FDA label 583e1507-2352-8e7d-e063-6294a90a82ac

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue VOSTALLY as soon as possible [see Warnings and Precautions (5.1) ] . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus [see Warnings and Precautions (5.1) ] . WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning When pregnancy is detected, discontinue VOSTALLY as soon as possible (5.1) . Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus (5.1) .

5 WARNINGS AND PRECAUTIONS Angioedema, increased risk in patients with a prior history ( 5.2 ) Hypotension ( 5.3 ) Rare cholestatic jaundice and hepatic failure ( 5.4 ) Renal impairment: monitor renal function during therapy ( 5.5 ) Hyperkalemia ( 5.6 ) 5.1 Fetal Toxicity VOSTALLY can cause fetal harm when administered to a pregnant woman. 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 VOSTALLY as soon as possible [see Use in Specific Populations (8.1) ]. 5.2 Angioedema and Anaphylactoid Reactions Angioedema Head and Neck Angioedema Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx, including airway obstruction and some fatal reactions, have occurred in patients treated with ACE inhibitors at any time during treatment. VOSTALLY should be promptly discontinued, and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications (4)] . ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Patients taking concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. [see Drug Interactions (7.7) ] 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 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 Dialysis Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.3 Hypotension General Considerations VOSTALLY can cause symptomatic hypotension, after the initial dose or when the dosage has been increased. Patients at risk of symptomatic hypotension include those with volume and/or salt depletion of any etiology (e.g., high dose diuretic therapy, dietary salt restriction, renal dialysis, diarrhea, or vomiting). Correct volume and/or salt depletion before initiating therapy with VOSTALLY and monitor for the first two weeks of treatment and whenever the dose of VOSTALLY and/or diuretic is increased. If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. VOSTALLY 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 VOSTALLY. If the initial dose of 2.5 mg VOSTALLY cannot be tolerated, use an initial dose of 1.25 mg VOSTALLY to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension. Congestive Heart Failure In patients with congestive heart failure, with or without associated renal insufficiency, VOSTALLY may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. In such patients, initiate VOSTALLY therapy under close medical supervision and monitor for the first 2 weeks of treatment and whenever the dose of VOSTALLY or diuretic is increased. Surgery and Anesthesia In patients undergoing surgery or during anesthesia with agents that produce hypotension, VOSTALLY may block angiotensin II secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion. 5.4 Hepatic Failure ACE inhibitors, including VOSTALLY, 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 VOSTALLY if patient develops jaundice or marked elevations of hepatic enzymes. 5.5 Worsening Renal Function Worsening renal function can be caused by ACE inhibitors, including VOSTALLY, as a consequence of inhibiting the renin-angiotensin-aldosterone system in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion), treatment with ACE inhibitors, including VOSTALLY, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death. In such patients, monitor renal function during the first few weeks of therapy. Consider dose reduction, withholding, or discontinuing VOSTALLY in patients who develop a clinically significant decrease in renal function. 5.6 Hyperkalemia Drugs that inhibit the renin angiotensin system, including VOSTALLY, can cause hyperkalemia. In clinical trials with ramipril, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving ramipril. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of other drugs that raise serum potassium levels. Monitor serum potassium periodically in patients treated with VOSTALLY [see Drug Interactions (7.2)] .

6 ADVERSE REACTIONS The most common adverse reactions included cough and hypotension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Rosemont Pharmaceuticals, LLC at 1-844-638-2235 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Hypertension Ramipril has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 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 common reasons for discontinuation of ramipril were cough (1.0%), dizziness (0.5%), and impotence (0.4%). 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. Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes HOPE Study Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials [see Warnings and Precautions (5.2) ] . Post-Myocardial Infarction Heart Failure AIRE Study In AIRE, the adverse reactions occurring more commonly in ramipril than placebo and in >5% of patients taking ramipril were hypotension (11%) and cough (8%). The follow-up time was between 6 and 46 months for this study. 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 (5.5) ] . 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. 6.2 Post-Marketing Experience Other Adverse Reactions Other adverse reactions reported in controlled clinical trials (in less than 1% of ramipril patients,) or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain): Cardiovascular : palpitations General disorders : edema, malaise, weight gain Hematologic : bone marrow depression, agranulocytosis, neutropenia, pancytopenia, hemolytic anemia, and thrombocytopenia Gastrointestinal : pancreatitis, abdominal pain, anorexia, constipation, dry mouth, dyspepsia, dysphagia, increased salivation, and taste disturbance Immune system : eosinophilic pneumonitis, hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), toxic epidermal necrolysis, Stevens-Johnson syndrome, an immune symptom complex which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations Musculoskeletal and connective tissue : arthralgia, arthritis, myalgia Neurologic and Psychiatric: a nxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances Respiratory, thoracic and mediastinal : dyspnea, epistaxis Reproductive system : impotence Skin and subcutaneous tissue : erythema multiforme, hyperhidrosis, photosensitivity, purpura, onycholysis, pemphigus, pemphigoid In addition to adverse reactions 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.