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 inbibitor [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)].

6 ADVERSE REACTIONS

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 tablets, 5.7% of patients onlisinopril tablets discontinued with adverse reactions.

The following adverse reactions (events 2% greater on lisinopril tablets than on placebo) were observed with lisinopril tablets alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2.5%).

Heart Failure

In patients with systolic heart failure treated with lisinopril tablets 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 Tablets for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.

The following adverse reactions (events 2% greater on lisinopril tablets than on placebo) were observed with lisinopril tablets: 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 tablets had a higher incidence of hypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patients not taking lisinopril tablets.

Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart

failure treated withlisinopril tablets 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 tablets-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 tablets 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 tablets 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 tablets 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 tablets 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

7 DRUG INTERACTIONS

7.1 Diuretics

Initiation of lisinopril tablets in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with lisinopril tablets can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with lisinopril tablets. If this is not possible, reduce the starting dose of lisinopril tablets [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)].

Lisinopril tablets 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 tablets 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.

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 tablets and other agents that affect the RAS.

Do not co-administer aliskiren with lisinopril tablets in patients with diabetes. Avoid use of aliskiren with lisinopril tablets 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 tablets.

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)]

13 NONCLINICAL TOXICOLOGY

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 14C 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

16 HOW SUPPLIED/STORAGE AND HANDLING

Lisinopril tablets, USP are available as uncoated tablets in bottles of 30, 90, 100, 500 and 1000.

Strength	Color	Shape	Scored	Side 1	Bottle Count	NDC 69117
2.5 mg	White	Round	No	Y11	30 Tablets	0036-1
2.5 mg	White	Round	No	Y11	90 Tablets	0036-2
2.5 mg	White	Round	No	Y11	100 Tablets	0036-3
2.5 mg	White	Round	No	Y11	500 Tablets	0036-4
2.5 mg	White	Round	No	Y11	1000 Tablets	0036-5
5 mg	Yellow	Capsule shape	Yes	Y12	30 Tablets	0037-1
5 mg	Yellow	Capsule shape	Yes	Y12	90 Tablets	0037-2
5 mg	Yellow	Capsule shape	Yes	Y12	100 Tablets	0037-3
5 mg	Yellow	Capsule shape	Yes	Y12	500 Tablets	0037-4
5 mg	Yellow	Capsule shape	Yes	Y12	1000 Tablets	0037-5
10 mg	Yellow	Round	No	Y13	30 Tablets	0038-1
10 mg	Yellow	Round	No	Y13	90 Tablets	0038-2
10 mg	Yellow	Round	No	Y13	100 Tablets	0038-3
10 mg	Yellow	Round	No	Y13	500 Tablets	0038-4
10 mg	Yellow	Round	No	Y13	1000 Tablets	0038-5
20 mg	Yellow	Round	No	Y14	30 Tablets	1001-1
30 mg	Yellow	Round	No	Y15	30 Tablets	1002-1
40 mg	Pink	Round	No	Y16	30 Tablets	1003-1

Store at 20-25°C (68-77°F). [See USP Controlled Room Temperature]. Protect from moisture, freezing and excessive heat. Dispense in a tight container.

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

Distributed by:

Yiling Pharmaceutical, Inc.

5348 Vegas Dr, Las Vegas, NV 89108, USA

Revised:06/2021