INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
DIABINESE 250 mg Tablet

Chlorpropamide
DIABINESE^®TABLETS
        S3
        Prescription
        Required

SCHEDULING STATUS:
Schedule 3

PROPRIETARY NAMES
(and dosage form):

DIABINESE 250 mg Tablet

COMPOSITION:
Each 250 mg Diabinese Tablet contains 250 mg Chlorpropamide.
Diabinese 250 mg Tablets contain the following inert ingredients: Ethyl cellulose, starch, FD & C Blue # 1, alginic acid, calcium carbonate, magnesium stearate, sodium lauryl sulphate and isopropanol.

PHARMACOLOGICAL CLASSIFICATION:
A.21.2 Oral hypoglycaemics.

PHARMACOLOGICAL ACTION:
Diabinese brand of chlorpropamide is an oral hypoglycaemic agent of the sulfonylurea class. The precise mechanism of action is not completely understood but it is not an oral insulin.
It’s mode of action is believed to be that of stimulation of synthesis and release of endogenous insulin, an effect that is dependent on functioning beta cells in the pancreas.
Diabinese (chlorpropamide) is absorbed rapidly from the gastro-intestinal 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 is not significantly metabolized or deactivated. It is slowly excreted in the urine, for the most part as unchanged chlorpropamide. 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.
With normal hepatic and renal function, 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 (chlorpropamide) exerts a hypoglycaemic effect in non-diabetic subjects within one hour, becoming maximal at 3 to 6 hours. The effect could persist for as long as 96 hours. Some experimental results suggest that the long duration of action may be the result of slower excretion and absence of significant deactivation.

INDICATIONS:
Diabinese (chlorpropamide) is indicated in patients with non-insulin-dependent diabetesmellitus (NIDDM), which cannot be completely controlled by diet alone.
Patient selection: A trial period may be indicated in certain patients who might be expected to respond to this type of medication. The most likely patient for therapy is one in whom diabetes is of the maturity-onset type, stable, and not controllable by dietary regulation alone.
The final evaluation of response in patients who qualify as candidates for Diabinese (chlorpropamide) is a therapeutic trial for a period of at least seven days. During the trial period, the absence of ketonuria together with a satisfactory reduction of glycosuria and hyperglycaemia, or maintenance of previously satisfactory control, indicates that the patient is responsive and amenable to control with the medicine. However, the development of ketonuria within 24 hours after withdrawal of insulin usually will be indicative of a poor response.
The patient is considered non-responsive if he fails to achieve satisfactory lowering of blood sugar levels or fails to obtain objective or subjective clinical improvement and if he develops ketonuria or glycosuria. Insulin is indicated for the therapy of such patients.
Concurrent Diabinese (chlorpropamide)-Biguanide Therapy: The concurrent use of Diabinese (Chlorpropamide) with a biguanide (phenformin, metformin) is indicated in the treatment of non-insulin-dependent diabetes mellitus (NIDDM), which cannot be controlled by diet alone, by diet and insulin, or by diet and sulfonylurea agents. The appropriate biguanide product document should be consulted for complete details of patient selection, indications, warnings and dose.
Diabinese (chlorpropamide) in Diabetes Insipidus: Limited studies to date have shown that chlorpropamide is also useful in the treatment of idiopathic diabetes insipidus. In using chlorpropamide for this purpose, the physician must remain constantly aware of the possible occurrence of hypoglycaemic reactions in such individuals, particularly when unrelated illness, or other causes, reduce food intake. When chlorpropamide must be temporarily discontinued in such cases, therapy with antidiuretic hormone should be substituted.
In the treatment of diabetes insipidus, daily dosage has been in the range of 100 mg-500 mg daily for older children and adults.
Because of the risk of hypoglycaemia that can develop in these individuals, it is desirable to start therapy at the lower range, gradually adjusting the dose as indicated. Patients, and particularly the parents of children who are patients, should be warned of the possibility and treatment of hypoglycaemic reactions, especially during inter-current infections or other periods of impaired food intake. In such circumstances, chlorpropamide therapy should be promptly discontinued and the patient's physician contacted.
When physicians are considering Diabinese (chlorpropamide) for the treatment of diabetes insipidus, it is essential that they read this product document completely and particularly those paragraphs relating to side effects and special precautions.

CONTRA-INDICATIONS:
Use of Diabinese (chlorpropamide) is contra-indicated in patients having:

	1.	Insulin-dependent diabetes mellitus (IDDM), formerly known as Juvenile or growth-onset diabetes mellitus
	2.	Severe or unstable "brittle" diabetes.
	3.	Diabetes complicated by ketosis and acidosis, diabetic coma, surgery, infection or trauma.
	4.	In patients with a known hypersensitivity to chlorpropamide.

