Pregnancy

8.1 Pregnancy Pregnancy Category D 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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue PRINIVIL as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus. In the unusual case that there is no appropriate alternative therapy to 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. If oligohydramnios is observed, discontinue PRINIVIL, unless it is considered lifesaving for the mother. 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 PRINIVIL for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

Drug Interactions

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, syncope, and hyperkalemia (7.4) Lithium: Symptoms of lithium toxicity (7.5) Gold: Nitritoid reactions (7.6) 7.1 Diuretics Initiation of PRINIVIL in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with PRINIVIL can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with PRINIVIL. If this is not possible, reduce the starting dose of PRINIVIL [see Dosage and Administration (2.2) and Warnings and Precautions (5.4)]. PRINIVIL 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 PRINIVIL 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 direct renin inhibitors (such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. The Veterans Affairs Nephropathy in Diabetes (VA NEPHRON-D) 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 stage 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. Monitor blood pressure, renal function and electrolytes in patients on PRINIVIL and other agents that affect the RAS. Do not coadminister aliskiren with PRINIVIL in patients with diabetes. Avoid use of aliskiren with PRINIVIL 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 PRINIVIL. 7.7 Mammalian Target of Rapamycin (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 Inhibitors Patients taking a concomitant neprilysin inhibitor (e.g., sacubitril) may be at increased risk for angioedema [see Contraindications (4) and Warnings and Precautions (5.2)].

Indications And Usage

1 INDICATIONS AND USAGE PRINIVIL is an angiotensin converting enzyme (ACE) inhibitor indicated for: Treatment of hypertension in adults and pediatric patients ≥6 years of age (1.1) Adjunctive therapy for heart failure (1.2) Treatment of acute myocardial infarction (1.3) 1.1 Hypertension PRINIVIL 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. PRINIVIL may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1)]. 1.2 Heart Failure PRINIVIL is indicated to reduce signs and symptoms of heart failure in patients who are not responding adequately to diuretics and digitalis [see Clinical Studies (14.2)]. 1.3 Acute Myocardial Infarction PRINIVIL 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)].

Clinical Studies

14 CLINICAL STUDIES 14.1 Hypertension Adult Patients: Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of PRINIVIL was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20, or 80 mg of PRINIVIL. In controlled clinical studies in patients with mild to moderate hypertension, PRINIVIL 20-80 mg has been compared to hydrochlorothiazide 12.5-50 mg and with atenolol 50-500 mg, and in patients with moderate, to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic blood pressure in a population that was 75% Caucasian. PRINIVIL was approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure and had somewhat greater effects on systolic blood pressure. PRINIVIL had similar effectiveness and adverse effects in younger and older (>65 years) patients. It was less effective in Blacks than in Caucasians. In hemodynamic studies of PRINIVIL in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of PRINIVIL, there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of lisinopril on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large. In patients with renovascular hypertension PRINIVIL has been shown to be well tolerated and effective in reducing blood pressure [see Warnings and Precautions (5.3)]. Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed <50 kg received either 0.625, 2.5, or 20 mg of lisinopril daily and patients who weighed ≥50 kg received either 1.25, 5, or 40 mg of lisinopril daily. At the end of 2 weeks, lisinopril administered once daily lowered trough blood pressure in a dose-dependent manner with consistent antihypertensive efficacy demonstrated at doses >1.25 mg (0.02 mg/kg). This effect was confirmed in a withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than it did in patients who were randomized to remain on the middle and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several demographic subgroups: age, Tanner stage, gender, and race. In this study, lisinopril was generally well-tolerated. In the above pediatric studies, lisinopril was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form [see Dosage and Administration (2.5)]. 14.2 Heart Failure In two placebo controlled, 12-week clinical studies compared the addition of PRINIVIL up to 20 mg daily to digitalis and diuretics alone. The combination of PRINIVIL, digitalis and diuretics reduced the following signs and symptoms of heart failure: edema, rales, paroxysmal nocturnal dyspnea and jugular venous distention. In one of the studies, the combination of PRINIVIL, digitalis and diuretics reduced orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV, and it improved exercise tolerance. A large (over 3000 patients) survival study, the ATLAS Trial, comparing 2.5 and 35 mg of lisinopril in patients with systolic heart failure, showed that the higher dose of lisinopril had outcomes at least as favorable as the lower dose. During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of PRINIVIL resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate. 14.3 Acute Myocardial Infarction The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto Miocardico (GISSI-3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction (MI) admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Hemodynamically-stable patients presenting within 24 hours of the onset of symptoms were randomized, in a 2 × 2 factorial design, to 6 weeks of either 1) PRINIVIL alone (n=4841), 2) nitrates alone (n=4869), 3) PRINIVIL plus nitrates (n=4841), or 4) open control (n=4843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients. The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria >500 mg per 24 h). Patients randomized to PRINIVIL received 5 mg within 24 hours of the onset of symptoms, 5 mg after 24 hours, and then 10 mg daily thereafter. Patients with systolic blood pressure less than 120 mmHg at baseline received 2.5 mg of PRINIVIL. If hypotension occurred, the PRINIVIL dose was reduced or if severe hypotension occurred PRINIVIL was stopped [see Dosage and Administration (2.3)]. The primary outcomes of the trial were the overall mortality at 6 weeks and a combined endpoint at 6 months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction ≤35%, or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving PRINIVIL (n=9646), alone or with nitrates, had an 11% lower risk of death (p =0.04) compared to patients who did not receive PRINIVIL (n=9672) (6.4% vs. 7.2%, respectively) at 6 weeks. Although patients randomized to receive PRINIVIL for up to 6 weeks also fared numerically better on the combined endpoint at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of PRINIVIL, between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this endpoint. Patients with acute myocardial infarction, treated with PRINIVIL, had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure <90 mmHg for more than 1 hour) and renal dysfunction (2.4% versus 1.1%) in-hospital and at 6 weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration) [see Adverse Reactions (6.1)].

