Lisinopril

6 ADVERSE REACTIONS 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 Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

4 CONTRAINDICATIONS Lisinopril tablets are contraindicated in combination with a neprilysin (e.g., sacubitril). Do not administer lisinopril tablets within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [see Warning and Precaution (5.2) ]. Lisinopril tablets are 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 tablets 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 Tablets in patients with diabetes ( 4 , 7.4 )

11 DESCRIPTION Lisinopril, USP is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. Lisinopril, USP a synthetic peptide derivative, is chemically described as (S)-1-[N 2 -(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, USP 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: Lisinopril tablets, USP 2.5 mg - dibasic calcium phosphate dihydrate, mannitol, pregelatinized starch-1500, magnesium stearate. Lisinopril tablets, USP 5 mg and 10 mg – dibasic calcium phosphate dihydrate, mannitol, pregelatinized starch-1500, yellow iron oxide, magnesium stearate. Lisinopril Tablets, USP 20 and 30 mg - corn starch, croscarmellose sodium, dibasic calcium phosphate, magnesium sterate, mannitol, yellow iron oxide. Lisinopril Tablets, USP 40 mg - corn starch, croscarmellose sodium, dibasic calcium phosphate, magnesium sterate, mannitol, red iron oxide. "Image Description"

2 DOSAGE AND ADMINISTRATION 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/1.73m 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 )

1 INDICATIONS AND USAGE Lisinopril tablets 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 )

10 OVERDOSAGE Following a single oral dose of 20 g/kg no lethality occurred in rats, and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution. Lisinopril can be removed by hemodialysis [see Clinical Pharmacology (12.3) ] .

7 DRUG INTERACTIONS 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 ).

12 CLINICAL PHARMACOLOGY

12.2 Pharmacodynamics Hypertension Adult Patients: Administration of lisinopril tablets to patients with hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is usually not observed although it can occur and should be anticipated in volume and/or salt-depleted patients [see Warnings and Precautions (5.4) ] . When given together with thiazide-type diuretics, the blood pressure lowering effects of the two drugs are approximately additive. In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of lisinopril tablets, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses; however, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing. The antihypertensive effects of lisinopril tablets are maintained during long-term therapy. Abrupt withdrawal of lisinopril tablets has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels. Non-Steroidal Anti-Inflammatory Agents In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of lisinopril tablets alone were compared to lisinopril tablets given concomitantly with indomethacin, the use of indomethacin was associated with a reduced effect, although the difference between the two regimens was not significant.

12.3 Pharmacokinetics Adult Patients : Following oral administration of lisinopril tablets, peak serum concentrations of lisinopril occur within about 7 hours, although there was a trend to a small delay in time taken to reach peak serum concentrations in acute myocardial infarction patients. Food does not alter the bioavailability of lisinopril tablets. Declining serum concentrations exhibit a prolonged terminal phase, which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Upon multiple dosing, lisinopril exhibits an effective half-life of 12 hours. Lisinopril does not appear to be bound to other serum proteins. Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of lisinopril is approximately 25%, with large inter subject variability (6% to 60%) at all doses tested (5mg to 80 mg). The absolute bioavailability of lisinopril is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of lisinopril in patients with acute myocardial infarction is similar to that in healthy volunteers. Impaired renal function decreases elimination of lisinopril, which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough lisinopril levels increase, time to peak concentration increases and time to attain steady state is prolonged [see Dosage and Administration (2.4) ] . Lisinopril can be removed by hemodialysis. Pediatric Patients: The pharmacokinetics of lisinopril were studied in 29 pediatric hypertensive patients between 6 years and 16 years with glomerular filtration rate > 30 mL/min/1.73 m 2 . After doses of 0.1mg per kg to 0.2 mg per kg, steady state peak plasma concentrations of lisinopril occurred within 6 hours and the extent of absorption based on urinary recovery was about 28%. These values are similar to those obtained previously in adults. The typical value of lisinopril oral clearance (systemic clearance/absolute bioavailability) in a child weighing 30 kg is 10 L/h, which increases in proportion to renal function. In a multicenter, open-label pharmacokinetic study of daily oral lisinopril in 22 pediatric hypertensive patients with stable kidney transplant (ages 7-17 years; estimated glomerular filtration rate > 30 mL/min/1.73 m 2 ), dose normalized exposures were in the range reported previously in children without a kidney transplant.

