LISINOPRIL

Lisinopril is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. Lisinopril, a synthetic peptide derivative, is chemically described as (S)-1-[N2-(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is C 21 H 31 N 3 O 5 •2H 2 O and its structural formula is: Lisinopril is a white to off-white, crystalline powder, with a molecular weight of 441.53. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol. Lisinopril tablets, USP, are supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets for oral administration. Inactive Ingredients: 2.5 mg tablets – Mannitol, dibasic calcium phosphate, pregelatinized starch * , corn starch, colloidal silicon dioxide, sodium starch glycolate and magnesium stearate. 5 mg tablets – Mannitol, dibasic calcium phosphate, pregelatinized starch * , corn starch, colloidal silicon dioxide, sodium starch glycolate, magnesium stearate and yellow ferric oxide. 10 mg tablets – Mannitol, dibasic calcium phosphate, pregelatinized starch * , corn starch, colloidal silicon dioxide, sodium starch glycolate, magnesium stearate and red ferric oxide. 20 and 30 mg tablets - Mannitol, dibasic calcium phosphate, pregelatinized starch * , corn starch, colloidal silicon dioxide, magnesium stearate and red ferric oxide. 40 mg tablets - Mannitol, dibasic calcium phosphate, pregelatinized starch * , corn starch, colloidal silicon dioxide, magnesium stearate and yellow ferric oxide. * : Pregelatinized starch is a physically modified corn (maize) starch. Chemical Structure

Lisinopril is an angiotensin converting enzyme (ACE) inhibitor indicated for: Treatment of hypertension in adults and pediatric patients 6 years of age and older (1.1) Adjunct therapy for heart failure (1.2) Treatment of Acute Myocardial Infarction (1.3) 1.1 Hypertension Lisinopril tablets, USP, are indicated for the treatment of hypertension in adult patients and pediatric patients 6 years of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal 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. 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 1 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. Lisinopril tablets, USP, may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1) ]. 1.2 Heart Failure Lisinopril tablets, USP, are indicated to reduce signs and symptoms of systolic heart failure [see Clinical Studies (14.2) ] . 1.3 Reduction of Mortality in Acute Myocardial Infarction Lisinopril tablets, USP, are indicated for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers [see Clinical Studies (14.3) ].

Hypertension: Initial adult dose is 10 mg once daily. Titrate up to 40 mg daily based on blood pressure response. Initiate patients on diuretics at 5 mg once daily (2.1) Pediatric patients with glomerular filtration rate > 30 mL/min/1.73 m 2 : Initial dose in patients 6 years of age and older is 0.07 mg per kg (up to 5 mg total) once daily (2.1) Heart Failure: Initiate with 5 mg once daily. Increase dose as tolerated to 40 mg daily (2.2) Acute Myocardial Infarction (MI): Give 5 mg within 24 hours of MI. Followed by 5 mg after 24 hours, then 10 mg once daily (2.3) Renal Impairment: For patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, halve usual initial dose. For patients with creatinine clearance < 10 mL/min or on hemodialysis, the recommended initial dose is 2.5 mg (2.4) 2.1 Hypertension Initial Therapy in adults: The recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 mg to 40 mg per day administered in a single daily dose. Doses up to 80 mg have been used but do not appear to give greater effect. Use with diuretics in adults If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of lisinopril. The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per day. Pediatric Patients 6 years of age and older with hypertension For pediatric patients with glomerular filtration rate > 30 mL/min/1.73m 2 , the recommended starting dose is 0.07 mg per kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response up to a maximum of 0.61 mg per kg (up to 40 mg) once daily. Doses above 0.61 mg per kg (or in excess of 40 mg) have not been studied in pediatric patients [see Clinical Pharmacology (12.3) ]. Lisinopril is not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73m 2 [see Use in Specific Populations (8.4) and Clinical Studies (14.1) ]. 2.2 Heart Failure The recommended starting dose for lisinopril, when used with diuretics and (usually) digitalis as adjunctive therapy for systolic heart failure, is 5 mg once daily. The recommended starting dose in these patients with hyponatremia (serum sodium < 130 mEq/L) is 2.5 mg once daily. Increase as tolerated to a maximum of 40 mg once daily. Diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to hypotension [see Warnings and Precautions (5.4) , and Drug Interactions (7.1) ] . The appearance of hypotension after the initial dose of lisinopril does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. 2.3 Reduction of Mortality in Acute Myocardial Infarction In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, give lisinopril 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily. Dosing should continue for at least six weeks. Initiate therapy with 2.5 mg in patients with a low systolic blood pressure (≤ 120 mmHg and > 100 mmHg) during the first 3 days after the infarct [see Warnings and Precautions (5.4) ] . If hypotension occurs (systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) lisinopril should be withdrawn. 2.4 Dose in Patients with Renal Impairment No dose adjustment of lisinopril is required in patients with creatinine clearance > 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of lisinopril to half of the usual recommended dose i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily. For patients on hemodialysis or creatinine clearance < 10 mL/min, the recommended initial dose is 2.5 mg once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

