Anaphylactoid and related reactions
Because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Cibacen) may experience a variety of anaphylactoid and related reactions, some of them serious.
Angioneurotic oedema has been reported rarely with ACE inhibitors including Cibacen. In some cases symptoms have been observed up to 2 years after initiation of treatment. Such reactions should be regarded as an indication to discontinue therapy immediately and the patient closely monitored.
Where swelling is confined to the face, lips and mouth, the condition will usually resolve without further treatment, although antihistamines may be useful in relieving symptoms. These patients should be followed carefully until the swelling has resolved. However, where there is involvement of the tongue, glottis or larynx, likely to cause airways obstruction, appropriate therapy such as subcutaneous adrenaline (0.5mil 1: 1000) should be administered promptly when indicated.
Angioedema with laryngeal oedema can be fatal.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angiodema while receiving an ACE inhibitor (see also "Contraindications ''). Other hypersensitivity reactions have been reported.
The incidence of angioedema during ACE inhibitor therapy has been reported to be higher in black patients of African origin than in non-black patients.
Anaphylactoid reactions during desensitisation
Two patients undergoing desensitising treatment with Hymenoptera venom while receiving ACE inhibitors had life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid reactions during membrane exposure
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes while receiving an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulphate absorption.
As with other ACE inhibitors, symptomatic hypotension has been observed in rare cases, typically in patients with volume or salt depletion as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting.
Volume and/or salt depletion should be corrected before starting therapy with Cibacen. If hypotension occurs, the patient should be placed in the supine position and if necessary given physiological saline IV.
Treatment with Cibacen can be continued once blood pressure and volume have returned to normal. In patients with severe congestive heart failure, ACE inhibitor therapy can cause excessive hypotension which may be associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure.
In such patients, therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of benazepril or diuretic is increased.
Another ACE inhibitor, Captopril, has been shown to cause agranulocytosis and bone marrow depression; such effects occur more frequently in patients with renal impairment, especially if they also have a collagen-vascular disease such as systemic lupus erythematosus or scleroderma. Not enough data are available from clinical trials of benazepril to show whether or not it causes a similar incidence of agranulocytosis. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
Hepatitis and hepatic failure
There have been rare reports of predominantly cholestatic hepatitis and isolated cases of acute liver failure, some of them fatal, in patients on ACE inhibitors. The mechanism is not understood.
Patients receiving ACE inhibitors who develop jaundice or marked elevation of hepatic enzymes should discontinue the ACE inhibitor and be kept under medical surveillance.
ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately, and, if appropriate, alternative therapy should be started (see Sections 4.3 and 4.6).
Foetal/neonatal morbidity and mortality
ACE inhibitors can cause foetal and neonatal morbidity and death when given to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is established, ACE inhibitors should be discontinued as soon as possible.
Use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with foetal and neonatal damage, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios, presumably due to impaired foetal renal function, has been reported. Oligohydramnios in this setting has been associated with foetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these were due to ACE inhibitor exposure.
No such adverse effects appear to have occurred after intrauterine ACE inhibitor exposure during the first trimester. This should be made clear to women who have taken ACE inhibitors only during the first trimester. If a patient becomes pregnant, the physician is nevertheless advised to discontinue benazepril as soon as possible.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Changes in renal function may occur in susceptible patients. In patients with severe congestive heart failure, whose renal function may depend on the activity of the renin- angiotensin-aldosterone system, treatment with ACE inhibitors may be associated with oliguria and/or progressive azotaemia and (rarely) acute renal failure. In a small study of hypertensive patients with renal artery stenosis in one kidney or bilateral renal artery stenosis, treatment with Cibacen was associated with increases in blood urea nitrogen, and serum creatinine; these increases were reversible on discontinuation of Cibacen or diuretic therapy, or both. If such patients are treated with ACE inhibitors, renal function should be monitored during the first few weeks of therapy.
Some hypertensive patients with no apparent pre-existing renal vascular disease have developed elevated blood urea nitrogen and serum creatinine levels (usually minor and transient), especially when Cibacen was given with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Cibacen and/or discontinuation of the diuretic may be required. Evaluation of the hypertensive patient should always include assessment of renal function (see Dosage).
Persistent non-productive cough has been reported with ACE inhibitors, presumably due to inhibited degradation of endogenous bradykinin. This cough always resolves after discontinuation of therapy. ACE-inhibitor -induced cough must be considered in the differential diagnosis of cough.
The pharmacological action of benazepril may prevent the normal body response to induction of hypotension during anaesthesia or shock. Before surgery the anesthetist should be informed that the patient is receiving an ACE inhibitor. During anaesthesia with agents that induce hypotension, ACE inhibitors may block angiotensin II formation secondary to compensatory renin release. Hypotension occurring by this mechanism should be corrected by volume expansion.
During treatment with ACE inhibitors, elevated serum potassium levels have been observed on rare occasions. No discontinuations of Cibacen due to hyperkalaemia have been reported in clinical trials in hypertension. Risk factors for development of hyperkalaemia may include renal insufficiency, diabetes mellitus, and concomitant use of agents to treat hypokalaemia (see Interactions). In a trial involving patients with progressive chronic renal disease, some patients discontinued treatment because of hyperkalaemia. In patients with progressive chronic renal disease serum potassium should be monitored.
Aortic or mitral stenosis
As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.