ADVERSE REACTIONS
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.
Hypertension
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
|
ZESTRIL
(n=1349)
Incidence
(discontinuation)
|
ZESTRIL/
Hydrochlorothiazide
(n=629)
Incidence
(discontinuation)
|
PLACEBO
(n=207)
Incidence
(discontinuation)
|
Body as a Whole
|
|
|
|
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)
|
Cardiovascular
|
|
|
|
Hypotension
|
1.2 (0.5)
|
1.6 (0.5)
|
0.5 (0.5)
|
Digestive
|
|
|
|
Diarrhea
|
2.7 (0.2)
|
2.7 (0.3)
|
2.4 (0.0)
|
Nausea
|
2.0 (0.4)
|
2.5 (0.2)
|
2.4 (0.0)
|
Vomiting
|
1.1 (0.2)
|
1.4 (0.1)
|
0.5 (0.0)
|
Dyspepsia
|
0.9 (0.0)
|
1.9 (0.0)
|
0.0 (0.0)
|
Musculoskeletal
|
|
|
|
Muscle Cramps
|
0.5 (0.0)
|
2.9 (0.8)
|
0.5 (0.0)
|
Nervous/Psychiatric
|
|
|
|
Headache
|
5.7 (0.2)
|
4.5 (0.5)
|
1.9 (0.0)
|
Dizziness
|
5.4 (0.4)
|
9.2 (1.0)
|
1.9 (0.0)
|
Paresthesia
|
0.8 (0.1)
|
2.1 (0.2)
|
0.0 (0.0)
|
Decreased Libido
|
0.4 (0.1)
|
1.3 (0.1)
|
0.0 (0.0)
|
Vertigo
|
0.2 (0.1)
|
1.1 (0.2)
|
0.0 (0.0)
|
Respiratory
|
|
|
|
Cough
|
3.5 (0.7)
|
4.6 (0.8)
|
1.0 (0.0)
|
Upper Respiratory
Infection
|
2.1 (0.1)
|
2.7 (0.1)
|
0.0 (0.0)
|
Common Cold
|
1.1 (0.1)
|
1.3 (0.1)
|
0.0 (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)
|
Skin
|
|
|
|
Rash
|
1.3 (0.4)
|
1.6 (0.2)
|
0.5 (0.5)
|
Urogenital
|
|
|
|
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.
Heart Failure
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.
Controlled Trials
|
ZESTRIL
(n=407)
Incidence
(discontinuation)
12 weeks
|
Placebo
(n=155)
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)
|
Cardiovascular
|
|
|
Hypotension
|
4.4 (1.7)
|
0.6 (0.6)
|
Digestive
|
|
|
Diarrhea
|
3.7 (0.5)
|
1.9 (0.0)
|
Nervous/Psychiatric
|
|
|
Dizziness
|
11.8 (1.2)
|
4.5 (1.3)
|
Headache
|
4.4 (0.2)
|
3.9 (0.0)
|
Respiratory
|
|
|
Upper Respiratory
Infection
|
1.5 (0.0)
|
1.3 (0.0)
|
Skin
|
|
|
Rash
|
1.7 (0.5)
|
0.6 (0.6)
|
Also observed at > 1% with ZESTRIL but more frequent or as frequent on placebo than ZESTRIL in controlled trials were asthenia, angina pectoris, nausea, dyspnea, cough, and pruritus.
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
(N=1568)
|
Low Dose
(N=1596)
|
Dizziness
|
18.9
|
12.1
|
Hypotension
|
10.8
|
6.7
|
Creatinine increased
|
9.9
|
7.0
|
Hyperkalemia
|
6.4
|
3.5
|
NPN increased
|
9.2
|
6.5
|
Syncope
|
7.0
|
5.1
|
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.
Hematologic: Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia.
Endocrine: Diabetes mellitus, inappropriate antidiuretic hormone secretion.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain.
Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported in post-marketing experience (See PRECAUTIONS, Drug Interactions).
Musculoskeletal: Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago.
Nervous System/Psychiatric: Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, nervousness and mood alterations (including depressive symptoms).
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. Other severe skin reactions have been reported rarely, including toxic epidermal necrolysis and Stevens-Johnson Syndrome; causal relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance.
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).
Fetal/Neonatal Morbidity and Mortality: See WARNINGS, Fetal/Neonatal Morbidity and Mortality.
