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warnings and cautions
5 WARNINGS AND PRECAUTIONS ACE inhibitor use has been associated with the following: Angioedema, with increased risk in patients with a prior history (5.1) Hypotension and hyperkalemia ( 5.5 , 5.8) Renal impairment: monitor renal function during therapy (5.3) Increased risk of renal impairment when combined with another blocker of the renin-angiotensin-aldosterone system (5.7) Rare cholestatic jaundice and hepatic failure (5.2) Rare neutropenia and agranulocytosis (5.4) 5.1 Anaphylactoid and Possibly Related Reactions Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including ramipril) may be subject to a variety of adverse reactions, some of them serious. Angioedema Head and Neck Angioedema Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with ramipril and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [ see ADVERSE REACTIONS ( 6 ) ]. In considering the use of ramipril, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients. In a large U.S. postmarketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically. Intestinal Angioedema Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Anaphylactoid Reactions During Desensitization Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained 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 dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.2 Hepatic Failure and Impaired Liver Function Rarely, ACE inhibitors, including ramipril, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue ramipril if patient develops jaundice or marked elevations of hepatic enzymes. As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function. 5.3 Renal Impairment As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ramipril, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death. In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of ramipril and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when ramipril has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction of ramipril and/or discontinuation of the diuretic may be required. 5.4 Neutropenia and Agranulocytosis In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function. 5.5 Hypotension General Considerations Ramipril can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, ramipril, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume-and salt-depletion before initiating therapy with ramipril. If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Ramipril treatment usually can be continued following restoration of blood pressure and volume. Heart Failure Post-Myocardial Infarction In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of ramipril. Congestive Heart Failure In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. Surgery and Anesthesia In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. 5.6 Fetal/Neonatal Morbidity and Mortality Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, discontinue ACE inhibitors as soon as possible. The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal 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 occurrences were caused by the ACE inhibitor exposure. In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been confirmed. Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin-aldosterone system will be found. In these rare cases, inform mothers about the potential hazards to their fetuses, and perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios is observed, discontinue ramipril unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test, or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to ACE inhibitors for hypotension, oliguria, and hyperkalemia. If oliguria occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which crosses the placenta, can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants. 5.7 Dual Blockade of the Renin-Angiotensin-Aldosterone System Telmisartan The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended. 5.8 Hyperkalemia In clinical trials with ramipril, hyperkalemia (serum potassium > 5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ramipril. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with ramipril [ see Drug Interactions ( 7.1 ) ]. 5.9 Cough Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.