20230710

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3 DOSAGE FORMS AND STRENGTHS Lisinopril tablets, USP 2.5 mg are white, round, biconvex, uncoated tablets, engraved with “Y11” on one side. Lisinopril tablets, USP 5 mg are yellow, capsule shape, uncoated tablets, debossed with “Y12” on one side and a functional scoring on another side. Lisinopril tablets, USP 10 mg are yellow, round, biconvex, uncoated tablets, debossed with “Y13” on one side, plain on another side. Lisinopril tablets, USP 20 mg are yellow, round, biconvex, uncoated tablets, debossed with “Y14” on one side, plain on another side. Lisinopril tablets, USP 30 mg are yellow, round, biconvex, uncoated tablets, debossed with “Y15” on one side, plain on another side. Lisinopril tablets, USP 40 mg are light pink to pink, round, biconvex, uncoated tablets, debossed with “Y16” on one side, plain on another side. Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg ( 3 )

Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE LISINOPRIL LISINOPRIL ANHYDROUS biconvex Y11 Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE FERRIC OXIDE YELLOW LISINOPRIL LISINOPRIL ANHYDROUS Y12 Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE FERRIC OXIDE YELLOW LISINOPRIL LISINOPRIL ANHYDROUS biconvex Y13 Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE CROSCARMELLOSE SODIUM FERRIC OXIDE YELLOW LISINOPRIL LISINOPRIL ANHYDROUS biconvex Y14 Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE CROSCARMELLOSE SODIUM FERRIC OXIDE YELLOW LISINOPRIL LISINOPRIL ANHYDROUS biconvex Y15 Lisinopril Lisinopril STARCH, CORN MANNITOL DIBASIC CALCIUM PHOSPHATE DIHYDRATE MAGNESIUM STEARATE CROSCARMELLOSE SODIUM FERRIC OXIDE RED LISINOPRIL LISINOPRIL ANHYDROUS biconvex Y16

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg per kg per day (about 56 or 9 times* the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg per kg per day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice. Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow. There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg per kg per day of lisinopril. This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m 2 , respectively. Studies in rats indicate that lisinopril crosses the blood brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14 C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses. * Calculations assume a human weight of 50 kg and human body surface area of 1.62m 2

13 NONCLINICAL TOXICOLOGY

ANDA212041

Lisinopril

Lisinopril

62135-642

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Lisinopril Tablets, USP 2.5mg - NDC 62135-640-90- 90's Bottle Label Lisinopril Tablets, USP 2.5mg - NDC 62135-640-31- 300's Bottle Label Lisinopril Tablets, USP 5mg - NDC 62135-641-90- 90's Bottle Label Lisinopril Tablets, USP 5mg - NDC 62135-641-31- 300's Bottle Label Lisinopril Tablets, USP 10mg - NDC 62135-642-90- 90's Bottle Label Lisinopril Tablets, USP10mg - NDC 62135-642-31- 300's Bottle Label Lisinopril Tablets, USP 20mg - NDC 62135-643-90- 90's Bottle Label Lisinopril Tablets, USP 20mg - NDC 62135-643-31- 300's Bottle Label Lisinopril Tablets, USP 30mg - NDC 62135-644-90- 90's Bottle Label Lisinopril Tablets, USP 30mg - NDC 62135-644-31- 300's Bottle Label Lisinopril Tablets, USP 40mg - NDC 62135-645-90- 90's Bottle Label Lisinopril Tablets, USP 40mg - NDC 62135-645-31- 300's Bottle Label "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description" "Image Description"

1.1 Hypertension Lisinopril tablets 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 may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1) ] .

