INDICATIONS     CONTRA-INDICATIONS     DOSAGE     SIDE-EFFECTS     PREGNANCY     OVERDOSE     IDENTIFICATION     PATIENT INFORMATION
HYPOMIDE®-100 TABLETS
HYPOMIDE®-250 TABLETS

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

HYPOMIDE^®-100 TABLETS
HYPOMIDE^®-250 TABLETS

COMPOSITION:
Each tablet contains Chlorpropamide 100 mg or 250 mg.

PHARMACOLOGICAL CLASSIFICATION:
A 21.2 Oral Hypoglycaemics.

PHARMACOLOGICAL ACTION:
The mode of action of chlorpropamide is believed to be that of stimulation of the synthesis and release of endogenous insulin. There is evidence that improvement in pancreatic beta cell function, with consequent improvement in glucose tolerance may occur with prolonged administration of chlorpropamide.

INDICATIONS:
Chlorpropamide is indicated in uncomplicated diabetes mellitus of the stable, mild or moderately severe, non-ketotic, maturity-onset type, which cannot be controlled by diet alone. Patients should be carefully selected for chlorpropamide therapy. Evaluation of response in patients who qualify as candidates for 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 hyperglycemia, or maintenance of previously satisfactory control, indicates that the patient is responsive and amendable to control with the drug. 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, fails to obtain objective or subjective clinical improvement and if he develops ketonuria or glycosuria. Insulin is indicated for the therapy of such patients.

CONTRA-INDICATIONS:
Use of chlorpropamide as the sole specific agent of therapy is not indicated in patients having juvenile or growth-onset type of diabetes mellitus, unstable or severely “brittle” type of diabetes and adult or maturity-onset type of diabetes complicated by ketosis, acidosis, diabetic coma, fever, severe trauma, gangrene, Raynaud's disease, or serious impairment of renal, hepatic or thyroid function. Chlorpropamide is also contra-indicated in pregnancy.
Chlorpropamide is dangerous in patients suffering from acute forms of porphyria, especially variegate porphyria, and to a lesser extent acute intermittent porphyria and hereditary coproporphyria.

DOSAGE AND DIRECTIONS FOR USE:
The total daily dosage is generally taken at a single time each morning after 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.
Initiation of Chlorpropamide:
Therapy and adjustment of dosage to maintenance levels can be accomplished readily in most patients utilising the 100 mg and 250 mg tablet.
Initiation of therapy and method of administration: the dosage recommendations for chlorpropamide are as follows:

1.	The mild or moderately severe middle-aged or slightly older stable adult diabetic patient, whether or not he is receiving insulin, should be started on 250 mg daily.
2.	Because the geriatric patient appears to be more sensitive to the hypoglycaemic effects of chlorpropamide, consideration should be given to starting older patients on as little as 100 mg - 125 mg daily.

No diabetic patients should be started on more than 500 mg of chlorpropamide daily. After three to five days, the blood concentration of chlorpropamide will have reached maximal therapeutic levels. According to patient response, dosage can then be adjusted to an effective level by increasing or decreasing daily dosage by 50 mg to 125 mg at intervals of three to five days. Most patients are adequately controlled on a maintenance dosage of 50 mg to 500 mg daily. Minimal effective doses may sometimes be administered every other day. As a general rule 500 mg daily should be considered the maximal maintenance dose and should not be exceeded.
Insulin should not be stopped abruptly in the severe or “brittle” diabetic patient or, in the patient receiving over 40 units of insulin per day. However, the large majority of diabetic patients taking insulin receive less than 40 units per day. In these patients, when oral antidiabetic therapy is indicated, insulin administration may be discontinued with initiation of chlorpropamide therapy. In patients requiring more than 40 units of insulin daily, chlorpropamide therapy may be initiated and insulin administration be decreased at the same time. Depending upon the response of the patient to chlorpropamide, insulin dosage may then be further reduced as indicated.
During the insulin withdrawal period urine examination will serve to check on the progress of the patient and his response to therapy. The patient should be carefully instructed to report to his physician immediately on the occurence of subjective or objective evidence of illness, and should be taught the early recognition and treatment of hypoglycaemia.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
The majority of the 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.
Chlorpropamide has a somewhat higher reported incidence of side-effects than tolbutamide.
Certain untoward reactions associated with idiosyncrasy of hypersensitivity have occurred, including jaundice, skin eruptions rarely progressing to erythema multiforme and exfoliative dermatitis, and probably depression of formed elements of the blood, showing 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 drug. Rare cases of phototoxic reactions
have been reported.
The more severe manifestations may require other therapeutic measures, including corticosteroid therapy. 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.
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. Rarely, 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 drug and such other therapeutic, measures as are indicated by the circumstances, should be instituted.
Leukopenia, thrombocytopenia and mild anemia, which occur occasionally, are generally benign and revert to normal, following cessation of the drug, leukopenia of mild degree, and not associated with a shift in the differential count, may be transient and frequently reverts to normal even while the drug 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, and epigastric discomfort as evidence of gastro-intestinal intolerance, and various vague neurologic symptoms, particularly weakness and paraesthesias. These manifestations are generally a direct function of dosage and were reported much more frequently during the early clinical history of the drug 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.
Chlorpropamide may infrequently induce a syndrome of inappropiate secretion of antidiuretic hormone characterized by water retention, hyponatraemia, and central nervous system signs.
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. Caution should be exercised when antibacterial sulfonamides, phenylbutazone, salicylates, probenecid, dicoumarol, or MAO inhibitors are administered concomitantly with chlorpropamide as hypoglycaemia resultant from either potentiation or accumulation of sulfonylureas has been reported. Compounds that may diminish the hypoglycaemic effect and thus cause an increase in the dosage requirement of chlorpropamide include rifampicin and the thiazide diuretics.
Chlorpropamide should not be used to replace dietetic therapy in the obese.
Ether and suxamethonium antagonise the hypoglycaemic action of chlorpropamide.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
In cases of accidental poisoning or overdosage, due note should be taken of the fact that 3-5 days are required for complete elimination of chlorpropamide from the body, and the patients should be kept under close observation for this period of time despite apparent recovery. The anorectic patient or the profoundly hypoglycaemic patient should be hospitalised. Hypoglycaemic symptoms should be treated as for insulin with dextrose by mouth, by stomach tube, or by the intravenous route.

IDENTIFICATION:

Hypomide®-100:	Flat, white, round, bevelled-edged tablets, bisected on the one side and engraved with a mortar and pestle on the other side.
Hypomide®-250:	Flat, white, round, bevelled-edged tablets, quadrisected on one side and engraved with a mortar and pestle on the other side.

PRESENTATION:

Hypomide®-100:	Packs of 100 and 500 tablets.
Hypomide®-250:	Packs of 100 and 500 tablets.

STORAGE DIRECTIONS:
Store below 25°C.
Protect from moisture.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBERS:

Hypomide®-100:	H/21.2/29
Hypomide®-250:	G/21.2/219

NAME AND BUSINESS ADDRESS OF APPLICANT:
Lennon Limited
7 Fairclough Road
PORT ELIZABETH
6001

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
22/01/1991
K4298

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