Zestril Dailymed

Warning: Fetal Toxicity

• When pregnancy is detected, discontinue ZESTRIL 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)].

WARNING: FETAL TOXICITY

See full prescribing information for complete boxed warning.

• When pregnancy is detected, discontinue Zestril as soon as possible. (5.1)
• Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. (5.1)

1 Indications And Usage

Zestril is an angiotensin converting enzyme (ACE) inhibitor indicated for:

• Treatment of hypertension in adults and pediatric patients 6 years of age and older (1.1)
• Adjunct therapy for heart failure (1.2)
• Treatment of Acute Myocardial Infarction (1.3)

1.1 Hypertension

Zestril is indicated for the treatment of hypertension in adult patients and pediatric patients 6 years of age and older to lower blood pressure. Lowering blood pressure lowers the risk of fatal and non-fatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than 1 drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

Zestril may be administered alone or with other antihypertensive agents [see Clinical Studies (14.1) ].

1.2 Heart Failure

Zestril is indicated to reduce signs and symptoms of systolic heart failure [see Clinical Studies (14.2) ].

1.3 Reduction of Mortality in Acute Myocardial Infarction

Zestril is indicated for the reduction of mortality in treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin and beta-blockers [see Clinical Studies (14.3) ].

• 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)
• Renal Impairment: For patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, halve usual initial dose. For patients with creatinine clearance < 10 mL/min or on hemodialysis, the recommended initial dose is 2.5 mg (2.4)

2.1 Hypertension

Initial 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 Zestril 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 Zestril.

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) ].

Zestril is 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 Failure

The recommended starting dose for Zestril, 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 < 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 Zestril 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

In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, give Zestril 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily.  Dosing should continue for at least six weeks.

Initiate therapy with 2.5 mg in patients with a low systolic blood pressure (≤ 120 mmHg and > 100 mmHg) during the first 3 days after the infarct [see Warnings and Precautions (5.4 ) ].  If hypotension occurs (systolic blood pressure ≤ 100 mmHg) a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed.  If prolonged hypotension occurs (systolic blood pressure < 90 mmHg for more than 1 hour) Zestril should be withdrawn.

2.4 Dose in Patients with Renal Impairment

No dose adjustment of Zestril is required in patients with creatinine clearance > 30 mL/min. In patients with creatinine clearance ≥ 10 mL/min and ≤ 30 mL/min, reduce the initial dose of Zestril to half of the usual recommended dose i.e., hypertension, 5 mg; systolic heart failure, 2.5 mg and acute MI, 2.5 mg. Up titrate as tolerated to a maximum of 40 mg daily. For patients on hemodialysis or creatinine clearance < 10 mL/min, the recommended initial dose is 2.5 mg once daily [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ].

3 Dosage Forms And Strengths

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


Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg (3)

4 Contraindications

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

Zestril is contraindicated in patients with:

• a history of angioedema or hypersensitivity related to previous treatment with an angiotensin converting enzyme inhibitor
• hereditary or idiopathic angioedema

Do not co-administer aliskiren with ZESTRIL in patients with diabetes [see Drug Interactions (7.4) ].

• 
  Angioedema or a history of hereditary or idiopathic angioedema (4)
  
• Hypersensitivity (4)
• Co-administration of aliskiren with Zestril in patients with diabetes (4, 7.4)

5 Warnings And Precautions

• Angioedema: Discontinue Zestril, 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

Zestril can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death.  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 Zestril 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 Zestril, 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. Zestril 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 Zestril.  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 Zestril.  Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Zestril [see Adverse Reactions (6.1) , Drug Interactions (7.4) ].

5.4 Hypotension

Zestril 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, Zestril 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 Zestril and/or diuretic is increased. Avoid use of Zestril 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, Zestril 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 Zestril. 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

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 TWi Pharmaceuticals, Inc. at 1-844-518-2989 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Hypertension

In clinical trials in patients with hypertension treated with Zestril, 5.7% of patients on Zestril discontinued with adverse reactions.

The following adverse reactions (events 2% greater on Zestril than on placebo) were observed with Zestril alone: headache (by 3.8%), dizziness (by 3.5%), cough (by 2.5%).

Heart Failure

In patients with systolic heart failure treated with Zestril for up to four years, 11% discontinued therapy with adverse reactions.  In controlled studies in patients with heart failure, therapy was discontinued in 8.1% of patients treated with Zestril for 12 weeks, compared to 7.7% of patients treated with placebo for 12 weeks.

The following adverse reactions (events 2% greater on Zestril than on placebo) were observed with Zestril: hypotension (by 3.8%), chest pain (by 2.1%).

In the two-dose ATLAS trial [see Clinical Studies (14.2) ] in heart failure patients, withdrawals due to adverse reactions were not different between the low and high groups, either in total number of discontinuation (17% to 18%) or in rare specific reactions (< 1%).  The following adverse reactions, mostly related to ACE inhibition, were reported more commonly in the high dose group:

Table 1 Dose-related Adverse Drug Reactions: ATLAS trial

	High Dose (n=1568)	Low Dose (n=1596)
Dizziness	19%	12%
Hypotension	11%	7%
Creatinine increased	10%	7%
Hyperkalemia	6%	4%
Syncope	7%	5%

Acute Myocardial Infarction

Patients treated with Zestril had a higher incidence of hypotension (by 5.3%) and renal dysfunction (by 1.3%) compared with patients not taking Zestril.

Other clinical adverse reactions occurring in 1% or higher of patients with hypertension or heart failure treated with Zestril in controlled clinical trials and do not appear in other sections of labeling are uled below:

Body as a whole: Fatigue, asthenia, orthostatic effects.

Digestive: Pancreatitis, constipation, flatulence, dry mouth, diarrhea.

Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia.

Endocrine: Diabetes mellitus, inappropriate antidiuretic hormone secretion.

Metabolic: Gout.

Skin: Urticaria, alopecia, photosensitivity, erythema, flushing, diaphoresis, cutaneous pseudolymphoma, toxic epidermal necrolysis, Stevens - Johnson syndrome, and pruritus.

Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance.

Urogenital: Impotence.

Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, leukocytosis, paresthesia and vertigo.  Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.

Clinical Laboratory Test Findings

Serum Potassium: In clinical trials hyperkalemia (serum potassium greater than 5.7 mEq/L) occurred in 2.2% and 4.8% of Zestril-treated patients with hypertension and heart failure, respectively [see Warnings and Precautions (5.5) ].

Creatinine, Blood Urea Nitrogen:  Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2% of patients with hypertension treated with Zestril alone.  Increases were 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 Zestril 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 Zestril 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 Zestril 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) ].

Nervous system and psychiatric disorders

Mood alterations (including depressive symptoms), mental confusion, hallucinations

Skin and subcutaneous tissue disorders

Psoriasis