosteroid therapy may exhibit a diminished response to toxoids and live or inactivated vaccines due to inhibition of antibody response. Corticosteroids may also potentiate the replication of some organisms contained in live attenuated vaccines. Routine administration of vaccines or toxoids should be deferred until corticosteroid therapy is discontinued if possible (see WARNINGS, Infections, Vaccination).

Carcinogenesis, Mutagenesis, Impairment of Fertility

No adequate studies have been conducted in animals to determine whether corticosteroids have a potential for carcinogenesis or mutagenesis.

Steroids may increase or decrease motility and number of spermatozoa in some patients.

Pregnancy

Teratogenic effects

Pregnancy Category C

Corticosteroids have been shown to be teratogenic in many species when given in doses equivalent to the human dose. Animal studies in which corticosteroids have been given to pregnant mice, rats, and rabbits have yielded an increased incidence of cleft palate in the offspring. There are no adequate and well-controlled studies in pregnant women. Corticosteroids should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born to mothers who have received corticosteroids during pregnancy should be carefully observed for signs of hypoadrenalism.

Nursing Mothers

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Because of the potential for serious adverse reactions in nursing infants from corticosteroids, a decision should be made whether to continue nursing, or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The efficacy and safety of corticosteroids in the pediatric population are based on the well-established course of effect of corticosteroids which is similar in pediatric and adult populations. Published studies provide evidence of efficacy and safety in pediatric patients for the treatment of nephrotic syndrome (>2 years of age), and aggressive lymphomas and leukemias (>1 month of age). Other indications for pediatric use of corticosteroids, e.g., severe asthma and wheezing, are based on adequate and well-controlled trials conducted in adults, on the premises that the course of the diseases and their pathophysiology are considered to be substantially similar in both populations.

The adverse effects of corticosteroids in pediatric patients are similar to those in adults (see ADVERSE REACTIONS). Like adults, pediatric patients should be carefully observed with frequent measurements of blood pressure, weight, height, intraocular pressure, and clinical evaluation for the presence of infection, psychosocial disturbances, thromboembolism, peptic ulcers, cataracts, and osteoporosis. Pediatric patients who are treated with corticosteroids by any route, including systemically administered corticosteroids, may experience a decrease in their growth velocity. This negative impact of corticosteroids on growth has been observed at low systemic doses and in the absence of laboratory evidence of HPA axis suppression (i.e., cosyntropin stimulation and basal cortisol plasma levels). Growth velocity may therefore be a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The linear growth of pediatric patients treated with corticosteroids should be monitored, and the potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the availability of treatment alternatives. In order to minimize the potential growth effects of corticosteroids, pediatric patients should be titrated to the lowest effective dose.

Geriatric Use

Clinical studies 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

The following adverse reactions have been reported with Solu-Cortef or other corticosteroids:

Allergic reactions: Allergic or hypersensitivity reactions, anaphylactoid reaction, anaphylaxis, angioedema.

Cardiovascular: Bradycardia, cardiac arrest, cardiac arrhythmias, cardiac enlargement, circulatory collapse, congestive heart failure, fat embolism, hypertension, hypertrophic cardiomyopathy in premature infants, myocardial rupture following recent myocardial infarction (see WARNINGS), pulmonary edema, syncope, tachycardia, thromboembolism, thrombophlebitis, vasculitis.

Dermatologic: Acne, allergic dermatitis, burning or tingling (especially in the perineal area, after intravenous injection), cutaneous and subcutaneous atrophy, dry scaly skin, ecchymoses and petechiae, edema, erythema, hyperpigmentation, hypopigmentation, impaired wound healing, increased sweating, rash, sterile abscess, striae, suppressed reactions to skin tests, thin fragile skin, thinning scalp hair, urticaria.

Endocrine: Decreased carbohydrate and glucose tolerance, development of cushingoid state, glycosuria, hirsutism, hypertrichosis, increased requirements for insulin or oral hypoglycemic agents in diabetes, manifestations of latent diabetes mellitus, menstrual irregularities, secondary adrenocortical and pituitary unresponsiveness (particularly in times of stress, as in trauma, surgery, or illness), suppression of growth in pediatric patients.

Fluid and electrolyte disturbances: Congestive heart failure in susceptible patients, fluid retention, hypokalemic alkalosis, potassium loss, sodium retention.

Gastrointestinal: Abdominal distention, bowel/bladder dysfunction (after intrathecal administration), elevation in serum liver enzyme levels (usually reversible upon discontinuation), hepatomegaly, increased appetite, nausea, pancreatitis, peptic ulcer with possible perforation and hemorrhage, perforation of the small and large intestine (particularly in patients with inflammatory bowel disease), ulcerative esophagitis.

Metabolic: Negative nitrogen balance due to protein catabolism.

Musculoskeletal: Aseptic necrosis of femoral and humeral heads, Charcot-like arthropathy, loss of muscle mass, muscle weakness, osteoporosis, pathologic fracture of long bones, postinjection flare (following intra-articular use), steroid myopathy, tendon rupture, vertebral compression fractures.

Neurologic/Psychiatric: Convulsions, depression, emotional instability, euphoria, headache, increased intracranial pressure with papilledema (pseudotumor cerebri) usually following discontinuation of treatment, insomnia, mood swings, neuritis, neuropathy, paresthesia, personality changes, psychic disorders, vertigo. Arachnoiditis, meningitis, paraparesis/paraplegia, and sensory disturbances have occurred after intrathecal administration (see WARNINGS, Neurologic).