Lisinopril is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Lisinopril within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warnings and Precautions (5.2)] . Lisinopril is contraindicated in patients with: a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme inhibitor hereditary or idiopathic angioedema Do not co-administer aliskiren with lisinopril in patients with diabetes [see Drug Interactions (7.4)] . Angioedema or a history of hereditary or idiopathic angioedema ( 4 ) Hypersensitivity ( 4 ) Co-administration of aliskiren with lisinopril in patients with diabetes ( 4 , 7.4 )

Common adverse reactions (events 2% greater than placebo) by use: Hypertension: headache, dizziness and cough (6.1) Heart Failure: hypotension and chest pain (6.1) Acute Myocardial Infarction: hypotension (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Solco Healthcare US, LLC at 1-866-257-2597 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, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Hypertension In clinical trials in patients with hypertension treated with lisinopril, 5.7% of patients on lisinopril discontinued with adverse reactions. The following adverse reactions (events 2% greater on lisinopril than on placebo) were observed with lisinopril alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2.5%). Heart Failure In patients with systolic heart failure treated with lisinopril for up to four years, 11% discontinued therapy with adverse reactions. In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with lisinopril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks. The following adverse reactions (events 2% greater on lisinopril than on placebo) were observed with lisinopril: hypotension (by 3.8%), chest pain (by 2.1%). In the two-dose ATLAS trial [see Clinical Studies (14.2) ] in heart failure patients, withdrawals due to adverse reactions were not different between the low and high groups, either in total number of discontinuation (17-18%) or in rare specific reactions (< 1%). The following adverse reactions, mostly related to ACE inhibition, were reported more commonly in the high dose group: Table 1 Dose-related Adverse Drug Reactions: ATLAS trial High Dose (n=1568) Low Dose (n=1596) Dizziness 19% 12% Hypotension 11% 7% Creatinine increased 10% 7% Hyperkalemia 6% 4% Syncope 7% 5% Acute Myocardial Infarction Patients treated with lisinopril had a higher incidence of hypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patients not taking lisinopril. Other clinical adverse reactions occurring in 1 % or higher of patients with hypertension or heart failure treated with lisinopril in controlled clinical trials and do not appear in other sections of labeling are listed below: Body as a whole : Fatigue, asthenia, orthostatic effects. Digestive : Pancreatitis, constipation, flatulence, dry mouth, diarrhea. Hematologic : Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia. Endocrine : Diabetes mellitus, inappropriate antidiuretic hormone secretion. Metabolic : Gout. Skin : Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis, cutaneous pseudolymphoma, toxic epidermal necrolysis, Stevens-Johnson syndrome, and pruritus. Special Senses : Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance. Urogenital : Impotence. Miscellaneous : A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis, paresthesia and vertigo. Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms. Clinical Laboratory Test Findings Serum Potassium : In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in 2.2% and 4.8% of lisinopril-treated patients with hypertension and heart failure, respectively [see Warnings and Precautions (5.5) ]. Creatinine, Blood Urea Nitrogen : Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2% of patients with hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis [see Warnings and Precautions (5.4) ] . Reversible minor increases in blood urea nitrogen and serum creatinine were observed in 11.6% of patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased. Patients with acute myocardial infarction in the GISSI-3 trial treated with lisinopril had a higher (2.4% versus 1.1% in placebo) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). Hemoglobin and Hematocrit : Small decreases in hemoglobin and hematocrit (mean decreases of approximately 0.4 g% and 1.3 vol%, respectively) occurred frequently in patients treated with lisinopril but were rarely of clinical importance in patients without some other cause of anemia. In clinical trials, less than 0.1% of patients discontinued therapy due to anemia. 6.2 Post-marketing Experience The following adverse reactions have been identified during post-approval use of lisinopril that are not included in other sections of labeling. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Other reactions include: Metabolism and nutrition disorders Hyponatremia [see Warnings and Precautions (5.4) ] , cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin [see Drug Interactions (7.2) ] Nervous system and psychiatric disorders Mood alterations (including depressive symptoms), mental confusion, hallucinations Skin and subcutaneous tissue disorders Psoriasis

