Tolerance and safety of enalapril

Br. J. clin. Pharmac. (1984), 18, 249S-253S Tolerance and safety of enalapril W. McFATE SMITH, R. 0. DAVIES, M. A. GABRIEL, D. M. KRAMSCH, F. MONCLOA, JANET E. RUSH & J. F. WALKER Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania 19486, USA 1 Enalapril is the result of a targeted research programme to develop a non-mercapto converting enzyme inhibitor with a long duration of action and an improved safety profile for use in the therapy of hypertension and congestive heart failure. 2 Over 3500 patients world-wide have received enalapril or enalaprilat. Long-term experience at present includes over 2500 patients. 3 While enalapril and captopril produce similar efficacy, enalapril is better tolerated and appears not to be associated with occurrence of captopril-type side-effects, particularly the skin rash, taste loss, leukopenia and proteinuria. 4 Enalapril and other converting enzyme inhibitors may be associated with renal insufficiency when given to patients with bilateral renovascular hypertension. Keywords enalapril hypertension efficacy safety therapy Introduction Enalapril is the product of a targeted research programme to develop a non-sulphydryl containing angiotensin converting enzyme (ACE) inhibitor with a long duration of action and an improved safety profile for use in the management of hypertension and congestive heart failure. The objective of the clinical research programme for enalapril was to demonstrate efficacy in hypertension of all degrees of severity, alone and in conjunction with hydrochlorothiazide; effectiveness of a once-daily regimen; efficacy in congestive heart failure; short and long-term safety and acceptability, including the absence of specific adverse effects associated with the sulphydryl containing captopril. Studies on the efficacy of enalapril are presented elsewhere in this supplement. Safety and tolerability Approximately 3500 patients have been treated with enalapril to date. The exposure in controlled trials in normal volunteers and in patients with hypertension or congestive heart failure as filed for registration, includes 2249 subjects. Over 600 patients have been treated for more than 1 year and approximately 200 for over 2 years. In the controlled trials, investigators regularly monitored adverse experiences using nonleading questions. Additional emphasis was placed on those side-effects previously reported for captopril. The number of patients worldwide who received enalapril alone and those who received both enalapril and hydrochlorothiazide are shown in Table 1. These two groups are not mutually exclusive since some patients received enalapril alone initially, and subsequently received enalapril with hydrochlorothiazide. In the third group, mostly from clinical pharmacology studies, patients received enalapril with other antihypertensive agents other than hydrochlorothiazide. The placebo group includes patients with hypertension who received only placebo, and patients in congestive heart failure studies who received placebo plus diuretics and digitalis. Finally, a large number of patients received other antihypertensive drugs in comparative studies. 249S

250S Table 1 W. McFate Smith et al. Population observed for adverse experiences Enalapril alone 1855 Enalapril and hydrochlorothiazide 727 Enalapril and other antihypertensives 153 Placebo 317 Other antihypertensive agents 1628 Note: 2249 patients on enalapril. Skin rash Twenty-two patients on enalapril and eight further patients on enalapril with hydrochlorothiazide reported skin rash, but the drug was discontinued in only six patients (Table 2). This low incidence of skin rash is about twice that reported for patients receiving placebo, similar to that in patients receiving control drugs and considerably lower than captopril (see Table 7). Moreover, the complaint of skin rash was usually mild in the enalapril patients with only one severe skin rash being recorded. Taste disturbance Only one patient receiving enalapril alone reported transient taste loss (Table 3), and one further patient on the combination. Five patients reported taste loss in the group receiving control drugs, and all of these patients were receiving captopril. No patient had the drug discontinued because of taste loss in the enalapril group. A number of reports of altered taste were recorded probably because investigators were sensitive to the possibility of taste disturbances. These were not clinically important. White blood cell counts Neither neutropenia nor agranulocytosis was encountered using the Squibb/FDA definition of less than 300 neutrophils/mm3. As shown in Table 3 Incidence of taste disturbance Taste loss Taste alteration Enalapril alone 1* (0.1%) 8 (0.4%) Enalapril 1* (0.1%) 2 (0.3%) hydrochlorothiazide Placebo 0 0 Control drugs St (0.3%) 3 (0.2%) *Transient and disappeared on continued therapy. tall captopril. Table 4, an isolated value of 900 total white blood cells/mm3 was reported in one patient. All counts in the weeks before and after this observation were within normal limits; this one value was considered a probable laboratory error. In four patients, values between 1000 and 2500 cells/mm3 were reported. In a case report published by Studer & Vetter (1982), a count of 1700 mm3 total white cells following a single dose of 0.6 mg enalapril was noted. This patient also had fever and a transient skin rash. No similar occurrence has been reported in either patients or normal volunteers, and in this case the relationship to therapy may be questioned. A low white count was noted in one patient with systemic lupus erythematosis and scleroderma, who had been treated with captopril prior to receiving a week's therapy on enalapril. White counts were reduced by the disease itself and occurred during the captopril therapy prior to receiving enalapril. In subsequent months when the patient was off converting enzyme inhibitors, a similar haematological pattern recurred consistent with the possibility that the earlier low counts were manifestations of the disease rather than the treatment. Two additional isolated values were reported (Table 4) as the last value on therapy during a 4-week dose finding study. No follow-up data were available. Table 2 Incidence of skin rash (%) Treatment Number of cases Number discontinued Enalapril alone 22 (1.2%) 6 (0.3%) Severity (mild-moderate-severe) [12-8-1] [1-4-1] Enalapril/hydrochlorothiazide 8 (1.1%) 0 Placebo 2 (0.6%) 0 Control drugs 14 (0.9%) 4 (0.3%) Severity (mild-moderate-severe) [9-5-0] [2-24]

