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.<br/>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 . 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.<br/>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.
DIABINESE' (chlorpropamide), is an oral blood-glucose-lowering drug of the sulfonylurea class. Chlorpropamide is 1-[(p-Chlorophenyl)sulfonyl]-3-propylurea, CHClNOS, 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.
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 96hours, 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.
DIABINESE is contraindicated in patients with:
RECOMMENDED STORAGE: Store below 86��F (30��C).
Body as a Whole: Disulfiram-like reactions have rarely been reported with DIABINESE .<br/>Central and Peripheral Nervous System: Dizziness (ref. 3) and headache (ref. 4).<br/>Hypoglycemia: See PRECAUTIONS and OVERDOSAGE sections.<br/>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.<br/>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.<br/>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.<br/>Hematologic Reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia, pancytopenia, and eosinophilia have been reported with sulfonylureas.<br/>Metabolic/Nutritional Reactions: Hypoglycemia . Hepatic porphyria and disulfiram-like reactions have been reported with DIABINESE. See DRUG INTERACTIONS section.<br/>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.
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 2��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.
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.