Zestril

1 INDICATIONS AND USAGE Zestril 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 Zestril is 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. Zestril may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1) ] . 1.2 Heart Failure Zestril is indicated to reduce signs and symptoms of systolic heart failure [see Clinical Studies (14.2) ] . 1.3 Reduction of Mortality in Acute Myocardial Infarction Zestril is 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) ] .

1.1 Hypertension Zestril is 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 …

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 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) ] . Zestril is not recommended in pediatric patients 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 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of Zestril 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 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) ] . Zestril is not recommended in pediatric patients 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 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of Zestril 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) ] .

3 DOSAGE FORMS AND STRENGTHS 2.5 mg are white, round, biconvex, uncoated tablets identified as “ZESTRIL 2 1/2” on one side and “135” on the other side. 5 mg are pink, capsule-shaped, biconvex, bisected, uncoated tablets identified as “ZESTRIL” on one side and “130” on the other side. 10 mg are pink, round, biconvex, uncoated tablets identified as “ZESTRIL 10” on one side and “131” on the other side. 20 mg are pale brownish red, round, biconvex, uncoated tablets identified as “ZESTRIL 20” on one side and “132” on the other side. 30 mg are pale brownish red, round, biconvex, uncoated tablets identified as “ZESTRIL 30” on one side and “133” on the other side. 40 mg are yellow, round, biconvex, uncoated tablets identified as “ZESTRIL 40” on one side and “134” on the other side. Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg ( 3 )

4 CONTRAINDICATIONS Zestril is contraindicated in combination with a neprilysin inhibitor (e.g., sacubitril). Do not administer Zestril within 36 hours of switching to or from sacubitril/valsartan, a neprilysin inhibitor [ see Warnings and Precautions (5.2)] . Zestril 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 ZESTRIL 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 Zestril in patients with diabetes ( 4 , 7.4 )

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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 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 Zestril, 5.7% of patients on Zestril discontinued with adverse reactions. The following adverse reactions (events 2% greater on Zestril than on placebo) were observed with Zestril alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2.5%). Heart Failure In patients with systolic heart failure treated with Zestril 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 Zestril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks. The following adverse reactions (events 2% greater on Zestril than on placebo) were observed with Zestril: 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% to 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 Zestril had a higher incidence of hypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patients not taking Zestril. Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart failure treated with Zestril 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 Zestril-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 Zestril alone. Increases were mor …

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) 7.1 Diuretics Initiation of Zestril in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with Zestril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Zestril. If this is not possible, reduce the starting dose of Zestril [see Dosage and Administration (2.2) and Warnings and Precautions (5.4) ] . Zestril 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 Zestril 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 1,448 patients with type 2 diabetes, elevated urinary-albumin-to-creatinine ratio, and decreased estimated glomerular filtration rate (GFR 30 mL/min 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 Zestril and other agents that affect the RAS. Do not co-administer aliskiren with Zestril in patients with diabetes. Avoid use of aliskiren with Zestril 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 Zestril. 7.7 mTOR Inhibitor s Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, ev …

8 USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. ( 8.2 ) Race: Less antihypertensive effect in blacks than non blacks ( 8.6 ) 8.1 Pregnancy Risk Summary Zestril 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 Zestril 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% to 4% and 15% to 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 Zestril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero exposure to Zestril, 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. 8.2 Lactation Risk Summary No data are available regarding the presence of lisinopril in human milk or the effects of lisinopril on the breastfed infant or on milk production. Lisinopril is present in rat milk. Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with Zestril. 8.4 Pediatric Use Antihypertensive effects and safety of Zestril 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 Zestril have not been established in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate 30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ] .

8.6 Race ACE inhibitors, including Zestril, have an effect on blood pressure that is less in black patients than in non blacks.

8.7 Renal Impairment Dose adjustment of Zestril is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. No dose adjustment of Zestril is required in patients with creatinine clearance > 30 mL/min …

12.1 Mechanism of Action Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Zestril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with Zestril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L [see Clinical Studies (14.1) ] . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Zestril remains to be elucidated. While the mechanism through which Zestril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Zestril is antihypertensive even in patients with low-renin hypertension. Although Zestril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non Black patients. Concomitant administration of Zestril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.

11 DESCRIPTION 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. Zestril is 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 - calcium phosphate, magnesium stearate, mannitol, starch. 5 mg, 10 mg, 20 mg and 30 mg tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch. 40 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch, yellow ferric oxide.

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) ] .

16 HOW SUPPLIED/STORAGE AND HANDLING Zestril is available as uncoated biconvex tablets in bottles of 90. Strength Color Shape Scored Side 1/Side 2 NDC 24979- 2.5 mg White Round No ZESTRIL 21⁄2/135 238-07 5 mg Pink Capsule-Shaped Yes ZESTRIL/130 239-07 10 mg Pink Round No ZESTRIL 10/131 240-07 20 mg Pale Brownish Red Round No ZESTRIL 20/132 241-07 30 mg Pale Brownish Red Round No ZESTRIL 30/133 242-07 40 mg Yellow Round No ZESTRIL 40/134 243-07 Store at controlled room temperature, 20° to 25°C (68° to 77°F) [see USP]. Protect from moisture, freezing and excessive heat. Dispense in a tight container.