Diabinese (chlorpropamide) is contra-indicated during pregnancy. Safe conditions for the use of Diabinese (chlorpropamide) in pregnancy have not been established and serious consideration should be given to the potential hazard of its use in women of the childbearing age who may become pregnant.
Diabinese (chlorpropamide) is contra-indicated in patients with serious impairment of hepatic, renal or thyroid function.
It is not recommended that a women breast feed while taking this medication.
Safety and effectiveness in children have not been established.

WARNINGS:
DIABINESE (chlorpropamide) SHOULD NOT BE USED IN IDDM OR IN DIABETES COMPLICATED BY ACIDOSIS, COMA, INFECTION, SURGICAL PROCEDURES, OR TRAUMA. HERE, INSULIN IS INDISPENSABLE.
Although Diabinese (chlorpropamide) given alone has controlled some patients with mild maturity-onset diabetes of the stable type during the stress of mild infection or minor surgery, insulin therapy is generally essential during intercurrent complications (for example, ketoacidosis, severe trauma, major surgical procedures, severe infections, severe diarrhoea, nausea and vomiting, etc).
IN CASE OF ACCIDENTAL INGESTION BY CHILDREN, DUE NOTE SHOULD BE TAKEN OF THE FACT THAT 3 - 5 DAYS ARE REQUIRED FOR COMPLETE ELIMINATION OF CHLORPROPAMIDE FROM THE BODY, AND THE PATIENT SHOULD BE KEPT UNDER CLOSE OBSERVATION FOR THIS PERIOD OF TIME DESPITE APPARENT RECOVERY.
Since insulin still remains the standard therapy for patients during periods of stress or complication, the patient on chlorpropamide must be instructed in the use of insulin. The patient must also be alerted to the early detection and prompt treatment of hypoglycaemia since this complication, although less frequent, may develop on sulfonylurea therapy as well as on insulin therapy.
During the initial period of therapy with chlorpropamide, hypoglycaemic reactions may occasionally occur, particularly during the transition from insulin to oral agent.
Hypoglycaemia, 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.
Diabinese (chlorpropamide) should be used with caution in elderly patients.

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

Initial therapy: The mild to moderately severe, middle-aged stable diabetic patient should be started on 250 mg daily. Because the geriatric diabetic patient appears to be more sensitive to the hypoglycaemic effect of sulphonylurea’s, older patients should be started on smaller amounts of Diabinese (chlorpropamide), in the range of 100 mg to 125 mg daily.
No transition period is necessary when transferring patients from other oral hypoglycaemic agents to Diabinese (chlorpropamide). The other agent may be discontinued abruptly and chlorpropamide started at once. In prescribing chlorpropamide, due consideration must be given to its greater potency. The large majority of mild to moderately severe middle-aged, stable diabetic patients receiving insulin can be placed directly on the oral agent and their insulin abruptly discontinued.
For patients requiring more than 40 units of insulin daily, therapy with Diabinese (chlorpropamide) may be initiated with a 50% reduction in insulin for the first few days, with subsequent further reductions dependent upon the response.
During the insulin withdrawal period, the patient should test his urine for sugar and ketone bodies at least three times daily and report the results frequently to his physician. If they are abnormal, the physician should be notified immediately. In some cases, it may be advisable to consider hospitalisation 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 mg to 125 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 diabetic patients are controlled by approximately 250 mg daily. Many investigators have found that some milder diabetics do well on daily doses of 100 mg - 125 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 / Phenformin Dosage: The dosage of DIABINESE should be maintained at or increased to 500 mg. If control is still inadequate, phenformin may be added in accordance with the dosage recommendation appearing in the local phenformin product document. In no case should the daily dose of phenformin exceed 100 mg.
If adequate control is obtained without side effects, reduction in dosage of both DIABINESE and phenformin should be undertaken slowly (reducing the dosage of one medicine at a time) in an attempt to maintain control with the least possible medication.

Diabinese / Metformin Dosage: The dosage of DIABINESE should be maintained at or increased to 500 mg. If control is still inadequate, metformin may be added at a dosage of 0,5 gram twice daily, increasing by 0,5 to 1,0 gram every one to two weeks to a maximum of 3 grams daily.
If adequate control is obtained without side effects, reduction in dosage of both DIABINESE and metformin should be undertaken slowly (reducing the dosage of one medicine at a time) in an attempt to maintain control with the least possible medication.

