Lisinopril 40 MG Oral Tablet

Details

Generic Name: LISINOPRIL

Brand Name: LISINOPRIL

Substance Name(s):
LISINOPRIL

DRUG INTERACTIONS

SECTION 7.1 DiureticsInitiation 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. If this is not possible, reduce the starting dose of lisinopril [see Dosage and Administration (2.2)and Warnings and Precautions (5.4)]. Lisinopril 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 AntidiabeticsConcomitant administration of lisinopril 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 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 and other agents that affect the RAS. Do not co-administer aliskiren with lisinopril in patients with diabetes. Avoid use of aliskiren with lisinopril in patients with renal impairment (GFR <60 mL/min). 7.5 LithiumLithium 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 GoldNitritoid 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.

OVERDOSAGE

SECTION 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)].

DESCRIPTION

SECTION 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 C21H31N3O5 • 2H2O and its structural formula is: Chemical Structure 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, for oral administration, is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets. Inactive Ingredients: 2.5 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch. 5 mg, 10 mg and 30 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, red iron oxide, corn starch. 20 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, red iron oxide, corn starch, yellow iron oxide. 40 mg tablets – dibasic calcium phosphate, magnesium stearate, mannitol, corn starch, yellow iron oxide.

CLINICAL STUDIES

SECTION 14.1 HypertensionTwo 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 lisinopril was seen with 5 mg of lisinopril in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10 mg, 20 mg or 80 mg of lisinopril than patients treated with 5 mg of lisinopril. In controlled clinical studies of patients with mild to moderate hypertension, patients were treated with lisinopril 20 mg to 80 mg daily, hydrochlorothiazide 12.5 mg to 50 mg daily or atenolol 50 mg to 200 mg daily; and in other studies of patients with moderate to severe hypertension, patients were treated with lisinopril 20 mg to 80 mg daily or metoprolol 100 mg to 200 mg daily. Lisinopril demonstrated superior reductions of systolic and diastolic compared to hydrochlorothiazide in a population that was 75% Caucasian. Lisinopril was approximately equivalent to atenolol and metoprolol in reducing diastolic blood pressure, and had somewhat greater effects on systolic blood pressure. Lisinopril had similar blood pressure reductions and adverse effects in younger and older (> 65 years) patients. It was less effective in reducing blood pressure in Blacks than in Caucasians. In hemodynamic studies of lisinopril 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 lisinopril, 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 lisinopril 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 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. At the end of 2 weeks, lisinopril lowered trough blood pressure in a dose-dependent manner with antihypertensive efficacy demonstrated at doses > 1.25 mg (0.02 mg per kg). This effect was confirmed in a randomized withdrawal phase, where the diastolic pressure rose by about 9 mmHg more in patients randomized to placebo than compared to patients who remained 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 (2.1)]. 14.2 Heart FailureIn two placebo controlled, 12-week clinical studies compared the addition of lisinopril up to 20 mg daily to digitalis and diuretics alone. The combination of lisinopril, 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 lisinopril, digitalis and diuretics reduced orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV; and improved exercise tolerance. A large (over 3,000 patients) survival study, the ATLAS Trial, comparing 2.5 mg 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 with systolic heart failure receiving digitalis and diuretics, single doses of lisinopril 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 InfarctionThe 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 x 2 factorial design, to six weeks of either 1) lisinopril alone (n=4,841), 2) nitrates alone (n=4,869), 3) lisinopril plus nitrates (n=4,841), or 4) open control (n=4,843). 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 2 mg per dL and/or proteinuria > 500 mg per 24 h). Patients randomized to lisinopril 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 lisinopril. If hypotension occurred, the lisinopril dose was reduced or if severe hypotension occurred lisinopril was stopped [see Dosage and Administration (2.3)]. The primary outcomes of the trial were the overall mortality at 6 weeks and a combined end point 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 45%. Patients receiving lisinopril (n=9,646), alone or with nitrates, had an 11% lower risk of death (p = 0.04) compared to patients who did not receive lisinopril (n=9,672) (6.4% vs. 7.2%, respectively) at six weeks. Although patients randomized to receive lisinopril for up to six weeks also fared numerically better on the combined end point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of lisinopril between 6 weeks and 6 months in the group randomized to 6 weeks of lisinopril, preclude any conclusion about this end point. Patients with acute myocardial infarction, treated with lisinopril, 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 six weeks (increasing creatinine concentration to over 3 mg per dL or a doubling or more of the baseline serum creatinine concentration) [see Adverse Reactions (6.1)].

DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION 2.5 mg are white, oval, biconvex, uncoated tablets debossed “E25” on one side and plain on the other side. 5 mg are pink, oval, biconvex, uncoated tablets debossed “E54” on one side and bisected on the other side. 10 mg are pink, round, biconvex, uncoated tablets debossed “E101” on one side and plain on the other side. 20 mg are peach, round, biconvex, uncoated tablets debossed “E102” on one side and plain on the other side. 30 mg are red, round, biconvex, uncoated tablets debossed “E103” on one side and plain on the other side. 40 mg are yellow, round, biconvex, uncoated tablets debossed “E104” on one side and plain on the other side.

INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION 1.1 HypertensionLisinopril tablets USP 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 USP may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1)]. 1.2 Heart FailureLisinopril tablets USP are indicated to reduce signs and symptoms of systolic heart failure [see Clinical Studies (14.2)]. 1.3 Reduction of Mortality in Acute Myocardial InfarctionLisinopril tablets USP 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)].

BOXED WARNING

SECTION WARNING: FETAL TOXICITYSee full prescribing information for complete boxed warning.•When pregnancy is detected, discontinue lisinopril 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)].Close

WARNING AND CAUTIONS

WARNINGS AND PRECAUTIONS SECTION 5.1 Fetal ToxicityPregnancy 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 lisinopril as soon as possible [see Use in Specific Populations (8.1)]. 5.2 Angioedema and Anaphylactoid ReactionsAngioedema 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 FunctionMonitor 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 HypotensionLisinopril 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 HyperkalemiaSerum 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)]. 5.6 Hepatic FailureACE 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.

DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION 2.1 HypertensionInitial Therapy in adults: The recommended initial dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response. The usual dosage range is 20 mg to 40 mg per day administered in a single daily dose. Doses up to 80 mg have been used but do not appear to give greater effect. Use with diuretics in adults If blood pressure is not controlled with lisinopril tablets alone, a low dose of a diuretic may be added (e.g., hydrochlorothiazide, 12.5 mg). After the addition of a diuretic, it may be possible to reduce the dose of lisinopril tablets. The recommended starting dose in adult patients with hypertension taking diuretics is 5 mg once per day. Pediatric Patients 6 years of age and older with hypertension For pediatric patients with glomerular filtration rate > 30 mL/min/1.73m2, 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)]. Lisinopril tablets are not recommended in pediatric patients < 6 years or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73m2 [see Use in Specific Populations (8.4)and Clinical Studies (14.1)]. 2.2 Heart FailureThe recommended starting dose for lisinopril tablets, when used with diuretics and (usually) digitalis as adjunctive therapy for systolic heart failure, is 5 mg once daily. The recommended starting dose in these patients with hyponatremia (serum sodium 100 mm Hg) 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 lisinopril tablets 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)].