英文药名: Diabinese(Chlorpropamide Tablets)

中文药名: 氯磺丙脲片,特泌胰片

药品名称

通用名称：氯磺丙脲
英文名：Chlorpropamide
其它中文名：特泌胰
其它英文名：Bioglumin、Catanil、Chlorglypropamide、Chloromide、Chloronase、Chlorpropam、Clordiabet、Diabetasi、Diabexan、Diabinese、Glucosulfina、Stabinol
药理作用　

药效学
本品为磺脲类口服降血糖药。其作用机制与甲磺丁脲相同，但作用强度为6倍，血中半减期长，排泄缓慢，每日服药1次即可。本品能使胰腺β细胞功能改善，使患者的葡萄糖耐量趋向“正常化”。
①促进胰腺胰岛B细胞分泌胰岛素，先决条件是胰岛B细胞还有一定的合成和分泌胰岛素的功能；
②通过增加门静脉胰岛素水平或对肝脏直接作用，抑制肝糖原分解和糖原异生作用，肝生成和输出葡萄糖减少；
③也可能增加胰外组织对胰岛素的敏感性和糖的利用(可能主要通过受体后作用)，因此，总的作用是降低空腹血糖与餐后血糖。
药动学
本品自胃肠道吸收迅速，口服后1h内出现降血糖作用，2～4h达血药浓度峰值。生物半减期为36h。本品经肝脏代谢，80％～90％于服药后96h内随尿排泄。
口服吸收，蛋白结合率很高，为88～96％。口服后2～6小时血药浓度达峰值，持续作用 24～48小时，个体差异大，个别作用可达数周，Ｔ1/2为 25～60小时。口服量的80～90％经肾排出。
适应症　　

适用于单用饮食控制疗效不满意的轻、中度非胰岛素依赖型糖尿病，病人胰岛B细胞有一定的分泌胰岛素功能，并且无严重的并发症。本品还可用于中枢性尿崩症。
用于非胰岛素依赖型糖尿病、无并发症和酮症患者，也可试用于其他磺脲类控制症状不满意的患者。由于本品容易发生严重低血糖症的不良反应，现已很少使用。本品曾用于治疗特发性尿崩症。
用法用量　　

口服常用量一次0.1～0.5g，一日1次。开始在早餐前服0.1～0.2g，以后每周增加50mg，一般剂量每日0.3g，最大剂量每日0.5g；分次服可减少胃肠反应，也可改善高血糖的控制。
对成人垂体性尿崩症，每日0.1～0.2g，一次服，每2～3日按需递增50mg，最大剂量0.5g。
开始用量0.2-0.3g,逐渐减为0.1-0.2g,一日1次。
口服，新近诊断为糖尿病的患者，开始每日早晨用250mg，5～7日后，每3～5日调整1次，每次增加或减少50～125mg，直到取得最佳效果。对老年患者，开始每日用100～125mg，以后视病情调整。
一般维持量为：成年人每日250mg，老年人每日100mg，严重的患者每日剂量可增至500mg。
任何疑问，请遵医嘱！
给药说明　　

(1)排泄较甲苯磺丁脲馒，引起低血糖反应时间持久而严重，纠正低血糖后也要注意观察3～5日。
(2)本品可刺激下丘脑-垂体，不适当地分泌抗利尿激素，故可引起水潴留。本品是磺酰脲类药物中不良反应最多者。
(3)一般于早餐前服药，不要在晚上不进食情况下服药，否则易发生夜间低血糖。
(4)从其他口服降糖药改用本品时，可直接换药；从胰岛素治疗改用本品时，如原用胰岛素量每日小于40单位，可直接换药，如原用胰岛素每日大于40单位，开始几天在减少胰岛素剂量50％基础上加用本品，视血糖、尿糖情况逐渐减少胰岛素。
禁用/慎用　

肝肾功能不全、酗酒、经受较大手术、孕妇及对本品过敏者忌用。
糖尿病酮症酸中毒、胰岛素依赖型(幼年型)糖尿病禁用。孕妇慎用，如妊娠时使用，则至少在预产期前1个月停用，授乳期妇女给药应停止授乳。
不良反应　

