ADVERSE EFFECTS

A very high percentage of patients treated with LYSODREN have shown at least one type of side effect. The main types of adverse reactions consist of the following:

1. Gastrointestinal disturbances, which consisted of anorexia, nausea or vomiting, and in some cases diarrhea, occurred in about 80% of the patients.

2. Central nervous system side effects occurred in 40% of the patients. These consisted primarily of depression as manifested by lethargy and somnolence (25%), and dizziness or vertigo (15%).

3. Skin toxicity was observed in about 15% of the cases. In some instances, however, this side effect subsided while the patients were maintaining on drug.

Infrequently occurring side effects involve the eye (visual blurring, diplopia, lens opacity, toxic retinopathy); the genito-urinary system (hematuria, hemorrhagic cystitis, and albuminuria); cardiovascular system (hypertension, orthostatic hypotension, and flushing); and some miscellaneous complaints including generalized aching, hyperpyrexia, and lowered PBI.

ANIMAL STUDIES

Dogs were used for much of the experimental work with LYSODREN (1). Doses as low as 4 mg/kg/day may produce some effects upon the canine adrenals. However, most of the data suggest that toxicity occurs between 80-200 mg/kg/day, primarily as a result of LYSODREN'S effect upon the adrenals. At doses of 100 mg/kg and higher of LYSODREN, deaths occurred in some of the dogs after two to four weeks of administration. The primary action of LYSODREN is upon the adrenal cortex. The toxicity observed in animals appears to result from suppression of the activity of the adrenal cortex. The production of adrenal steroids has been shown to be reduced in most of the studies. A toxicity study was conducted in rats at doses as high as 300 mg/kg/day for 28 days. There were no deaths nor was there any evidence of organ changes in these animals. In this study even the adrenal cortex showed no evidence of change, indicating that the rodent appears to be highly resistant to LYSODREN. In both dogs and rats, there was a dose-related rise in alkaline phosphatase. In dogs, there were signs of histological changes in the liver at the high doses (50-100 mg/kg/day). A dose of 300 mg/kg/day administered to guinea pigs resulted in deaths in one of three animals and a reduction in cortisol levels. Death was probably due to adrenal insufficiency (2).

METABOLIC STUDIES OF LYSODREN IN MAN

One study (3) with adrenal carcinoma patients indicated that about 40% of oral LYSODREN was absorbed, and approximately 10% was recovered in the urine as a water-soluble metabolite. A small amount was excreted in the bile and the balance was apparently stored in the tissues. When administered parenterally, approximately 25% of the dose was found in the urine as a water-soluble metabolite. Blood levels were determined during and following administration of LYSODREN. Both unchanged drug and a metabolite were measured. The levels in patients receiving doses from 5-15 grams per day varied from 7-90 micrograms/ml of unchanged LYSODREN and 29-54 micrograms/ml of the metabolite. These studies indicated no relationship between blood levels and therapeutic and/or toxic effects. Following discontinuation of the drug, blood levels fell, but persisted for several weeks. In most patients blood levels became undetectable after six to nine weeks. In one patient who had received a total of 1900 grams of LYSODREN, high blood levels were found ten weeks after stopping the drug. Autopsy data have provided evidence that LYSODREN is found in most tissues of the body. Fat tissues were the primary site of storage. In one patient a very large number of tissues were examined and the drug was found in essentially every tissue. LYSODREN appears to be converted, in part, to a water-soluble metabolite. This material has not been characterized, but is only found in the urine and blood of patients receiving LYSODREN. Examination of bile was made and found to contain no unchanged LYSODREN. There was metabolite in the bile, and this would indicate that biliary excretion is a significant route of removal of this metabolite from the body.

CLINICAL STUDIES

Hutter and Kayhoe (4) reported on the clinical features and the results of LYSODREN treatment of 138 patients with adrenal cortical carcinoma, and compared their findings with 48 treated patients previously reported in the literature. Subsequent to their report, 115 patients given drug were studied. There is no evidence of a cure as a consequence of the administration of LYSODREN. A number of patients have been treated intermittently, treatment being restarted when severe symptoms reappear. Patients often do not respond after the third or fourth such course. Experience accumulated to date suggests that continuous treatment with the maximum possible dosage of LYSODREN would be the best approach. A substantial percentage of the patients treated showed signs of adrenal insufficiency. It therefore appears necessary to watch for and institute steroid replacement in those patients. It has been shown that metabolism of exogenous steroids is modified and consequently somewhat higher doses than just replacement therapy may be required. There was significant reduction in tumour mass following LYSODREN administration in about 50%, and a significant reduction in elevated steroid excretion in about 80% of the evaluable patients studied to date (4). Clinical effectiveness can be shown by reduction in tumor mass, reduction in pain, weakness or anorexia, and reduction of steroid symptoms.

DOSAGE AND ADMINISTRATION

Two dosage regimens may be used. The patient may be started on 2-6 gm a day, in divided doses q.i.d. or t.i.d. and the dosage increased as quickly as possible to as much drug as can be tolerated, preferably arriving at 8-10 gm or more. or Start the patient at 9-10 gm of LYSODREN per day in divided doses, either q.i.d. or t.i.d. since most patients will have side effects initially irrespective of starting dosage. If severe side effects appear, the dose should be reduced until the maximum tolerated dose is achieved. If the patient can tolerate higher doses and improved clinical response appears possible, the dose should be increased until adverse reactions interfere. Experience has shown that the maximum tolerated dose (MTD) will vary from 2-16 gm per day, but has usually been 8-10 gm per day. The highest doses used in the studies to date were 18- 19 gm per day.

TREATMENT SHOULD BE INSTITUTED IN THE HOSPITAL UNTIL A STABLE DOSAGE REGIMEN IS ACHIEVED

Treatment should be continued as long as clinical benefits are observed. Maintenance of clinical status or slowing of growth of metastatic lesions can be considered clinical benefits if they can clearly be shown to have occurred. If no clinical benefits are observed after three months at the maximum tolerated dose, the case may be considered a clinical failure. However, 10% of the patients who showed a measurable response required more than three months at the MTD. Early diagnosis and prompt institution of treatment improve the probability of a positive clinical response.