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HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ZESTRIL safely and effectively. See full prescribing information for ZESTRIL Zestril®^ (lisinopril) tablets, for oral use Initial U.S. Approval: 1988 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 rennin-angiotensin system can cause injury and death to the developing fetus. (5.1) --------------------------- 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 ) ---------------------- 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/1.73m^2 : 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) --------------------- DOSAGE FORMS AND STRENGTHS ------------------- Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg (3) ------------------------------ CONTRAINDICATIONS ----------------------------
- 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) ----------------------- 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) ------------------------------ 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 AstraZeneca Pharmaceuticals LP at 1-800-236-9933 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 ---------------------
- Pregnancy: Discontinue drug if pregnancy is detected (5.1, 8.1)
- Pediatrics: Safety and effectiveness have not been established in patients < 6 years of age or with glomerular filtration rate < 30 mL/min/1.73m^2 (8.4)
- Race: Less antihypertensive effect in blacks than non blacks (8.6) See 17 for PATIENT COUNSELING INFORMATION Revised: 12/
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 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 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 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.
FULL PRESCRIBING INFORMATION
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) ]****.
1 INDICATIONS AND USAGE
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) ].
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 red, round, biconvex, uncoated tablets identified as “ZESTRIL 20” on one side and “132” on the
other side.
30 mg are 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.
4 CONTRAINDICATIONS
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) ]
5 WARNINGS AND PRECAUTIONS
5.1 Fetal Toxicity
Pregnancy Category D
Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy
reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios
can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects
include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue
Zestril 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 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 (eg, 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.
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 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.
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
7 DRUG INTERACTIONS
7.1 Diuretics
Initiation of Zestril in patients on diuretics may result in excessive reduction of blood pressure. The possibility of hypotensive effects with Zestril can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Zestril. If this is not possible, reduce the starting dose of Zestril [see Dosage and Administration (2.2) and Warnings and Precautions (5.4) ].
Zestril 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 Zestril 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-
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.
8.3 Nursing Mothers
Milk of lactating rats contains radioactivity following administration of 14 C lisinopril. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ACE inhibitors, a decision should be made whether to discontinue nursing or discontinue Zestril, taking into account the importance of the drug to the mother.
8.4 Pediatric Use
Antihypertensive effects and safety of Zestril 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.
Safety and effectiveness of Zestril have not been established in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m^2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1) ].
Neonates with a history of in utero exposure to Zestril
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
8.5 Geriatric Use
No dosage adjustment with Zestril is necessary in elderly patients. In a clinical study of Zestril in patients with myocardial infarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In this study, 4.8 % of patients aged 75 years and older discontinued Zestril treatment because of renal dysfunction vs. 1.3% of patients younger than 75 years. No other differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Race
ACE inhibitors, including Zestril, have an effect on blood pressure that is less in black patients than in non blacks.
8.7 Renal Impairment
Dose adjustment of Zestril is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. No dose adjustment of Zestril is required in patients with creatinine clearance > 30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ].
10 OVERDOSAGE
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) ].
11 DESCRIPTION
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 C21H31N 3 O52H 2 O and its structural formula is:
Lisinopril 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.
Zestril is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg and 40 mg tablets for oral administration.
Inactive Ingredients:
2.5 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch.
5, 10, 20 and 30 mg tablets - calcium phosphate, magnesium stearate, mannitol, red ferric oxide, starch.
40 mg tablets - calcium phosphate, magnesium stearate, mannitol, starch, yellow ferric oxide.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Lisinopril inhibits angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of lisinopril in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Zestril alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with Zestril and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L [see Clinical Studies (14.1) ]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Zestril remains to be elucidated.
While the mechanism through which Zestril lowers blood pressure is believed to be primarily suppression of the renin- angiotensin-aldosterone system, Zestril is antihypertensive even in patients with low-renin hypertension. Although Zestril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non Black patients.
Concomitant administration of Zestril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.
12.2 Pharmacodynamics
Hypertension
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
There was no evidence of a tumorigenic effect when lisinopril was administered for 105 weeks to male and female rats at doses up to 90 mg per kg per day (about 56 or 9 times* the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when lisinopril was administered for 92 weeks to (male and female) mice at doses up to 135 mg per kg per day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.
