Are there any published case reports of tiredness (fatigue), anxiety, depression, asthenia or palpi

Fråga: Are there any published case reports of tiredness (fatigue), anxiety, depression, asthenia or palpitations in patients treated with enalapril? What is the prevalence of these events in larger trials?

This question concerns a man who suffered from glomerulonephritis eleven years ago. He is regularly controlled at the hospital because of hypertension and glomerulonephritis. The hypertension is treated with enalapril 20 mg per day. The last months, he has by mistake been administered only 5 mg per day. A month ago he was reintroduced to 20 mg per day. Two weeks later he experienced tiredness or fatigue, feebleness, symptoms of anxiety and palpitations.

Sammanfattning: The incidence of fatigue, anxiety and palpitations (tachycardia) differ between studies and sources. Fatigue, somnolence or tiredness is reported in 2.0-5.8 percent and tachycardia (palpitations) in 0.9-13 percent of the patients treated with enalapril. There are single case reports describing patients that experienced depression in association with the treatment of enalapril. Anxiety is not reported as an adverse reaction in these studies.

Svar: In a review of the safety profiles of captopril and enalapril for different diagnoses (n=2677), fatigue was reported for 2.8 percent of the patients treated with enalapril compared with 2.6 percent of placebo treated patients (1). In the Studies of Left Ventricular Dysfunction (SOLVD) fatigue was reported in 5.8 percent of the patients treated with enalapril compared to 3.5 percent in the placebo group (5). In a four-week open-label, noncomparative study of 1017 patients with mild to moderate hypertension treated with enalapril, 1.3 percent were reported to have experienced somnolence and 0.7 percent tiredness (4). In a study, that compared the efficacy and tolerability of enalapril and sustained-release diltiazem in mild to moderate essential hypertension, fatigue was reported in 2.6 (2/77) percent of the enalapril treated patients (8). In a multicenter trial of enalapril in the treatment of essential hypertension fatigue was reported in 2.5 percent of the patients (9).

In a prescription-event monitoring study of enalapril in hypertension or heart failure, tachycardia (palpitations) was reported in 1.5 percent (194/13713) of the patients (2). In a study, that compared the efficacy and tolerability of enalapril and sustained-release diltiazem in mild to moderate essential hypertension, tachycardia was reported in 1.3 (1/77) percent of the enalapril treated patients (8). Between eight and thirteen percent of the patients experienced palpitations in three different trials of enalapril in the treatment of hypertension (10-12). In a four week open label, noncomparative study of 1017 patients with mild to moderate hypertension treated with enalapril, 0.9 percent were reported to have experienced palpitations (4).

Two single case-reports of patients with hypertension treated with enalapril, indicate that enalapril may induce depression in susceptible individuals (3,7).

Anxiety has not been reported in association with enalapril in the references mentioned above.

To SADRAC (The Swedish Adverse Drug Reactions Advisory Committee) 963 reports of adverse events concerning enalapril have been reported. Among these 886 were judged as possibly or probably related to the drug. Symptoms of somnolence (one), tiredness (twenty-two), anxiety (two), depressed mood (five), depression (six) and psychastenia (one) are reported (13).

The manufacturer confirmed that the main part of the reported adverse reactions of enalapril are post-marketing events. Tiredness is reported in 3 percent of patients treated with enalapril (n=2314) compared to 2.6 percent in placebo treated patients (n=230) (14).

In FASS tiredness is reported in more than one percent ; asthenia, somnolence and palpitations in 0.1-1.0 percent and depression in less than 0.1 percent of the treated patients (15).

In WHO´s adverse reaction database Intdis, there are 86 reports of anxiety, 138 reports of asthenia, 187 reports of depression, 543 reports of fatigue and 216 reports of palpitations in association with the use of enalapril. However, these reports are not evaluated due to differences of the reporting systems in the participating countries (16). 1 Irvin JD, Viau JM: Safety profiles of the angiotensin converting enzyme inhibitors captopril and enalapril. Am J Med 1986; 81(Suppl 4C): 46-50 2 Inman WH, Rawson NS, Wilton LV, Pearce GL, Speirs CJ: Postmarketing surveillance of enalapril. I: Results of prescription-event monitoring. Br Med J 1988; 297: 826-829 3 Patterson JF: Depression assosiated with enalapril. South Med J 1989; 82: 402-403 4 Medina-Ruiz A, Feliu JF: A cooperative study to evaluate the efficacy and safety of enalapril in Puerto Rican patients with mild to moderate hypertension. Drugs 1990; 39(suppl 2): 77-82 5 Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB Jr, Kohn RM, Kubo SH, Schron E, Weiss MB, Willis PW III, Young JB, Probstfield J: Adverse effects of enalapril in the studies of left ventricular dysfunction (SOLVD). Am Heart J 1996; 131: 350-355 6 Keane WF, Polis A, Wolf D, Faison E, Shahinfar S: The long-term tolerability of enalapril in hypertensive patients with renal impairment. Nephrol Dial Transplant 1997; 12(Suppl 2): 75-81 7 Ahmad S: Enalapril-induced acute psychosis dicp. Ann Pharmacother 1991; 25: 558-559 8 Weir MR, Haynie R, Vertes V, Pinson R, Kong BW, Jenkins P, Lavin PT: A comparison of the efficacy and tolerability of enalapril and sustained-release diltiazem in mild to moderate essential hypertension. Clin Ther 1990; 12: 473-481 9 Gavras H: A multicenter trial of enalapril in the treatment of essential hypertension. Clin Ther 1986; 9: 24-38 10 Batlouni M, Armaganijan D, Assef JE: Efeitos do enalapril na hipertrofia ventricular esquerda em pacientes com hipertensao essencial leve ou moderada. Arq Bras Cardiol 1990; 54: 347-350 11 New Zeland Hypertension Study Group: Enalapril as first choice treatment of mild, moderate and severe essential hypertension: results of an open multicentre clinical trial. N Z Med J 1987; 100: 137-139 12 Knecht A, Grossman E, Rosenthl T: Enalapril in the treatment of renovascular hypertension. Clin Exp Hypertens A 1985; 7: 1377-1393

13 Swedis (The Swedish Drug Information System)
14 Personal communication with Christina Ekedahl, MSD, Sweden
15 FASS 1999 (The Swedish catalogue of approved medical products)

16 Intdis (International Drug Information System): WHO:s adverse drug reactions database