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ZESTRIL has been found to be generally well tolerated in controlled clinical trials involving 1969 patients with hypertension or heart failure. For the most part, adverse experiences were mild and transient.
In clinical trials in patients with hypertension treated with ZESTRIL, discontinuation of therapy due to clinical adverse experiences occurred in 5.7% of patients. The overall frequency of adverse experiences could not be related to total daily dosage within the recommended therapeutic dosage range.
For adverse experiences occurring in greater than 1% of patients with hypertension treated with ZESTRIL or ZESTRIL plus hydrochlorothiazide in controlled clinical trials, and more frequently with ZESTRIL and/or ZESTRIL plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:
PERCENT OF PATIENTS IN CONTROLLED STUDIES
|Body as amm|
|Fatigue||2.5 (0.3)||4.0 (0.5)||1.0 (0.0)|
|Asthenia||1.3 (0.5)||2.1 (0.2)||1.0 (0.0)|
|Orthostatic Effects||1.2 (0.0)||3.5 (0.2)||1.0 (0.0)|
|Nasal Congestion||0.4 (0.1)||1.3 (0.1)||0.0 (0.0)|
|Influenza||0.3 (0.1)||1.1 (0.1)||0.0 (0.0)|
|Rash||1.3 (0.4)||1.6 (0.2)||0.5 (0.5)|
|Impotence||1.0 (0.4)||1.6 (0.5)||0.0 (0.0)|
Chest pain and back pain were also seen, but were more common on placebo than ZESTRIL.
In patients with heart failure treated with ZESTRIL for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11.0% of patients. 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 table lists those adverse experiences which occurred in greater than 1% of patients with heart failure treated with ZESTRIL or placebo for up to 12 weeks in controlled clinical trials, and more frequently on ZESTRIL than placebo.
Incidence (discontinuation) 12 weeks
Incidence (discontinuation) 12 weeks
|Body as a Whole|
|Chest Pain||3.4 (0.2)||1.3 (0.0)|
|Abdominal Pain||2.2 (0.7)||1.9 (0.0)|
|Hypotension||4.4 (1.7)||0.6 (0.6)|
|Diarrhea||3.7 (0.5)||1.9 (0.0)|
|Dizziness||11.8 (1.2)||4.5 (1.3)|
|Headache||4.4 (0.2)||3.9 (0.0)|
|Upper Respiratory Infection||1.5 (0.0)||1.3 (0.0)|
|Rash||1.7 (0.5)||0.6 (0.6)|
Worsening of heart failure, anorexia, increased salivation, muscle cramps, back pain, myalgia, depression, chest sound abnormalities, and pulmonary edema were also seen in controlled clinical trials, but were more common on placebo than ZESTRIL.
In the two-dose ATLAS trial in heart failure patients, withdrawals due to adverse events were not different between the low and high groups, either in total number of discontinuation (17-18%) or in rare specific events ( < 1%). The following adverse events, mostly related to ACE inhibition, were reported more commonly in the high dose group:
|% of patients Events||High Dose
|1 NPN = non-protein nitrogen|
Acute Myocardial Infarction
In the GISSI-3 trial, in patients treated with ZESTRIL for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
Patients treated with ZESTRIL had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking ZESTRIL.
In the GISSI-3 trial, hypotension (9.7%), renal dysfunction (2.0%), cough (0.5%), post infarction angina (0.3%), skin rash and generalized edema (0.01%), and angioedema (0.01%) resulted in withdrawal of treatment. In elderly patients treated with ZESTRIL, discontinuation due to renal dysfunction was 4.2%.
Other clinical adverse experiences occurring in 0.3% to 1.0% of patients with hypertension or heart failure treated with ZESTRIL in controlled clinical trials and rarer, serious, possibly drug-related events reported in uncontrolled studies or marketing experience are listed below, and within each category are in order of decreasing severity:
Body as a Whole: Anaphylactoid reactions (See WARNINGS, Anaphylactoid and Possibly Related Reactions), syncope, orthostatic effects, chest discomfort, pain, pelvic pain, flank pain, edema, facial edema, virus infection, fever, chills, malaise.
Cardiovascular: Cardiac arrest; myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high risk patients (See WARNINGS, Hypotension); pulmonary embolism and infarction, arrhythmias (including ventricular tachycardia, atrial tachycardia, atrial fibrillation, bradycardia and premature ventricular contractions), palpitations, transient ischemic attacks, paroxysmal nocturnal dyspnea, orthostatic hypotension, decreased blood pressure, peripheral edema, vasculitis.
Digestive: Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (See WARNINGS, Hepatic Failure), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, nervousness ,mood alterations (including depressive symptoms) and hallucinations.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, bronchospasm, asthma, pleural effusion, pneumonia, eosinophilic pneumonitis, bronchitis, wheezing, orthopnea, painful respiration, epistaxis, laryngitis, sinusitis, pharyngeal pain, pharyngitis, rhinitis, rhinorrhea.