Lisinopril was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril did not produce single strand DNA breaks in an in vitro alkaline elution rat hepatocyte assay. In addition, lisinopril did not produce increases in chromosomal aberrations in an in vitro test in Chinese hamster ovary cells or in an in vivo study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg per kg per day of lisinopril. This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m^2 , respectively.
Studies in rats indicate that lisinopril crosses the blood brain barrier poorly. Multiple doses of lisinopril in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14 C lisinopril. By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
*Calculations assume a human weight of 50 kg and human body surface area of 1.62m^2
14 CLINICAL STUDIES
14.1 Hypertension
Two dose-response studies utilizing a once-daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of Zestril was seen with 5 mg of Zestril in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of Zestril than patients treated with 5 mg of Zestril.
In controlled clinical studies of patients with mild to moderate hypertension, patients were treated with Zestril 20-80 mg daily, hydrochlorothiazide 12.5-50 mg daily or atenolol 50-200 mg daily; and in other studies of patients with moderate to severe hypertension, patients were treated with Zestril 20-80 mg daily or metoprolol 100-200 mg daily. Zestril demonstrated superior reductions of systolic and diastolic compared to hydrochlorothiazide in a population that was 75% Caucasian. Zestril was approximately equivalent to atenolol and metoprolol in reducing diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.
Zestril 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 Zestril 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 Zestril, 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 Zestril has been shown to be well tolerated and effective in reducing blood pressure [see Warnings and Precautions (5.3) ].
Pediatric Patients: In a clinical study involving 115 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 50 kg received either 0.625, 2.5 or 20 mg of Zestril once daily and patients who weighed > 50 kg received either 1.25, 5, or 40 mg of Zestril once daily. At the end of 2 weeks, Zestril 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 Zestril 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, Zestril 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 Failure
In two placebo controlled, 12-week clinical studies compared the addition of Zestril up to 20 mg daily to digitalis and diuretics alone. The combination of Zestril, 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 Zestril, 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 3000 patients) survival study, the ATLAS Trial, comparing 2.5 and 35 mg of lisinopril in patients with systolic heart failure, showed that the higher dose of lisinopril had outcomes at least as favorable as the lower dose.
During baseline-controlled clinical trials, in patients with systolic heart failure receiving digitalis and diuretics, single doses of Zestril resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.
14.3 Acute Myocardial Infarction
The Gruppo Italiano per lo Studio della Sopravvienza nell’Infarto Miocardico (GISSI-3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction (MI) admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with lisinopril, nitrates, their combination, or no therapy on short-term (6 week) mortality and on long-term death and markedly impaired cardiac function. Hemodynamically- stable patients presenting within 24 hours of the onset of symptoms were randomized, in a 2 x 2 factorial design, to six weeks of either 1) Zestril alone (n=4841), 2) nitrates alone (n=4869), 3) Zestril plus nitrates (n=4841), or 4) open control (n=4843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure < 100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine > 2 mg per dL and/or proteinuria > 500 mg per 24 h). Patients randomized to Zestril 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 Zestril. If hypotension occurred, the Zestril dose was reduced or if severe hypotension occurred Zestril 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 < 35% or an akinetic-dyskinetic [A-D] score > 45%. Patients receiving Zestril (n=9646), alone or with nitrates, had an 11% lower risk of death (p = 0.04) compared to patients who did not receive Zestril (n=9672) (6.4% vs. 7.2%, respectively) at six weeks. Although patients randomized to receive Zestril for up to six weeks also fared numerically better on the combined end point at 6 months, the open nature of the
Hypoglycemia: Tell diabetic patients treated with oral antidiabetic agents or insulin starting an ACE inhibitor to monitor for hypoglycaemia closely, especially during the first month of combined use [see Drug Interactions (7.2) ].
Leukopenia/Neutropenia: Tell patients to report promptly any indication of infection (eg, sore throat, fever), which may be a sign of leukopenia/neutropenia.
Zestril is a trademark of the AstraZeneca group of companies.
Distributed by: AstraZeneca Pharmaceuticals LP Wilmington, DE 19850 AstraZeneca 2014