Warnings And Cautions

5 WARNINGS AND PRECAUTIONS Angioedema: Discontinue PRINIVIL (5.2) Renal impairment: Monitor renal function periodically (5.3) Hypotension: Monitor blood pressure after initiation (5.4) Hyperkalemia: Monitor serum potassium periodically (5.5) Cholestatic jaundice and hepatic failure: Discontinue PRINIVIL (5.6) 5.1 Fetal Toxicity Pregnancy Category D 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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue PRINIVIL as soon as possible [see Use in Specific Populations (8.1)]. 5.2 Angioedema and Anaphylactoid Reactions Angioedema Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx, including some fatal reactions, have occurred in patients treated with angiotensin converting enzyme inhibitors, including PRINIVIL, at any time during treatment. Patients with involvement of the tongue, glottis or larynx are likely to experience airway obstruction, especially those with a history of airway surgery. PRINIVIL should be promptly discontinued and appropriate therapy and monitoring should be provided until complete and sustained resolution of signs and symptoms of angioedema has occurred. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor [see Contraindications (4)]. ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients. Patients receiving concomitant ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema [see Drug Interactions (7.7)]. Patients receiving concomitant ACE inhibitor and neprilysin inhibitor therapy may be at increased risk for angioedema [see Contraindications (4) and Drug Interactions (7.8)]. Intestinal Angioedema: Intestinal angioedema has occurred in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. In some cases, the angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Anaphylactoid Reactions Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with Hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. Anaphylactoid Reactions During Dialysis: Sudden and potentially life-threatening anaphylactoid reactions have occurred in some patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. In such patients, dialysis must be stopped immediately, and aggressive therapy for anaphylactoid reactions must be initiated. Symptoms have not been relieved by antihistamines in these situations. In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. 5.3 Impaired Renal Function Monitor renal function periodically in patients treated with PRINIVIL. Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g., patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, post-myocardial infarction or volume depletion) may be at particular risk of developing acute renal failure on PRINIVIL. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on PRINIVIL [see Adverse Reactions (6.1), Drug Interactions (7.4)]. 5.4 Hypotension PRINIVIL can cause symptomatic hypotension, sometimes complicated by oliguria, progressive azotemia, acute renal failure or death. Patients at risk of excessive hypotension include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, ischemic heart disease, cerebrovascular disease, hyponatremia, high dose diuretic therapy, renal dialysis, or severe volume and/or salt depletion of any etiology. In these patients, start PRINIVIL under medical supervision and follow such patients for the first two weeks of treatment and whenever the dose of PRINIVIL and/or diuretic is increased. Avoid use of PRINIVIL in patients who are hemodynamically unstable after acute MI. Symptomatic hypotension is also possible in patients with severe aortic stenosis or hypertrophic cardiomyopathy. Surgery/Anesthesia: In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRINIVIL may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion. 5.5 Hyperkalemia Monitor serum potassium periodically in patients receiving PRINIVIL. Drugs that inhibit the renin-angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.1)]. 5.6 Hepatic Failure ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice or hepatitis and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical treatment.

Overdosage

Adverse Reactions

Recent major changes

Dosage and Administration Preparation of Suspension (2.5) 10/2016 Contraindications (4) 09/2017 Warnings and Precautions Angioedema and Anaphylactoid Reactions (5.2) 09/2017

Mechanism

Contraindications

Nursing Mothers