Skin: Urticaria, alopecia, herpes zoster, photosensitivity, skin lesions, skin infections, pemphigus, erythema, flushing, diaphoresis, cutaneous pseudolymphoma, psoriasis. Other severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson Syndrome; causal relationship has not been established.
Urogenital System: Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction (See PRECAUTIONS and DOSAGE AND ADMINISTRATION), pyelonephritis, dysuria, urinary tract infection, breast pain.
Miscellaneous: A symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatological manifestations may occur alone or in combination with these symptoms.
Angioedema: Angioedema has been reported in patients receiving ZESTRIL with an incidence higher in Black than in non-Black patients. Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with ZESTRIL should be discontinued and appropriate therapy instituted immediately (See WARNINGS).
In rare cases, intestinal angioedema has been reported in post marketing experience.
Hypotension: In hypertensive patients, hypotension occurred in 1.2% and syncope occurred in 0.1% of patients with an incidence higher in Black than in non-Black patients. Hypotension or syncope was a cause of discontinuation of therapy in 0.5% of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3% and syncope occurred in 1.8% of patients. These adverse experiences were possibly dose-related (see above data from ATLAS Trial) and caused discontinuation of therapy in 1.8% of these patients in the symptomatic trials. In patients treated with ZESTRIL for six weeks after acute myocardial infarction, hypotension (systolic blood pressure ≤ 100 mmHg) resulted in discontinuation of therapy in 9.7% of the patients (See WARNINGS).
Cough: See PRECAUTIONS, Cough
Pediatric Patients: No relevant differences between the adverse experience profile for pediatric patients and that previously reported for adult patients were identified.
Clinical Laboratory Test Findings
Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen and serum creatinine, reversible upon discontinuation of therapy, were observed in about 2.0% of patients with essential hypertension treated with ZESTRIL alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (See PRECAUTIONS). Reversible minor increases in blood urea nitrogen and serum creatinine were observed in approximately 11.6% of patients with heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
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. Hemolytic anemia has been reported; a causal relationship to lisinopril cannot be excluded.
In hypertensive patients, 2.0% discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.6%), serum creatinine (0.5%) and serum potassium (0.4%).
In the heart failure trials, 3.4% of patients discontinued therapy due to laboratory adverse experiences; 1.8% due to elevations in blood urea nitrogen and/or creatinine and 0.6% due to elevations in serum potassium.
In the myocardial infarction trial, 2.0% of patients receiving ZESTRIL discontinued therapy due to renal dysfunction (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration); less than 1.0% of patients discontinued therapy due to other laboratory adverse experiences: 0.1% with hyperkalemia and less than 0.1% with hepatic enzyme alterations.
Read the Zestril (lisinopril) Side Effects Center for a complete guide to possible side effects
Hypotension - Patients on Diuretic Therapy
Patients on diuretics and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with ZESTRIL. The possibility of hypotensive effects with ZESTRIL can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with ZESTRIL. If it is necessary to continue the diuretic, initiate therapy with ZESTRIL at a dose of 5 mg daily, and provide close medical supervision after the initial dose until blood pressure has stabilized (See WARNINGS, and DOSAGE AND ADMINISTRATION). When a diuretic is added to the therapy of a patient receiving ZESTRIL, an additional antihypertensive effect is usually observed. Studies with ACE inhibitors in combination with diuretics indicate that the dose of the ACE inhibitor can be reduced when it is given with a diuretic (See DOSAGE AND ADMINISTRATION).
Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycemic agents) may cause an increased bloodglucose-lowering effect with risk of hypoglycemia. This phenomenon appeared to be more likely to occur during the first weeks of combined treatment and in patients with renal impairment. In diabetic patients treated with oral antidiabetic agents or insulin, glycemic control should be closely monitored for hypoglycemia, especially during the first month of treatment with an ACE inhibitor.
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.
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. Closely monitor blood pressure, renal function and electrolytes in patients on ZESTRIL and other agents that affect the RAS.
Do not co-administer aliskiren with ZESTRIL in patients with diabetes. Avoid use of aliskiren with ZESTRIL in patients with renal impairment (GFR < 60 ml/min).
ZESTRIL has been used concomitantly with nitrates and/or digoxin without evidence of clinically significant adverse interactions. This included post myocardial infarction patients who were receiving intravenous or transdermal nitroglycerin. No clinically important pharmacokinetic interactions occurred when ZESTRIL was used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of ZESTRIL.
Agents Increasing Serum Potassium
ZESTRIL attenuates potassium loss caused by thiazide-type diuretics. Use of ZESTRIL with potassium-sparing diuretics (e.g., spironolactone, eplerenone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium. Potassium-sparing agents should generally not be used in patients with heart failure who are receiving ZESTRIL.
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. It is recommended that serum lithium levels be monitored frequently if ZESTRIL is administered concomitantly with lithium.
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 ZESTRIL.
Read the Zestril Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 12/12/2013
This monograph has been modified to include the generic and brand name in many instances.
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