Tolerance and safety of enalapril Table 4 Number of cases of decreased total white blood cell counts (n = 1657) Per mm3 Values less than 1000/mm3 Isolated value in one case 900 Laboratory error Values between 1000 and 2500/mm3 Studer & Vetter case (1982) 1700 Single 0.6 mg dose Enalapril vs hydrochlorothiazide 2300 Last value on therapy Enalapril vs hydrochlorothiazide 2400 Last value on therapy SLE/scleroderma (CUP) 1900 Previous captopril CUP = compassionate use protocol; SLE = systemic lupus erythematosis. 251S Additionally, when mean white counts were analysed across the total groups, there was no trend suggesting a decrease in white blood cell count overall. Renal effects Uraemia Because of the importance of the renin-angiotensin system in renal function and especially the physiological contribution of angiotensin II, patients were carefully screened to select those patients with essential hypertension and normal renal function for controlled studies prior to initiating studies in patients with renal disease. Overall, renal function was well-maintained with only a small number of patients developing mild and reversible increases in serum creatinine (Table 5). Eleven cases (0.6%), eight of whom were receiving concomitant hydrochlorothiazide, were reported. In the control population, the incidence was 0.26%. One case from this group experienced a reversible increase in serum creatinine and glycosuria but no hyperglycaemia or aminoaciduria (Cressman et al., 1982). The increases were seen after hydrochlorothiazide was added to previous enalapril therapy but reversed when enalapril was discontinued and the thiazide maintained. There was no evidence of underlying renovascular hypertension in this patient. One additional patient in this group received concomitant lithium therapy and this may have been a factor in the uraemia. Elevated serum creatinines were also encountered in the congestive heart failure studies. Overall, the incidence was higher than in the hypertensive patients but was similar in the enalapril and placebo patients. Uraemia was encountered in some patients with bilateral renovascular hypertension. Eight cases in which increases in serum creatinine were seen and related to known or subsequently diagnosed bilateral renovascular hypertension are shown in Table 6. Six of the eight were also receiving diuretics. Uraemia reversed when enalapril or diuretic was discontinued. This phenomenon has been observed with both captopril and enalapril (Hricik et al., 1983) and is thought to be associated with angiotensin II dependency. A prospective study in patients with renovascular hypertension is continuing with careful monitoring of renal function and about a quarter of those with bilateral renal artery stenosis have developed uraemia. Proteinuria Routine collections of 12- or 24-h urinary protein were undertaken in Phase III studies. No case of nephrotic syndrome or membranous glomerulonephritis has been reported on enalapril. Only one patient had a major elevation (3-4 g/day) in urinary protein, this following transurethral resection in a patient with severe congestive heart failure. In hypertension studies, a few isolated, slightly abnormal values were reported in six patients in the enalapril group and in three patients on control therapy. In no case was there a pattern obviously related to therapy, and in most cases values returned to within the normal range during continued Table S Number (%) of patients developing elevated serum creatinine Hypertension Enalapril 1676 11* (0.66%) Control 762 2 (0.26%) Congestive heart failure Enalapril/diuretic 143 6 (4.2%) Control 59 3 (5.1%) *Eight patients on concomitant thiazide. n