有时引起腹胀,恶心,呕吐,腹泻,胆汁淤积,皮肤红斑,荨麻疹,粒细胞缺乏,白细胞及血小板减少,低血糖等, 引起肝损害。
主要为胃肠道紊乱、瘙痒等皮肤反应。容易致低血糖症。
肝、肾功能不全、老年人、虚弱、营养不良、肾上腺功能不全的患者易发生低血糖反应。当摄入热量不足、剧烈运动后、饮酒或合用其他降血糖药时，更易发生低血糖反应。反应与剂量有关，减量或停药后即可消失。如发生严重反应时必须采取应急措施，先迅速静注50％葡萄糖溶液，然后滴注10％的葡萄糖溶液，滴速应维持血糖于5.6mmol／L以上，并监护患者24～48h，以防低血糖症再次出现。
药物相互作用　

本品与水杨酸盐类、磺胺类、氯霉素、丙磺舒、香豆素类、单胺氧化酶抑制剂和β肾上腺素能阻滞药合用，可增强本品的降血糖作用；与噻嗪类利尿药、肾上腺皮质激素、苯噻嗪类、甲状腺制剂、雌激素、口服避孕药、苯妥英、烟酸、拟交感神经药、钙通道阻滞药及异烟肼合用可能降低本品的作用。
规格

氯磺丙脲片 (1)0.1g(2)0.25g

diabinese (chlorpropamide)  tablet 
[Pfizer Labs]

DESCRIPTION

DIABINESE® (chlorpropamide), is an oral blood-glucose-lowering drug of the sulfonylurea class. Chlorpropamide is 1-[(p-Chlorophenyl)sulfonyl]-3-propylurea, C10H13ClN2O3S, and has the structural formula:

Chlorpropamide is a white crystalline powder, that has a slight odor. It is practically insoluble in water at pH 7.3 (solubility at pH 6 is 2.2 mg/mL). It is soluble in alcohol and moderately soluble in chloroform. The molecular weight of chlorpropamide is 276.74. DIABINESE is available as 100 mg and 250 mg tablets.

Inert ingredients are: alginic acid; Blue 1 Lake; hydroxypropyl cellulose; magnesium stearate; precipitated calcium carbonate; sodium lauryl sulfate; starch.

CLINICAL PHARMACOLOGY

DIABINESE appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which DIABINESE lowers blood glucose during long-term administration has not been clearly established. Extra-pancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. While chlorpropamide is a sulfonamide derivative, it is devoid of antibacterial activity.

DIABINESE may also prove effective in controlling certain patients who have experienced primary or secondary failure to other sulfonylurea agents.

A method developed which permits easy measurement of the drug in blood is available on request.

Chlorpropamide does not interfere with the usual tests to detect albumin in the urine.

DIABINESE is absorbed rapidly from the gastrointestinal tract. Within one hour after a single oral dose, it is readily detectable in the blood, and the level reaches a maximum within two to four hours. It undergoes metabolism in humans and it is excreted in the urine as unchanged drug and as hydroxylated or hydrolyzed metabolites. The biological half-life of chlorpropamide averages about 36 hours. Within 96 hours, 80–90% of a single oral dose is excreted in the urine. However, long-term administration of therapeutic doses does not result in undue accumulation in the blood, since absorption and excretion rates become stabilized in about 5 to 7 days after the initiation of therapy.

DIABINESE exerts a hypoglycemic effect in healthy subjects within one hour, becoming maximal at 3 to 6 hours and persisting for at least 24 hours. The potency of chlorpropamide is approximately six times that of tolbutamide. Some experimental results suggest that its increased duration of action may be the result of slower excretion and absence of significant deactivation.

INDICATIONS AND USAGE

DIABINESE is indicated as an adjunct to diet to lower the blood glucose in patients with type 2 diabetes whose hyperglycemia cannot be controlled by diet alone.

In initiating treatment for non-insulin-dependent diabetes, diet should be emphasized as the primary form of treatment. Caloric restriction and weight loss are essential in the obese diabetic patient. Proper dietary management alone may be effective in controlling the blood glucose and symptoms of hyperglycemia. The importance of regular physical activity should also be stressed, and cardiovascular risk factors should be identified and corrective measures taken where possible.

If this treatment program fails to reduce symptoms and/or blood glucose, the use of an oral sulfonylurea or insulin should be considered. Use of DIABINESE must be viewed by both the physician and patient as a treatment in addition to diet, and not as a substitute for diet or as a convenient mechanism for avoiding dietary restraint. Furthermore, loss of blood glucose control on diet alone may be transient, thus requiring only short-term administration of DIABINESE.

