FDA label 4aa31712-abf3-a0af-e223-e962d14a8228

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue ramipril as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. See Warnings: Fetal Toxicity

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. Where 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 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. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. 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. 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 mild- in isolated cases severe- reduction in the red blood cell count and hemoglobin content, white blood cell or platelet count may develop. 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. 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 Toxicity Pregnancy category D Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ramipril as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ramipril, unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on 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 ramipril for hypotension, oliguria, and hyperkalemia (see PRECAUTIONS, Pediatric Use ). 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 Ramipril has been evaluated for safety in over 4,000 patients with hypertension; of these, 1,230 patients were studied in US controlled trials, and 1,107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in ramipril and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving ramipril in US placebo-controlled trials were: headache (5.4%),“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) 13 2 2 1 In 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 these patients requiring discontinuation of treatment. Heart Failure Post Myocardial Infarction Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than one percent of patients and more frequently on ramipril are shown below. The incidences represent the experiences from the AIRE study. The follow-up time was between 6 and 46 months for this study. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug Placebo-Controlled (AIRE) Mortality Study: Adverse Event RAMIPRIL PLACEBO (N=1004) (N=982) Hypotension 11 5 Cough Increased 8 4 Dizziness 4 3 Angina Pectoris 3 2 Nausea 2 1 Postural Hypotension 2 1 Syncope 2 1 Vomiting 2 0.5 Vertigo 2 0.7 Abnormal Kidney Function 1 0.5 Diarrhea 1 0.4 HOPE Study: Safety data in the HOPE trial were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the AIRE trial. The rate of angioedema was the same as in previous clinical trials (see WARNINGS ). RAMIPRIL PLACEBO (N=4645) (N=4652) % % Discontinuation at any time 34 32 Permanent discontinuation 29 28 Reasons for stopping Cough 7 2 Hypotension or Dizziness 1.9 1.5 Angioedema 0.3 0.1 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. 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 causal 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): Clinically important changes in standard laboratory tests were rarely associated with ramipril administration. Elevations of liver enzymes, serum bilirubin uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leukopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.

<table border="1" cellpadding="2" cellspacing="1" frame="hsides" rules="none"> <caption>PATIENTS IN US PLACEBO CONTROLLED STUDIES</caption> <colgroup> <col width="186*"/> <col align="center" width="78*"/> <col align="center" width="77*"/> <col align="center" width="78*"/> <col align="center" width="78*"/> </colgroup> <tbody> <tr> <td/> <td colspan="2"> <content styleCode="bold">RAMIPRIL</content> <paragraph> <content styleCode="bold">(n=651)</content> </paragraph> </td> <td colspan="2"> <content styleCode="bold">Placebo</content> <paragraph> <content styleCode="bold">(n=286)</content> </paragraph> </td> </tr> <tr> <td/> <td>n </td> <td>% </td> <td>n </td> <td>%</td> </tr> <tr> <td>Asthenia (Fatigue) </td> <td>13 </td> <td>2 </td> <td>2 </td> <td>1</td> </tr> </tbody> </table>

<table> <tbody> <tr> <td> <content styleCode="bold">Adverse Event</content> </td> <td> <content styleCode="bold">RAMIPRIL</content> </td> <td> <content styleCode="bold">PLACEBO</content> </td> </tr> <tr> <td colspan="1"/> <td align="center" colspan="1"> <content styleCode="bold">(N=1004)</content> </td> <td align="center" colspan="1"> <content styleCode="bold">(N=982)</content> </td> </tr> <tr> <td>Hypotension</td> <td align="center">11</td> <td align="center">5</td> </tr> <tr> <td>Cough Increased</td> <td align="center">8</td> <td align="center">4</td> </tr> <tr> <td>Dizziness</td> <td align="center">4</td> <td align="center">3</td> </tr> <tr> <td colspan="1">Angina Pectoris</td> <td align="center" colspan="1">3</td> <td align="center" colspan="1">2</td> </tr> <tr> <td colspan="1">Nausea</td> <td align="center" colspan="1">2</td> <td align="center" colspan="1">1</td> </tr> <tr> <td colspan="1">Postural Hypotension</td> <td align="center" colspan="1">2</td> <td align="center" colspan="1">1</td> </tr> <tr> <td colspan="1">Syncope</td> <td align="center" colspan="1">2</td> <td align="center" colspan="1">1</td> </tr> <tr> <td colspan="1">Vomiting</td> <td align="center" colspan="1">2</td> <td align="center" colspan="1">0.5</td> </tr> <tr> <td colspan="1">Vertigo</td> <td align="center" colspan="1">2</td> <td align="center" colspan="1">0.7</td> </tr> <tr> <td colspan="1">Abnormal Kidney Function</td> <td align="center" colspan="1">1</td> <td align="center" colspan="1">0.5</td> </tr> <tr> <td>Diarrhea</td> <td align="center">1</td> <td align="center">0.4</td> </tr> </tbody> </table>

<table> <tbody> <tr> <td/> <td> <content styleCode="bold">RAMIPRIL</content> </td> <td> <content styleCode="bold">PLACEBO</content> </td> </tr> <tr> <td colspan="1"/> <td align="center" colspan="1"> <content styleCode="bold">(N=4645)</content> </td> <td align="center" colspan="1"> <content styleCode="bold">(N=4652)</content> </td> </tr> <tr align="center"> <td/> <td>%</td> <td>%</td> </tr> <tr> <td>Discontinuation at any time</td> <td align="center" colspan="1" rowspan="1">34</td> <td align="center" colspan="1" rowspan="1">32</td> </tr> <tr> <td>Permanent discontinuation</td> <td align="center">29</td> <td align="center">28</td> </tr> <tr align="center"> <td>Reasons for stopping Cough</td> <td>7</td> <td>2</td> </tr> <tr> <td colspan="1">Hypotension or Dizziness</td> <td align="center" colspan="1">1.9</td> <td align="center" colspan="1">1.5</td> </tr> <tr> <td colspan="1">Angioedema</td> <td align="center" colspan="1">0.3</td> <td align="center" colspan="1">0.1</td> </tr> </tbody> </table>