252S W. McFate Smith et al. Table 6 Uraemia in renal vascular hypertension Creatinine (mgldl) Bilateral Baseline Treatment Diuretic stenosis Comments 1.9 5.9 No Yes Previous uraemia on captopril 2.0 3.9 Yes Yes 1.0 2.3 Yes Yes 2.4 7.8 Yes Yes Previous uraemia on captopril 1.6 4.2 No Not proven Prior diuretic, diarrhoea 1.7 4.0 Yes Not proven Congestive heart failure 1.9 2.8 Yes Yes 1.7 4.9 Yes Yes therapy. A number of other patients admitted with baseline values outside the normal range showed decreases in urinary protein excretion while on therapy. Enalapril vs captopril The relative incidence of adverse effects in captopril-treated patients and in enalapriltreated patients is presented in Table 7. The current captopril package insert shows the incidence of rash, taste disturbance, neutropenia and proteinuria which are distinctly higher than those recorded for enalapril. The captopril findings were drawn from the overall worldwide investigational experience, and included the results from early clinical trials when larger doses were used than is currently advocated. Additionally, patients with abnormal renal disease and/or collagen diseases were included, and these bad-risk patients had a higher incidence of side-effects. More recently, the percent of patients discontinued during captopril therapy for adverse effects has been reported and shown for patients with normal renal function and those with impaired renal function (Groel et al., 1983). Unlike earlier reports, these data were collected from patients who have been receiving lower doses of captopril. Data on the incidence of adverse effects not requiring discontinuation are not available. Data reported for enalapril show both the incidence of adverse reactions and the percent of patients discontinued. The most striking comparison is that of patients discontinuing for rash or for taste disturbance. The incidence was lower to nonexistent in the enalapril studies even when compared with low dose captopril in patients with normal renal function. While the incidence of neutropenia or agranulocytosis on captopril varies depending on renal function and underlying disease and has overall a low incidence in good risk patients, no case of significant neutropenia has been encountered with enalapril to date regardless of risk status or dosage level. A variable incidence of proteinuria has been reported on captopril which is higher in the presence of impaired renal function. The relationship to captopril therapy in some of these cases may be debatable, but in any event, no consistent pattern of proteinuria has been documented for enalapril. The definition of proteinuria used in the studies with captopril is quite demanding (Frohlich et al., 1984); not a single case of patients with hypertension treated with enalpril met such criteria. Compassionate use experience Since 1981, compassionate use protocols have been available for those patients who were either resistant to other therapy or who had responded well to captopril but had significant adverse effects requiring discontinuation of therapy. Of 59 patients on whom data are currently available, 34 had been admitted for prior skin rashes from captopril. In only two patients was there a recurrence on enalapril, and in both cases the rash was mild. In the other cases, patients had been maintained on enalapril, some for longer than 12 months, without recurrence. Biollaz et al. (1982) have recently reported three cases of rash and one of rash and fever due to captopril who have responded well and without recurrence on enalapril. Another hypertensive patient with a previous methimazole rash developed a similar eruption on low dose captopril which disappeared without loss of blood pressure control when enalapril was substituted for captopril (Ferguson et al., 1982). Five patients were admitted with significant proteinuria when on captopril; there was one recurrence on enalapril. Overall in these compassionate use protocols, the results with enalapril have confirmed the data from controlled trials and indicate that enalapril is well-tolerated in most patients who

Table 7 Tolerance and safety of enalapril Relative incidence of adverse effects in captopril-treated patients and in enalapril-treated patients 253S Enalapril Captopril Occurrence Discontinued Occurrence Discontinued Merck's NDA Labelling current Labelfing* current literaturet literature* Normal Impaired renal renal function function (discontinued) Dose Dose Low-high Low-high Skin rash 1.2 0.3 10.0 1.4-2.1% 2.5-5.1% Taste disturbance 0.5 0 7.0 0.5-1.3% 0.7-2.9% Neutropenia < 300/mm3 0 0 0.3 0.02% 0.05% 7.2%f Proteinuria 0 0 1.2 0.2-1.0% 1.0-3.5% *Results not available. tdiscontinued cases, overall incidence not reported, range shown because adverse experience varies with dose level. twith collagen disease Definition of proteinuria as in Frohlich et al. (1984). have experienced adverse effects while on treatment with captopril. We speculate that this is due to the absence of a sulphydryl group in the chemical structure of enalapril. References Biollaz, J., Brunner, H. R., Gavras, I., Waeber, B. & Gavras, H. (1982). Antihypertensive therapy with MK-421: Angiotensin II-renin relationships to evaluate efficacy of converting enzyme blockage. J. cardiovasc. Pharmac., 4, 966-972. Cressman, M. D., Vidt, D. G. & Acker, C. (1982). Renal glycosuria and azotemia after enalapril maleate (MK-421). Lancet, ii, 440. Ferguson, R. K., Vlasses, P. H., Swanson, B. N., Mojaverian, P., Hichens, M., Irvin, J. D. & Huber, P. B. (1982). Effects of enalapril, a new converting enzyme inhibitor, in hypertension. Clin. Pharmac. Ther., 32, 48-53. Frohlich, E. D., Cooper, R. A. & Lewis, E. J. (1984). Review of the overall experience of captopril in hypertension. Arch. Intern. Med., 144, 1441-1444.