VOSTALLY

Ramipril is an angiotensin converting enzyme (ACE) inhibitor. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°C–112°C. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3- phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester. The structural formula for ramipril is: Its empirical formula is C 23 H 32 N 2 O 5 and its molecular weight is 416.5 g/mol. VOSTALLY is a clear, colorless solution for oral use that contains 1 mg/mL ramipril. The inactive ingredients are citric acid monohydrate, ethylparaben sodium, frozen peppermint flavor 5015241T, methylparaben sodium, purified water, and sucralose. Chemical Structure

VOSTALLY is an angiotensin converting enzyme (ACE) inhibitor indicated: for the treatment of hypertension in adults, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions ( 1.1 ). In patients 55 years or older at high risk of developing a major cardiovascular event, VOSTALLY is indicated to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes ( 1.2 ). In adult patients with post-myocardial infarction heart failure to reduce the risk of cardiovascular death and hospitalization for heart failure ( 1.3 ). 1.1 Hypertension VOSTALLY is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy. VOSTALLY may be used alone or in combination with thiazide diuretics. 1.2 Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes VOSTALLY is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes. 1.3 Post-Myocardial Infarction Heart Failure VOSTALLY is indicated in adult patients with post-myocardial infarction heart failure to reduce the risk of cardiovascular death and hospitalization for heart failure [see Clinical Studies (14.3) ] .

Hypertension: Initial dose is 2.5 mg to 20 mg orally once daily. Adjust dosage according to blood pressure response after 2–4 weeks of treatment. The usual maintenance dose following titration is 2.5 mg to 20 mg orally daily as a single dose or equally divided doses ( 2.2 ). Reduction in the risk of myocardial infarction, stroke, or death from cardiovascular causes: 2.5 mg orally once daily for 1 week, 5 mg orally once daily for 3 weeks, and increased as tolerated to a maintenance dose of 10 mg orally once daily ( 2.3 ). Heart failure post-myocardial infarction: Starting dose of 2.5 mg orally twice daily. If patient becomes hypotensive at this dose, decrease dosage to 1.25 mg orally twice daily. Titrate at 3-week intervals as tolerated to a target dose of 5 mg orally twice daily ( 2.4 ). 2.1 Important Administration Information Instruct patients or caregivers to use an oral dosing syringe or oral dosing cup to correctly measure the prescribed amount of medication. Inform patients that oral dosing syringes may be obtained from their pharmacy. 2.2 Recommended Dosage in Hypertension The recommended initial dose for patients not receiving a diuretic is 2.5 mg orally once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg orally per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. 2.3 Recommended Dosage in Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes Initiate dosing at 2.5 mg orally once daily for 1 week, 5 mg orally once daily for the next 3 weeks, and then increase as tolerated, to a maintenance dose of 10 mg orally once daily. If the patient is hypertensive or recently post-myocardial infarction, VOSTALLY can also be given as a divided dose. 2.4 Recommended Dosage in Post-Myocardial Infarction Heart Failure For the treatment of patients with post-myocardial infarction heart failure, the recommended starting dose of VOSTALLY is 2.5 mg orally twice daily (5 mg orally per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg orally twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg orally twice daily, with dosage increases being about 3 weeks apart. After the initial dose of VOSTALLY, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of VOSTALLY does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see Warnings and Precautions (5.5), Drug Interactions (7.1) ] . 2.5 Dosage Adjustments Renal Impairment Establish baseline renal function in patients initiating VOSTALLY. In patients with creatinine clearance ≤40 mL/min, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see Use in Specific Populations (8.6) ] . Hypertension For patients with hypertension and renal impairment, the recommended initial dosage of VOSTALLY is 1.25 mg orally once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg orally. Heart Failure Post-Myocardial Infarction For patients with heart failure and renal impairment, the recommended initial dosage of VOSTALLY is 1.25 mg orally once daily. The dose may be increased to 1.25 mg orally twice daily, and up to a maximum dose of 2.5 mg orally twice daily depending on clinical response and tolerability. Volume Depletion or Renal Artery Stenosis Blood pressure decreases associated with any dose of VOSTALLY depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, initiate dosing at 1.25 mg orally once daily. Adjust dosage according to blood pressure response.

VOSTALLY is contraindicated in patients with: a history of angioedema or hypersensitivity to this product or any other ACE inhibitor [see Warnings and Precautions (5.2) ] hereditary or idiopathic angioedema [see Warnings and Precautions (5.2)] VOSTALLY is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer VOSTALLY within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Drug Interactions (7.3) ] Do not co-administer VOSTALLY with aliskiren in patients with diabetes [see Drug Interactions (7.3) ] Angioedema or hypersensitivity related to previous treatment with an ACE inhibitor, or a history of hereditary or idiopathic angioedema ( 4 ). VOSTALLY is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer VOSTALLY within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor ( 4 ). Do not co-administer aliskiren with VOSTALLY in patients with diabetes ( 4 ).

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.

Diuretics: Excessive drop in blood pressure ( 7.1 ). Potassium-sparing diuretics/potassium supplements: Hyperkalemia ( 7.2 ) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension, and hyperkalemia ( 7.3 ) Lithium: Increase serum lithium levels, symptoms of lithium toxicity ( 7.4 ). Gold: Nitritoid reactions have been reported ( 7.5 ). NSAID use may lead to increased risk of renal impairment and loss of antihypertensive effect ( 7.6 ). mTOR inhibitor or neprilysin inhibitor use may increase angioedema risk ( 7.7 ). 7.1 Diuretics Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with VOSTALLY. The possibility of hypotensive effects with VOSTALLY can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with VOSTALLY. If this is not possible, reduce the starting dose [see Dosage and Administration (2) ]. 7.2 Agents Increasing Serum Potassium Coadministration of VOSTALLY with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. 7.3 Dual Blockade of the Renin-Angiotensin-Aldosterone System Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on VOSTALLY and other agents that affect the RAS. 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 in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization 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 (including VOSTALLY) is not recommended. Aliskiren Do not co-administer aliskiren with VOSTALLY in patients with diabetes. Avoid concomitant use of aliskiren with VOSTALLY in patients with renal impairment (GFR <60 mL/min/1.73 m 2 ). 7.4 Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. 7.5 Gold Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy including VOSTALLY. 7.6 Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors) In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs. 7.7 mTOR Inhibitors or Other Drugs Known to Cause Angioedema Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema. [see Warnings and Precautions (5.2) ]

Storage and Handling Store in a refrigerator 2°C to 8°C (36°F to 46°F). Store and dispense in original packaging. After the bottle is opened, store it between 20°C to 25°C (68°F to 77°F) [ see USP Controlled Room Temperature ] and use it within 60 days.