HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`QBRELIS safely and effectively. See full prescribing information for
`QBRELIS.
`QBRELIS (lisinopril) oral solution
`Initial US Approval: 1988
`WARNING: FETAL TOXICITY
`See full prescribing information for complete boxed warning.
`When pregnancy is detected, discontinue QBRELIS as soon as
`possible. (5.1)
`Drugs that act directly on the rennin-angiotensin system can cause
`injury and death to the developing fetus. (5.1)
`--------------------------- INDICATIONS AND USAGE --------------------------
`QBRELIS 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)
`
`---------------------- 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/1.73m2:
`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)
`
`
`
`
`
`
`
`clearance < 10 mL/min or on hemodialysis, the recommended initial
`dose is 2.5 mg. (2.4)
`--------------------- DOSAGE FORMS AND STRENGTHS --------------------
`Oral solution: 1 mg/mL (3)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`WARNING: FETAL TOXICITY
`1 INDICATIONS AND USAGE
`1.1 Hypertension
`1.2 Heart Failure
`1.3 Reduction of Mortality in Acute Myocardial Infarction
`2 DOSAGE AND ADMINISTRATION
`2.1 Hypertension
`2.2 Heart Failure
`2.3 Reduction of Mortality in Acute Myocardial Infarction
`2.4 Dose in Patients with Renal Impairment
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1 Fetal Toxicity
`5.2 Angioedema and Anaphylactoid Reactions
`5.3
`Impaired Renal Function
`5.4 Hypotension
`5.5 Hyperkalemia
`5.6 Hepatic Failure
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Post-marketing Experience
`7 DRUG INTERACTIONS
`7.1 Diuretics
`7.2 Antidiabetics
`
`
`
`
`
`
`
`------------------------------ CONTRAINDICATIONS -----------------------------
`
`Angioedema or a history of hereditary or idiopathic angioedema (4)
`
`Hypersensitivity (4)
`
`Co-administration of aliskiren with QBRELIS in patients with diabetes
`(4, 7.4)
`----------------------- WARNINGS AND PRECAUTIONS ----------------------
`
`Angioedema: Discontinue QBRELIS; 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)
`------------------------------ 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
`Silvergate Pharmaceuticals, Inc., at 1-855-379-0383 or FDA at 1-800-
`FDA-1088 or www.fda.gov/medwatch.
`------------------------------ 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)
`
`----------------------- USE IN SPECIFIC POPULATIONS ----------------------
`
`Lactation: Advise not to breastfeed (8.2)
`
`Race: Less antihypertensive effect in Blacks than non-Blacks (8.6)
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`Revised: 07/2016
`
`7.3 Non-Steroidal Anti-Inflammatory Agents Including Selective
`Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)
`7.4 Dual Blockade of the Renin-Angiotensin System (RAS)
`7.5 Lithium
`7.6 Gold
`7.7 mTOR Inhibitors
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.2 Lactation
`8.4 Pediatric Use
`8.5 Geriatric Use
`8.6 Race
`8.7 Renal Impairment
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Hypertension
`14.2 Heart Failure
`14.3 Acute Myocardial Infarction
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not listed.
`
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`FULL PRESCRIBING INFORMATION
`
`WARNING: FETAL TOXICITY
`When pregnancy is detected, discontinue QBRELIS 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)].
`
`1 INDICATIONS AND USAGE
`
`1.1 Hypertension
`
`QBRELIS 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 nonfatal 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
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`(e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide
`selection of therapy.
`
`QBRELIS may be administered alone or with other antihypertensive agents [see Clinical Studies
`(14.1)].
`
`1.2 Heart Failure
`
`QBRELIS 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
`
`QBRELIS 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)].
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Hypertension
`
`Adults
`
`Initial Therapy in adults: The recommended initial dose is 10 mg taken orally once a day. Adjust
`dosage as needed according to blood pressure response. The usual dosage range is 20 to 40 mg
`per day administered in a single daily dose. Doses up to 80 mg per day have been used but do
`not appear to give greater effect.
`
`Use with diuretics in adults
`
`If blood pressure is not controlled with QBRELIS 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 QBRELIS.
`
`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 (up to 5 mg total) taken orally once daily. 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)].
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`QBRELIS is not recommended in pediatric patients less than 6 years of age 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 Failure
`
`The recommended starting dose for QBRELIS, when used with diuretics and (usually) digitalis
`as adjunctive therapy for systolic heart failure, is 5 mg taken orally once daily. The
`recommended starting dose in these patients with hyponatremia (serum sodium < 130 mEq/L) is
`2.5 mg once daily. Increase as tolerated to a maximum of 40 mg once daily.
`
`Diuretic dose may need to be adjusted to help minimize hypovolemia, which may contribute to
`hypotension [see Warnings and Precautions (5.4), and Drug Interactions (7.1)]. The appearance
`of hypotension after the initial dose of QBRELIS does not preclude subsequent careful dose
`titration with the drug, following effective management of the hypotension.