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
Serum Electrolytes: Hyperkalemia (See PRECAUTIONS), hyponatremia.
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.
Liver Function Tests: Rarely, elevations of liver enzymes and/or serum bilirubin have occurred (See WARNINGS, Hepatic Failure).
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.
|
REPORTS OF SUSPECTED ZESTRIL SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Zestril. The information is not vetted and should not be considered as verified clinical evidence.
Possible Zestril side effects / adverse reactions in 89 year old female
Reported by a consumer/non-health professional from United States on 2011-10-05
Patient: 89 year old female
Reactions: Pain, Abasia, Visual Acuity Reduced, Device Dislocation, Eye Infection, Cardiac Disorder, Oedema Peripheral, Eyelid Disorder, Hearing Impaired, Pleural Effusion, Blindness Unilateral, Intervertebral Disc Protrusion, Breast Cancer, Cataract, Pain in Extremity, Bladder Dysfunction, Functional Gastrointestinal Disorder, Angina Pectoris, Accident AT Home, Hypoaesthesia, Heart Rate Decreased, Cardiac Failure, Diarrhoea, Lymphoma, Spinal Column Stenosis
Adverse event resulted in: hospitalization, disablity
Suspect drug(s):
Tamoxifen Citrate
Administration route: Oral
Zestril
Administration route: Oral
Toprol-XL
Administration route: Oral
Indication: Atrial Fibrillation
Toprol-XL
Administration route: Oral
Toprol-XL
Administration route: Oral
Indication: Cardiac Failure Congestive
Toprol-XL
Administration route: Oral
Other drugs received by patient: Lasix; Coumadin; Thyroxin; Aspirin
Possible Zestril side effects / adverse reactions in 58 year old female
Reported by a consumer/non-health professional from United States on 2011-10-05
Patient: 58 year old female weighing 51.2 kg (112.6 pounds)
Reactions: Pain in Extremity, Headache, Cardiac Disorder, Malaise, Memory Impairment, Gait Disturbance, Feeling Abnormal, Hypersomnia
Suspect drug(s):
Procardia
Indication: Hypertension
Zestril
Administration route: Oral
Indication: Hypertension
Other drugs received by patient: Allergy Injection
Possible Zestril side effects / adverse reactions in 53 year old male
Reported by a consumer/non-health professional from United States on 2011-10-05
Patient: 53 year old male weighing 91.2 kg (200.6 pounds)
Reactions: Drug Dose Omission, Weight Decreased, Wrong Technique in Drug Usage Process, Sleep Talking, Somnolence, Fall, Loss of Consciousness, Suicidal Ideation, Abnormal Dreams, OFF Label USE, Laboratory Test Abnormal, Palpitations, Dizziness, Depression, Mood Swings, Myocardial Infarction, RIB Fracture, Blood Pressure Increased, Inappropriate Schedule of Drug Administration, Swelling Face, Clavicle Fracture, Amnesia, Aggression, Anxiety, Disease Recurrence, Diarrhoea, Withdrawal Syndrome, Asthenia
Adverse event resulted in: hospitalization
Suspect drug(s):
Seroquel
Administration route: Oral
Start date: 2011-04-01
Seroquel
Administration route: Oral
Start date: 2011-04-01
Crestor
Administration route: Oral
Start date: 2008-01-01
End date: 2011-03-01
Seroquel
Administration route: Oral
Start date: 2011-04-01
Zestril
Administration route: Oral
Indication: Hypertension
End date: 2009-01-01
Seroquel
Administration route: Oral
Indication: Sleep Disorder
Start date: 2011-02-01
End date: 2011-03-30
Seroquel
Administration route: Oral
Indication: Bipolar Disorder
Start date: 2011-02-01
End date: 2011-03-30
Seroquel
Administration route: Oral
Indication: Anxiety
Start date: 2011-02-01
End date: 2011-03-30
Seroquel
Administration route: Oral
Indication: Psychotic Disorder
Start date: 2011-02-01
End date: 2011-03-30
Seroquel
Administration route: Oral
Start date: 2011-04-01
Atacand
Administration route: Oral
Indication: Hypercholesterolaemia
Start date: 2009-01-01
End date: 2011-03-01
Other drugs received by patient: Metoprolol Tartrate; Clonipine; FOL-Niacin; Metformin HCL; Accof; Aspirin; Glucotrol; Metoprolol Tartrate; Celexa
|