During maintenance programs, DIABINESE should be discontinued if satisfactory lowering of blood glucose is no longer achieved. Judgments should be based on regular clinical and laboratory evaluations.

In considering the use of DIABINESE in asymptomatic patients, it should be recognized that controlling the blood glucose in non-insulin-dependent diabetes, has not been definitely established to be effective in preventing the long-term cardiovascular or neural complications of diabetes.

CONTRAINDICATIONS

DIABINESE is contraindicated in patients with:

1. Known hypersensitivity to any component of this medicine.
2. Diabetic ketoacidosis, with or without coma. This condition should be treated with insulin.
3. Type 1 diabetes.

WARNINGS

SPECIAL WARNING ON INCREASED RISK OF CARDIOVASCULAR MORTALITY

The administration of oral hypoglycemic drugs has been reported to be associated with increased cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the University Group Diabetes Program (UGDP), a long-term prospective clinical trial designed to evaluate the effectiveness of glucose-lowering drugs in preventing or delaying vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who were randomly assigned to one of four treatment groups (Diabetes, 19 [supp. 2]:747–830, 1970).

UGDP reported that patients treated for 5 to 8 years with diet plus a fixed dose of tolbutamide (1.5 grams per day) had a rate of cardiovascular mortality approximately 2½ times that of patients treated with diet alone. A significant increase in total mortality was not observed, but the use of tolbutamide was discontinued based on the increase in cardiovascular mortality, thus limiting the opportunity for the study to show an increase in over-all mortality. Despite controversy regarding the interpretation of these results, the findings of the UGDP study provide an adequate basis for this warning. The patient should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy.

Although only one drug in the sulfonylurea class (tolbutamide) was included in this study, it is prudent from a safety standpoint to consider that this warning may also apply to other oral hypoglycemic drugs in this class, in view of their close similarities in mode of action and chemical structure.

PRECAUTIONS

General

Hypoglycemia

All sulfonylurea drugs including chlorpropamide are capable of producing severe hypoglycemia, which may result in coma, and may require hospitalization. Patients experiencing hypoglycemia should be managed with appropriate glucose therapy and be monitored for a minimum of 24 to 48 hours (see Overdosage section). Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Regular, timely carbohydrate intake is important to avoid hypoglycemic events occurring when a meal is delayed or insufficient food is eaten or carbohydrate intake is unbalanced. Renal or hepatic insufficiency may affect the disposition of DIABINESE and may also diminish gluconeogenic capacity, both of which increase the risk of serious hypoglycemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more than one glucose-lowering drug is used.

Because of the long half-life of chlorpropamide, patients who become hypoglycemic during therapy require careful supervision of the dose and frequent feedings for at least 3 to 5 days. Hospitalization and intravenous glucose may be necessary.

Loss of control of blood glucose

When a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a loss of control may occur. At such times, it may be necessary to discontinue DIABINESE and administer insulin.

The effectiveness of any oral hypoglycemic drug, including DIABINESE, in lowering blood glucose to a desired level decreases in many patients over a period of time, which may be due to progression of the severity of the diabetes or to diminished responsiveness to the drug. This phenomenon is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective in an individual patient when first given. Adequate adjustment of dose and adherence to diet should be assessed before classifying a patient as a secondary failure.

Geriatric Use

The safety and effectiveness of DIABINESE in patients aged 65 and over has not been properly evaluated in clinical studies. Adverse event reporting suggests that elderly patients may be more prone to developing hypoglycemia and/or hyponatremia when using DIABINESE. Although the underlying mechanisms are unknown, abnormal renal function, drug interaction and poor nutrition appear to contribute to these events.

INFORMATION FOR PATIENTS

Patients should be informed of the potential risks and advantages of DIABINESE and of alternative modes of therapy. They should also be informed about the importance of adherence to dietary instructions, of a regular exercise program, and of regular testing of blood glucose.

The risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. Primary and secondary failure should also be explained.

Patients should be instructed to contact their physician promptly if they experience symptoms of hypoglycemia or other adverse reactions.

LABORATORY TESTS

Blood glucose should be monitored periodically. Measurement of glycosylated hemoglobin should be performed and goals assessed by the current standard of care.

DRUG INTERACTIONS

The following products can lead to hypoglycemia

The hypoglycemic action of sulfonylurea may be potentiated by certain drugs including nonsteroidal anti-inflammatory agents and other drugs that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such drugs are administered to a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for loss of control.