SIDE EFFECTS AND SPECIAL PRECAUTIONS:
The majority of side effects have been dose-related, transient and have responded to dose reduction or withdrawal of the medication. However, clinical experience thus far has shown that, as with other sulfonylureas, some side effects associated with hypersensitivity may be severe and deaths have been reported in some instances.
Certain untoward reactions associated with idiosyncrasy or hypersensitivity have occurred, including jaundice, skin eruptions less frequently progressing to erythema multiforme and exfoliative dermatitis, and probably depression of formed elements of the blood, show no direct relationship to the size of the dose. They occur characteristically during the first six weeks of therapy. With a few exceptions, these manifestations have been mild and readily reversible on the withdrawal of the medicine.
The more severe manifestations may require other therapeutic measures, including corticosteroid therapy. Diabinese (chlorpropamide) should be discontinued promptly when the development of sensitivity is suspected.
Jaundice has been reported and is usually promptly reversible on discontinuance of therapy. On the basis of considerable histopathologic evidence, the jaundice is cholangiolitic and results primarily from intracanalicular biliary stasis rather than hepatocellular degeneration.
The alkaline phosphatase which frequently shows serial and progressive elevation in these patients is of particular diagnostic value. THE OCCURRENCE OF PROGRESSIVE ELEVATION SHOULD SUGGEST THE POSSIBILITY OF INCIPIENT JAUNDICE AND CONSTITUTES AN INDICATION FOR WITHDRAWAL OF THE MEDICINE.
In contrast, transient alterations of certain liver function tests seen occasionally following institution of sulfonylurea therapy, appear to be of no clinical significance.
Pruritis, other allergic skin reactions e.g. urticaria and maculopapular eruptions, have been reported with the use of sulfonylureas.
Skin rash may be either the only manifestation of sensitivity, or occur in association with jaundice, frequently preceding it. Low grade fever and eosinophilia may also occur in association with, or preceding the development of clinical jaundice. Less frequently, severe diarrhoea, sometimes accompanied by bleeding into the lower bowel and due to nonspecific proctocolitis, has been associated with other hypersensitivity manifestations, particularly jaundice, skin rash, or both. The occurrence, singly or together, of any of these hypersensitivity manifestations, should constitute an indication for prompt termination of the medicine, and such other therapeutic measures as are dictated by the circumstances should be instituted.
Hematological reactions: Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, aplastic anemia and pancytopenia have been reported with sulfonylureas.
Leukopoenia, thrombocytopoenia and haemolytic anemia which occur occasionally, are generally benign and revert to normal, following cessation of the medicine. Leukopoenia of mild degree, and not associated with a shift in the differential count, may be transient and frequently reverts to normal even while the medicine is continued.
Cases of aplastic anemia and agranulocytosis, generally similar to blood dyscrasias associated with other sulfonylureas have been reported. Lymphocytosis appears to be of no clinical significance.
Dose-related side effects previously mentioned are generally transient and not of a serious nature and would include anorexia, nausea, vomiting, an increase in appetite and epigastric discomfort as evidence of gastro-intestinal intolerance, and various vague neurologic symptoms, particularly weakness and paresthesias. These manifestations are generally a direct function of dosage and were reported much more frequently during the early clinical history of the medicine when some clinicians employed relatively high doses. These side effects are reversible on reduction of the daily dosage, or if necessary, by withdrawal of the medication.
Administration of the total daily medicine requirement in two doses rather than one is sometimes an effective measure for alleviating symptoms of gastro-intestinal intolerance.
Hypoglycaemia, although not a true side effect but rather an exaggeration of the expected therapeutic action, may be the result of dosage in excess of the patient's immediate requirements, as is the case with any hypoglycaemic agent.
Since the development of hypoglycaemia is a function of many factors, including diet, this side effect is at times seen in patients on the usual recommended dosage. It is readily controlled by administration of glucose. Its occurrence is an obvious indication for immediate re-evaluation and adjustment of the insulin or chlorpropamide dosage.
Renal or hepatic insufficiency may cause elevated blood levels of DIABINESE and the latter may also diminish glyconeogenic capacity, both of which increase the risk of serious hypoglycaemic reactions. Elderly, debilitated or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycaemic action of glucose-lowering agents. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking agents. Hypoglycemia is more likely to occur when caloric intake is deficient, after severe or prolonged exercise, when alcohol is ingested, or when more then one glucose-lowering agent is used.

