FDA label 3c536fc0-9e2f-3c62-e054-00144ff8d46c

BOXED WARNING USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, ramipril should be discontinued as soon as possible. See WARNINGS: Fetal/neonatal morbidity and mortality .

WARNINGS Anaphylactoid and Possibly Related Reactions Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ramipril) may be subject to a variety of adverse reactions, some of them serious. 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. (See also CONTRAINDICATIONS .) Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with angiotensin converting enzyme inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with ramipril should be discontinued and appropriate therapy instituted immediately. When there is involvement of the tongue, glottis, or larynx, likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine solution 1:1,000 (0.3 mL to 0.5 mL)] should be promptly administered. (See ADVERSE REACTIONS .) Intestinal Angioedema 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%) of black patients and in 8/8680 (0.09%) of white patients. These rates were not different statistically. 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). Hypotension 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. Volume and/or salt depletion should be corrected before initiating therapy with ramipril. 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. In such patients, ramipril 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 ramipril or diuretic is increased. If hypotension occurs, the patient should be placed in a supine position and, if necessary, treated with intravenous infusion of physiological saline. Ramipril treatment usually can be continued following restoration of blood pressure and volume. Hepatic Failure 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. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. Neutropenia/Agranulocytosis As with other ACE inhibitors, rarely, a mildin isolated cases severereduction in the red blood cell count and hemoglobin content, white blood cell or patelet count may develop. In isolated cases, agranulocytosis, pancyotpenia, 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. 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. Fetal/Neonatal Morbidity and Mortality ACE 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, ACE inhibitors should be discontinued as soon as possible. The use of ACE inhibitors during the second and the 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 due to the ACE-inhibitor exposure. These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of ramipril as soon as possible. Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment. If oligohydramnios is observed, ramipril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST), or biophysical profiling (BPP) 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. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as 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. No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

ADVERSE REACTIONS Hypertension dizziness(2.2%) and fatigue or asthenia (2.0%), but only the last was more common in ramipril patients than in patients given placebo. Generally, the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 to 20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of US patients treated with ramipril. The most common reasons for discontinuation were: cough (1.0%),dizziness(0.5%), and impotence (0.4%). Of observed side effects considered possibly or probably related to study drug that occurred in US placebo-controlled trials in more than 1% of patients treated with ramipril, only asthenia (fatigue) was more common on ramipril than placebo (2% vs. 1%). PATIENTS IN US PLACEBO CONTROLLED STUDIES RAMIPRIL (n=651) Placebo (n=286) n%n% Asthenia (Fatigue)13221In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the ramipril group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of ramipril patients, with about 4% of patients requiring discontinuation of treatment. Other adverse experiences reported in controlled clinical trials (in less than 1% of ramipril patients), or rarer events seen in postmarketing experience, include the following (in some, a causal relationship to drug use is uncertain.): Body As a Whole: Anaphylactoid reactions. (See WARNINGS .) Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in US trials) (See WARNINGS and PRECAUTIONS ), syncope and palpitations. Hematologic: Pancytopenia, hemolytic anemia and thrombocytopenia. Renal: Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking ramipril, particularly when ramipril was given concomitantly with a diuretic. (See WARNINGS .) Acute renal failure. Angioneurotic Edema: Angioneurotic edema has been reported in 0.3% of patients in US clinical trials. (See WARNINGS .) Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation and taste disturbance. Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome. Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances. Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported. Fetal/Neonatal Morbidity and Mortality. See WARNINGS : Fetal/Neonatal Morbidity and Mortality . Other: arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain. Post-Marketing Experience In addition to adverse events reported from clinical trials, there have been rare reports of hypoglycemia reported during ramipril therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The casual relationship is unknown. Clinical Laboratory Test Findings Creatinine and Blood Urea Nitrogen Increases in creatinine levels occurred in 1.2% of patients receiving ramipril alone, and in 1.5% of patients receiving ramipril and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving ramipril alone and in 3% of patients receiving ramipril with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis. (See WARNINGS and PRECAUTIONS .) Since ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Potassium supplements and potassium-sparing diuretics should be given with caution, and the patient's serum potassium should be monitored frequently. (See WARNINGS and PRECAUTIONS .) Hemoglobin and Hematocrit Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5% respectively) were rare, occurring in 0.4% of patients receiving ramipril alone and in 1.5% of patients receiving ramipril plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit. Other (causal relationships unknown)