17 PATIENT COUNSELING INFORMATION NOTE: This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects. Pregnancy: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to notify their healthcare provider with a known or suspected pregnancy [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1) ]. Angioedema: Angioedema, including laryngeal edema may occur at any time during treatment with angiotensin converting enzyme inhibitors, including lisinopril. Tell patients to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in swallowing or breathing) and to take no more drug until they have consulted with the prescribing physician. Lactation: Advise women not to breastfeed during treatment with lisinopril [see Use in Specific Populations (8.2) ]. Symptomatic Hypotension: Tell patients to report light-headedness especially during the first few days of therapy. If actual syncope occurs, tell the patient to discontinue the drug until they have consulted with the prescribing physician. Tell patients that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; advise patients accordingly. Hyperkalemia: Tell patients not to use salt substitutes containing potassium without consulting their physician. Hypoglycemia: Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycaemia closely, especially during the first month of combined use [see Drug Interactions (7.2) ] . Leukopenia/Neutropenia: Tell patients to report promptly any indication of infection (eg, sore throat, fever), which may be a sign of leukopenia/neutropenia. Manufactured by: Yiling Pharmaceutical Ltd No.36 Zhujiang Road, Shijiazhuang,050035, China Manufactured for: Chartwell RX, LLC. Congers, NY 10920 Revised: 06/2023 L71496

14 CLINICAL STUDIES

8.5 Geriatric Use No dosage adjustment with lisinopril tablets is necessary in elderly patients. In a clinical study of lisinopril tablets in patients with myocardial infarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In this study, 4.8 % of patients aged 75 years and older discontinued lisinopril tablets treatment because of renal dysfunction vs. 1.3% of patients younger than 75 years. No other differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.4 Pediatric Use Antihypertensive effects and safety of lisinopril tablets have been established in pediatric patients aged 6 to 16 years [see Dosage and Administration (2.1) and Clinical Studies (14.1) ] . No relevant differences between the adverse reaction profile for pediatric patients and adult patients were identified. Safety and effectiveness of lisinopril tablets have not been established in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m 2 [see Dosage and Administration (2.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.1) ]. Neonates with a history of in utero exposure to lisinopril tablets If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

8.1 Pregnancy Risk Summary Lisinopril tablets 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. 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. When pregnancy is detected, discontinue lisinopril tablets as soon as possible. The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. In the general U.S. population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal Adverse Reactions Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia and skeletal deformations, including skull hypoplasia, hypotension, and death. 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. 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 lisinopril tablets for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to lisinopril tablets, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Race: Less antihypertensive effect in blacks than non blacks ( 8.6 )

16 HOW SUPPLIED/STORAGE AND HANDLING Lisinopril tablets, USP are available as uncoated tablets in bottles of 90 and 300. Strength Color Shape Scored Side 1 Bottle Count NDC 2.5 mg White Round No Y11 90 Tablets 62135-640-90 2.5 mg White Round No Y11 300 Tablets 62135-640-31 5 mg Yellow Capsule shape Yes Y12 90 Tablets 62135-641-90 5 mg Yellow Capsule shape Yes Y12 300 Tablets 62135-641-31 10 mg Yellow Round No Y13 90 Tablets 62135-642-90 10 mg Yellow Round No Y13 300 Tablets 62135-642-31 20 mg Yellow Round No Y14 90 Tablets 62135-643-90 20 mg Yellow Round No Y14 300 Tablets 62135-643-31 30 mg Yellow Round No Y15 90 Tablets 62135-644-90 30 mg Yellow Round No Y15 300 Tablets 62135-644-31 40 mg Pink Round No Y16 90 Tablets 62135-645-90 40 mg Pink Round No Y16 300 Tablets 62135-645-31 Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature]. Protect from moisture, freezing and excessive heat. Dispense in a tight container.

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue lisinopril tablets 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 lisinopril tablets 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 )