BECAUSE OF THE PROLONGED HYPOGLYCAEMIC ACTION OF DIABINESE (chlorpropamide), PATIENTS WHO BECOME HYPOGLYCAEMIC DURING THERAPY WITH THIS MEDICINE REQUIRE CLOSE SUPERVISION FOR A MINIMUM PERIOD OF 3 TO 5 DAYS, during which time frequent feedings or glucose administration are essential. The anorectic patient or the profoundly hypoglycaemic patient should be hospitalised.
Porphyria cutanea tarda and less frequent cases of photosensitive reactions have been reported with sulfonylureas.
Hepatic porphyria and disulfiram-like reactions have less frequently been reported with DIABINESE. see “Interactions“section
Mild to severe hyponatraemia with or without oedema has been frequently reported with Diabinese (chlorpropamide) therapy. This is thought to occur by potentiation of available ADH with subsequent water retention. The condition is usually readily reversible upon discontinuation of medication.
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.

INFORMATION FOR THE PATIENT:
During the first six weeks of therapy, the physician should be in contact with the patient at least once a week. During this initial period, the patient must be observed for evidence of occasional medicine reactions as described in the SIDE EFFECTS AND SPECIAL PRECAUTIONS section. Because of the possibility of the following manifestations of hypersensitivity the patient should be instructed to report immediately to his physician if he does not feel as well as usual, or notes any pruritus, rash, jaundice, dark urine, light colored stools, low-grade fever, sore throat, or diarrhoea. As with all medicines, careful attention must be given to weigh the therapeutic advantages against the nature and incidence of side effects. During the period of transition to Diabinese (chlorpropamide) the patient's urine should be tested for sugar and acetone at least three times daily and the results reviewed by the physician at least once a week. Frequent laboratory determinations of liver function should also be seriously considered.
Although transient minor alterations, particularly of cephalin flocculation, thymol turbidity, and serum alkaline phosphatase levels are not usual and are probably of no clinical significance, a progressive rise in the alkaline phosphatase value should alert the physician to the possibility of incipient biliary stasis and jaundice, and chlorpropamide therapy should be promptly discontinued. After the initial six weeks of therapy, subsequent patient-physician contacts may be at less frequent intervals, the exact frequency dependent on the judgment of the physician.
The medicine should be used as an adjunct to, not a substitute for, dietary regulation, for this remains the primary consideration of diabetic management. It does not alter the need to educate the patient to such standard prophylactic and therapeutic measures as weight and exercise control, proper hygiene, and prompt care of intercurrent infection.

INTERACTIONS:
Since animal studies suggest that the action of barbiturates may be prolonged by therapy with chlorpropamide, barbiturates should be employed with caution. Similarly, studies showing an exaggerated hypoglycaemic effect of chlorpropamide in adrenalectomised animals suggest cautious use in patients with Addison's disease.
In some patients, a disulfiram-like reaction may be produced by the ingestion of alcohol.
The hypoglycemic action of sulfonylureas may be potentiated by certain medicines including nonsteroidal anti-inflammatory agents and other agents that are highly protein bound, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, and beta adrenergic blocking agents. When such agents are administered to a patient receiving Diabinese, the patient should be observed closely for hypoglycaemia. When such agents are withdrawn from a patient receiving Diabinese, the patient should be observed closely for loss of control.
Certain medicines tend to produce hyperglycaemia and may lead to loss of control. These medicines include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking agents and isoniazid. When such medicines are administered to a patient receiving Diabinese, the patient should be closely observed for loss of control. When such medicines are withdrawn from a patient receiving Diabinese the patient should be observed closely for hypoglycemia.
A potential interaction between oral miconazole and oral hypoglycemic agents leading to severe hypoglycaemia has been reported with some sulfonylureas. Whether this interaction also occurs with intravenous, topical or vaginal preparations of miconazole is not known
Alcohol and decreased diet may lead to hypoglycaemia, ketosis, coma, and death.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Overdosage can produce severe and prolonged hypoglycemia.
Severe hypoglycemia may cause coma, seizure or neurological impairments, infrequently.
Treatment of overdosage:
Mild hypoglycemia symptoms without loss of consciousness or neurologic findings should be treated aggressively with oral glucose and adjustments in medicine 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.

IDENTIFICATION:
250 mg tablet: well formed round blue tablet, bisected on one side and with "Pfizer" and "250" on the reverse.

PRESENTATION:
Diabinese tablets:        250 mg scored tablets (blue) in packs of 100.

STORAGE INSTRUCTIONS:
Store below 30°C. Keep out of reach of children.

REGISTRATION NUMBERS:
250 mg Diabinese Tablets: G3031 (Act 101/1965)

NAME AND ADDRESS OF APPLICANT:
Pfizer Laboratories (Pty) LTD
102 Rivonia Road
SANDTON
2196

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
12 October 1982

Updated on this site: February 2000
SAEPI HOME PAGE      TRADE NAME INDEX      GENERIC NAME INDEX      FEEDBACK
Information presented by Malahyde Information Systems © Copyright 1996-2005