Lisinopril: uses, appearance and warnings

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 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) ]. 1.2 Heart Failure Lisinopril tablets 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 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) ].

2.5 mg Tablets – White to off-white, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and ‘20’ on the other side. 5 mg Tablets – Light red colored, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘2&1’ on either side of score line. 10 mg Tablets – Light yellow colored, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘22’. 20 mg Tablets – Light yellow colored, capsule shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘23’. 30 mg Tablets – Light yellow colored, round shaped, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘24’. 40 mg Tablets - Light yellow colored, capsule shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘25’. Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg (3)

Lisinopril Tablets USP, 2.5 mg are White to off-white, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and ‘20’ on the other side. Bottles of 30 NDC 65862-037-30 (Child Resistant Closure) Bottles of 100 NDC 65862-037-01 (Child Resistant Closure) Bottles of 100 NDC 65862-037-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-037-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-037-99 (Non Child Resistant Closure) Lisinopril Tablets USP, 5 mg – Light red colored, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘2&1’ on either side of score line. Bottles of 30 NDC 65862-038-30 (Child Resistant Closure) Bottles of 100 NDC 65862-038-01 (Child Resistant Closure) Bottles of 100 NDC 65862-038-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-038-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-038-99 (Non Child Resistant Closure) Lisinopril Tablets USP, 10 mg – Light yellow colored, round shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘22’. Bottles of 30 NDC 65862-039-30 (Child Resistant Closure) Bottles of 100 NDC 65862-039-01 (Child Resistant Closure) Bottles of 100 NDC 65862-039-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-039-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-039-99 (Non Child Resistant Closure) Lisinopril Tablets USP, 20 mg – Light yellow colored, capsule shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘23’. Bottles of 30 NDC 65862-040-30 (Child Resistant Closure) Bottles of 100 NDC 65862-040-01 (Child Resistant Closure) Bottles of 100 NDC 65862-040-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-040-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-040-99 (Non Child Resistant Closure) Lisinopril Tablets USP, 30 mg – Light yellow colored, round shaped, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘24’. Bottles of 30 NDC 65862-041-30 (Child Resistant Closure) Bottles of 100 NDC 65862-041-01 (Child Resistant Closure) Bottles of 100 NDC 65862-041-00 (Non Child Resistant Closure) Bottles of 500 NDC 65862-041-05 (Non Child Resistant Closure) Bottles of 1,000 NDC 65862-041-99 (Non Child Resistant Closure) Lisinopril Tablets USP, 40 mg - Light yellow colored, capsule shaped, biconvex, uncoated tablets, debossed with ‘A’ on one side and on other side with ‘25’. …

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

Angioedema: Discontinue lisinopril, provide appropriate therapy and monitor until resolved (5.2) Renal impairment: Monitor renal function periodically (5.3) Hypotension: Patients with other heart or renal diseases have increased risk, monitor blood pressure after initiation (5.4) Hyperkalemia: Monitor serum potassium periodically (5.5) Cholestatic jaundice and hepatic failure: Monitor for jaundice or signs of liver failure (5.6) 5.1 Fetal Toxicity Lisinopril 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. 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 lisinopril as soon as possible [see Use in specific Populations (8.1) ]. 5.2 Angioedema and Anaphylactoid Reactions Patients taking concomitant mTOR inhibitor (e.g. temsirolimus, sirolimus, everolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions (7.7 , 7.8) ]. 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 lisinopril, 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. Lisinopril 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. 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 lisinopril. 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 lisinopril. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on lisinopril [see Adverse Reactions (6.1) , Drug Interactions (7.4) ] . 5.4 Hypotension Lisinopril 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, lisinopril should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of lisinopril and/or diuretic is increased. Avoid use of lisinopril 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, lisinopril 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 Serum potassium should be monitored periodically in patients receiving lisinopril. 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) ]. …

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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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. …

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. …