Miconazole

A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycemia has been reported. Whether this interaction also occurs with intravenous, topical, or vaginal preparations of miconazole is not known.

Alcohol

In some patients, a disulfiram-like reaction may be produced by the ingestion of alcohol. Moderate to large amounts of alcohol may increase the risk of hypoglycemia (ref.1), (ref. 2).

The following products can lead to hyperglycemia

Certain drugs tend to produce hyperglycemia and may lead to loss of control. These drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid.

When such drugs are administered to a patient receiving DIABINESE, the patient should be closely observed for loss of control. When such drugs are withdrawn from a patient receiving DIABINESE, the patient should be observed closely for hypoglycemia.

Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide, barbiturates should be employed with caution.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Studies with DIABINESE have not been conducted to evaluate carcinogenic or mutagenic potential.

Rats treated with continuous DIABINESE therapy for 6 to 12 months showed varying degrees of suppression of spermatogenesis at a dose level of 250 mg/kg (five times the human dose based on body surface area). The extent of suppression seemed to follow that of growth retardation associated with chronic administration of high-dose DIABINESE in rats. The human dose of chlorpropamide is 500 mg/day (300 mg/M2). Six- and 12-month toxicity work in the dog and rat, respectively, indicates the 150 mg/kg is well tolerated. Therefore, the safety margins based upon body-surface-area comparisons are three times human exposure in the rat and 10 times human exposure in the dog.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Animal reproductive studies have not been conducted with DIABINESE. It is also not known whether DIABINESE can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. DIABINESE should be given to a pregnant woman only if the potential benefits justify the potential risk to the patient and fetus.

Because data suggest that abnormal blood glucose levels during pregnancy are associated with a higher incidence of congenital abnormalities, many experts recommend that insulin be used during pregnancy to maintain blood glucose levels as close to normal as possible.

Nonteratogenic Effects

Prolonged severe hypoglycemia (4 to 10 days) has been reported in neonates born to mothers who were receiving a sulfonylurea drug at the time of delivery. This has been reported more frequently with the use of agents with prolonged half-lives. If DIABINESE is used during pregnancy, it should be discontinued at least one month before the expected delivery date and other therapies instituted to maintain blood glucose levels as close to normal as possible.

Nursing Mothers

An analysis of a composite of two samples of human breast milk, each taken five hours after ingestion of 500 mg of chlorpropamide by a patient, revealed a concentration of 5 mcg/mL. For reference, the normal peak blood level of chlorpropamide after a single 250 mg dose is 30 mcg/mL. Therefore, it is not recommended that a woman breast feed while taking this medication.

Use in Children

Safety and effectiveness in children have not been established.

Ability to Drive and Use Machines

The effect of DIABINESE on the ability to drive or operate machinery has not been studied. However, there is no evidence to suggest that DIABINESE may affect these abilities. Patients should be aware of the symptoms of hypoglycemia and take caution while driving and operating machinery.

ADVERSE REACTIONS

Body as a Whole

Disulfiram-like reactions have rarely been reported with DIABINESE (see DRUG INTERACTIONS).

Central and Peripheral Nervous System

Dizziness (ref. 3) and headache (ref. 4).

Hypoglycemia

See PRECAUTIONS and OVERDOSAGE sections.

Gastrointestinal

Gastrointestinal disturbances are the most common reactions; nausea has been reported in less than 5% of patients, and diarrhea, vomiting, anorexia, and hunger in less than 2%. Other gastrointestinal disturbances have occurred in less than 1% of patients including proctocolitis. They tend to be dose-related and may disappear when dosage is reduced.

Liver/Biliary

Cholestatic jaundice may occur rarely; DIABINESE should be discontinued if this occurs. Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE.

Skin/Appendages

Pruritus has been reported in less than 3% of patients. Other allergic skin reactions, e.g., urticaria and maculopapular eruptions have been reported in approximately 1% or less of patients. These may be transient and may disappear despite continued use of DIABINESE; if skin reactions persist the drug should be discontinued.

As with other sulfonylureas, porphyria cutanea tarda and photosensitivity reactions have been reported.

Skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis have also been reported.

Hematologic Reactions

Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas.

Metabolic/Nutritional Reactions

Hypoglycemia (see PRECAUTIONS and OVERDOSAGE sections). Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. See DRUG INTERACTIONS section.