`
`2.3 Reduction of Mortality in Acute Myocardial Infarction
`
`Initiation
`
`In hemodynamically stable patients within 24 hours of the onset of symptoms of acute
`myocardial infarction, give QBRELIS 5 mg orally, followed by 5 mg after 24 hours, and then 10
`mg once daily. Dosing should continue for at least six weeks. In patients with a low systolic
`b
`100 mmHg) during the first 3 days after the infarct initiate
`therapy with 2.5 mg once daily [see Warnings and Precautions (5.4)] and titrate up based on
`tolerability.
`
`Maintenance
`
`The usual maintenance dose is 10 mg once daily.
`mmHg) occurs during maintenance treatment, give 5 mg once daily with temporary reductions to
`2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for
`more than 1 hour) QBRELIS should be withdrawn.
`
`2.4 Dose in Patients with Renal Impairment
`
`No dose adjustment of QBRELIS is required in patients with creatinine clearance > 30 mL/min.
`
`QBRELIS to half of the usual recommended dose, i.e., hypertension, 5 mg once daily; systolic
`heart failure, 2.5 mg once daily and acute myocardial infarction, 2.5 mg once daily. 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
`
`QBRELIS oral solution is available in a 150 mL bottle containing 1 mg/mL of lisinopril solution.
`QBRELIS oral solution is a clear to slightly opalescent liquid.
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`4 CONTRAINDICATIONS
`
`QBRELIS 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 QBRELIS in patients with diabetes [see Drug Interactions
`(7.4)].
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1
`
`Fetal Toxicity
`
`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 QBRELIS 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 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. QBRELIS 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 coadministration of an ACE inhibitor and mTOR (mammalian target of
`rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk
`for angioedema.
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`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 QBRELIS. 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 QBRELIS. Consider withholding or discontinuing
`therapy in patients who develop a clinically significant decrease in renal function on QBRELIS
`[see Adverse Reactions (6.1), Drug Interactions (7.4)].
`
`5.4 Hypotension
`
`QBRELIS 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, QBRELIS 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
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`QBRELIS and/or diuretic is increased. Avoid use of QBRELIS 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,
`QBRELIS 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 QBRELIS. 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.
`
`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, 5.7% of patients on
`lisinopril discontinued with adverse reactions.
`
`The following adverse reactions (events 2% greater on lisinopril than on placebo) were observed
`with lisinopril alone: headache (by 3.8%), dizziness (by 3.5%), and cough (by 2.5%).
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`Heart Failure
`
`In patients with systolic heart failure treated with lisinopril 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 for 12 weeks, compared to
`7.7% of patients treated with placebo for 12 weeks.
`
`The following adverse reactions (events 2% greater on lisinopril than on placebo) were observed
`with lisinopril: hypotension (by 3.8%), and 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 dose 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.
`
`Dizziness
`Hypotension
`Creatinine increased
`Hyperkalemia
`Syncope
`
`Dose-related Adverse Drug Reactions: ATLAS trial
`High Dose
`Low Dose
`(n=1568)
`(n=1596)
`19%
`12%
`11%
`7%
`10%
`7%
`6%
`4%
`7%
`5%
`
`Acute Myocardial Infarction
`
`Patients treated with lisinopril had a higher incidence of hypotension (by 5.3%) and renal
`dysfunction (by 1.3%) compared with patients not taking lisinopril.
`
`Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart
`failure treated with lisinopril 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.
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`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-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 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 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 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 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)].
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`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 QBRELIS in patients on diuretics may result in excessive reduction of blood
`pressure. The possibility of hypotensive effects with QBRELIS can be minimized by either
`decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of
`treatment with QBRELIS. If this is not possible, reduce the starting dose of QBRELIS [see
`Dosage and Administration (2.2) and Warnings and Precautions (5.4)].
`
`QBRELIS 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 QBRELIS 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, co-administration 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.
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`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 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. Closely monitor blood pressure, renal
`function and electrolytes in patients on QBRELIS and other agents that affect the RAS.
`
`Do not co-administer aliskiren with QBRELIS in patients with diabetes. Avoid use of aliskiren
`with QBRELIS 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.
`
`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)].
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1
`
`Pregnancy
`
`Risk Summary
`
`QBRELIS 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 QBRELIS 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
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`major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
`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 QBRELIS for hypotension,
`oliguria, and hyperkalemia. If oliguria or hypotension occur in neonates with a history of in utero
`exposure to QBRELIS, 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 QBRELIS.
`
`8.4
`
`Pediatric Use
`
`Antihypertensive effects and safety of lisinopril 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.
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`Safety and effectiveness of lisinopril have not been established in pediatric patients under the age
`6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m2 [see Dosage and
`Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].
`
`N