Ophthalmic: Exophthalmoses, glaucoma, increased intraocular pressure, posterior subcapsular cataracts, rare instances of blindness associated with periocular injections.

Other: Abnormal fat deposits, decreased resistance to infection, hiccups, increased or decreased motility and number of spermatozoa, injection site infections following non-sterile administration (see WARNINGS), malaise, moon face, weight gain.

Overdosage

Treatment of acute overdosage is by supportive and symptomatic therapy. For chronic overdosage in the face of severe disease requiring continuous steroid therapy, the dosage of the corticosteroid may be reduced only temporarily, or alternate day treatment may be introduced.

Solu-Cortef Dosage and Administration

Because of possible physical incompatilitbilites, Solu-Cortef should not be diluted or mixed with other solutions.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection. Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation.

Therapy is initiated by administering Solu-Cortef Sterile Powder intravenously over a period of 30 seconds (e.g., 100 mg) to 10 minutes (e.g., 500 mg or more). In general, high dose corticosteroid therapy should be continued only until the patient's condition has stabilized-usually not beyond 48 to 72 hours. When high dose hydrocortisone therapy must be continued beyond 48–72 hours, hypernatremia may occur. Under such circumstances it may be desirable to replace Solu-Cortef with a corticoid such as methylprednisolone sodium succinate which causes little or no sodium retention.

The initial dose of Solu-Cortef Sterile Powder is 100 mg to 500 mg, depending on the specific disease entity being treated. However, in certain overwhelming, acute, life-threatening situations, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.

This dose may be repeated at intervals of 2, 4 or 6 hours as indicated by the patient's response and clinical condition.

It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient. After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage that maintains an adequate clinical response is reached. Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient's individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment. In this latter situation it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient's condition. If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

In the treatment of acute exacerbations of multiple sclerosis, daily doses of 800 mg of hydrocortisone for a week followed by 320 mg every other day for one month are recommended (see PRECAUTIONS, Neuro-psychiatric).

In pediatric patients, the initial dose of hydrocortisone may vary depending on the specific disease entity being treated. The range of initial doses is 0.56 to 8 mg/kg/day in three or four divided doses (20 to 240 mg/m2bsa/day). For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

Cortisone, 25	Triamcinolone, 4
Hydrocortisone, 20	Paramethasone, 2
Prednisolone, 5	Betamethasone, 0.75
Prednisone, 5	Dexamethasone, 0.75
Methylprednisolone, 4

These dose relationships apply only to oral or intravenous administration of these compounds. When these substances or their derivatives intramuscularly or into joint spaces, their relative properties may be greatly altered.

Preparation of Solutions 100 mg Plain

For intravenous or intramuscular injection, prepare solution by aseptically adding not more than 2 mL of Bacteriostatic Water for Injection or Bacteriostatic Sodium Chloride Injection to the contents of one vial. For intravenous infusion, first prepare solution by adding not more than 2 mL of Bacteriostatic Water for Injection to the vial; this solution may then be added to 100 to 1000 mL of the following: 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction).

DIRECTIONS FOR USING THE ACT-O-VIAL SYSTEM

1. Press down on plastic activator to force diluent into the lower compartment.
2. Gently agitate to effect solution.
3. Remove plastic tab covering center of stopper.
4. Sterilize top of stopper with a suitable germicide.
5. Insert needle squarely through center of stopper until tip is just visible. Invert vial and withdraw dose.

Further dilution is not necessary for intravenous or intramuscular injection. For intravenous infusion, first prepare solution as just described. The 100 mg solution may then be added to 100 to 1000 mL of 5% dextrose in water (or isotonic saline solution or 5% dextrose in isotonic saline solution if patient is not on sodium restriction). The 250 mg solution may be added to 250 to 1000 mL, the 500 mg solution may be added to 500 to 1000 mL and the 1000 mg solution to 1000 mL of the same diluents. In cases where administration of a small volume of fluid is desirable, 100 mg to 3000 mg of Solu-Cortef may be added to 50 mL of the above diluents. The resulting solutions are stable for at least 4 hours and may be administered either directly or by IV piggyback.

When reconstituted as directed, pH's of the solutions range from 7 to 8 and the tonicities are: 100 mg ACT-O-VIAL, .36 osmolar; 250 mg ACT-O-VIAL, 500 mg ACT-O-VIAL, and the 1000 mg ACT-O-VIAL, .57 osmolar. (Isotonic saline=.28 osmolar.)

How is Solu-Cortef Supplied

Solu-Cortef Sterile Powder is available in the following packages:

100 mg Plain—NDC 0009-0825-01
100 mg ACT-O-VIAL (Single-Dose Vial)	250 mg ACT-O-VIAL (Single-Dose Vial)
2 mL—NDC 0009-0011-03	2 mL—NDC 0009-0013-05
25 × 2 mL—NDC 0009-0011-04	25 × 2 mL—NDC 0009-0013-06
500 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0016-12
1000 mg ACT-O-VIAL (Single-Dose Vial)—NDC 0009-0005-01

STORAGE CONDITIONS

Store unreconstituted product at controlled room temperature 20° to 25°C (68° to 77°F).

Store solution at controlled room temperature 20° to 25°C (68° to 77°F) and protect from light. Use solution only if it is clear. Unused solution should be discarded after 3 days.