Endocrine Reactions

On rare occasions, chlorpropamide has caused a reaction identical to the syndrome of inappropriate antidiuretic hormone (ADH) secretion. The features of this syndrome result from excessive water retention and include hyponatremia, low serum osmolality, and high urine osmolality. This reaction has also been reported for other sulfonylureas.

OVERDOSAGE

Overdosage of sulfonylureas including DIABINESE can produce hypoglycemia. Mild hypoglycemic symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in drug dosage and/or meal patterns. Close monitoring should continue until the physician is assured that the patient is out of danger. Severe hypoglycemic reactions with coma, seizure, or other neurological impairment occur infrequently, but constitute medical emergencies requiring immediate hospitalization. If hypoglycemic coma is diagnosed or suspected, the patient should be given a rapid intravenous injection of concentrated (50%) glucose solution. This should be followed by a continuous infusion of a more dilute (10%) glucose solution at a rate that will maintain the blood glucose at a level above 100 mg/dL. Patients should be closely monitored for a minimum of 24 to 48 hours since hypoglycemia may recur after apparent clinical recovery.

DOSAGE AND ADMINISTRATION

There is no fixed dosage regimen for the management of type 2 diabetes with DIABINESE or any other hypoglycemic agent. The patient's blood glucose must be monitored periodically to determine the minimum effective dose for the patient; to detect primary failure, i.e., inadequate lowering of blood glucose at the maximum recommended dose of medication; and to detect secondary failure, i.e., loss of an adequate blood glucose lowering response after an initial period of effectiveness. Glycosylated hemoglobin levels may also be of value in monitoring the patient's response to therapy.

Short-term administration of DIABINESE may be sufficient during periods of transient loss of control in patients usually controlled well on diet.

The total daily dosage is generally taken at a single time each morning with breakfast. Occasionally cases of gastrointestinal intolerance may be relieved by dividing the daily dosage. A LOADING OR PRIMING DOSE IS NOT NECESSARY AND SHOULD NOT BE USED.

Initial Therapy

1. The mild to moderately severe, middle-aged, stable type 2 diabetes patient should be started on 250 mg daily. In elderly patients, debilitated or malnourished patients, and patients with impaired renal or hepatic function, the initial and maintenance dosing should be conservative to avoid hypoglycemic reactions (see PRECAUTIONS section). Older patients should be started on smaller amounts of DIABINESE, in the range of 100 to 125 mg daily.

2. No transition period is necessary when transferring patients from other oral hypoglycemic agents to DIABINESE. The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency.

Many mild to moderately severe, middle-aged, stable type 2 diabetes patients receiving insulin can be placed directly on the oral drug and their insulin abruptly discontinued. For patients requiring more than 40 units of insulin daily, therapy with DIABINESE may be initiated with a 50 per cent reduction in insulin for the first few days, with subsequent further reductions dependent upon the response.

During the initial period of therapy with chlorpropamide, hypoglycemic reactions may occasionally occur, particularly during the transition from insulin to the oral drug. Hypoglycemia within 24 hours after withdrawal of the intermediate or long-acting types of insulin will usually prove to be the result of insulin carry-over and not primarily due to the effect of chlorpropamide.

During the insulin withdrawal period, the patient should self-monitor glucose levels at least three times daily. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalization during the transition period.

Five to seven days after the initial therapy, the blood level of chlorpropamide reaches a plateau. Dosage may subsequently be adjusted upward or downward by increments of not more than 50 to l25 mg at intervals of three to five days to obtain optimal control. More frequent adjustments are usually undesirable.

Maintenance Therapy

Most moderately severe, middle-aged, stable type 2 diabetes patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg or less. Many of the more severe diabetics may require 500 mg daily for adequate control. PATIENTS WHO DO NOT RESPOND COMPLETELY TO 500 MG DAILY WILL USUALLY NOT RESPOND TO HIGHER DOSES. MAINTENANCE DOSES ABOVE 750 mg DAILY SHOULD BE AVOIDED.

HOW SUPPLIED

Strength	Tablet Description	Tablet Code	NDC	Package Size
DIABINESE (chlorpropamide) 100 mg	Blue, D-shaped, scored	393	0069-3930-66	100's
DIABINESE (chlorpropamide) 250 mg	Blue, D-shaped, scored	394	0069-3940-66 0069-3940-82	100's 1000's

RECOMMENDED STORAGE: Store below 86°F (30°C).