Diuretics: Excessive drop in blood pressure (7.1) NSAIDS: Increased risk of renal impairment and loss of antihypertensive efficacy (7.3) Dual inhibition of the renin-angiotensin system: Increased risk of renal impairment, hypotension and hyperkalemia (7.4) Lithium: Symptoms of lithium toxicity (7.5) Gold: Nitritoid reactions have been reported (7.6) Concomitant mTOR inhibitor or neprilysin inhibitor use may increase angioedema risk ( 7.7 , 7.8 ) 7.1 Diuretics Initiation of lisinopril in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with lisinopril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril. If this is not possible, reduce the starting dose of lisinopril [see Dosage and Administration (2.2) and Warnings and Precautions (5.4) ] . Lisinopril attenuates potassium loss caused by thiazide-type diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient’s serum potassium frequently. 7.2 Antidiabetics Concomitant administration of lisinopril and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased blood-glucose-lowering effect with risk of hypoglycemia. 7.3 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, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including lisinopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving lisinopril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including lisinopril, may be attenuated by NSAIDs. 7.4 Dual Blockade of the Renin-Angiotensin System (RAS) 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. The VA NEPHRON trial enrolled 1448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 to 89.9 ml/min), randomized them to lisinopril or placebo on a background of losartan therapy and followed them for a median of 2.2 years. Patients receiving the combination of losartan and lisinopril did not obtain any additional benefit compared to monotherapy for the combined endpoint of decline in GFR, end state renal disease, or death, but experienced an increased incidence of hyperkalemia and acute kidney injury compared with the monotherapy group. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on lisinopril and other agents that affect the RAS. Do not co-administer aliskiren with lisinopril in patients with diabetes. Avoid use of aliskiren with lisinopril in patients with renal impairment (GFR <60 ml/min). 7.5 Lithium Lithium toxicity has been reported in patients receiving lithium concomitantly with drugs, which cause elimination of sodium, including ACE inhibitors. Lithium toxicity was usually reversible upon discontinuation of lithium and the ACE inhibitor. Monitor serum lithium levels during concurrent use. 7.6 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 lisinopril. 7.7 mTOR Inhibitors Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema. [see Warnings and Precautions (5.2) ] 7.8 Neprilysin Inhibitor Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema. [ see Warnings and Precautions (5.2) ]

Storage Store at 20 ºC to 25ºC (68ºF to 77ºF) [see USP controlled room temperature]. Protect from light, moisture and freezing. Dispense in a tight, light-resistant container.