Lisinopril Tablets have 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 Lisinopril Tablets, 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 Lisinopril Tablets or Lisinopril Tablets plus hydrochlorothiazide in controlled clinical trials, and more frequently with Lisinopril Tablets and/or Lisinopril Tablets plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:
PERCENT OF PATIENTS IN CONTROLLED STUDIES
LISINOPRIL TABLETS/LISINOPRIL TABLETSHydrochlorothiazidePLACEBO(11=1349)(n=629)(n=207)IncidenceIncidenceIncidence(discontinuation)(discontinuation)(discontinuation)Body as a WholeFatigue2.5 (0.3)4.0 (0.5)1.0 (0.0)Asthenia1.3 (0.5)2.1 (0.2)1.0 (0.0)Orthostatic Effects1.2 (0.0)3.5 (0.2)1.0 (0.0)CardiovascularHypotension1.2 (0.5)1.6 (0.5)0.5 (0.5)DigestiveDiarrhea2.7 (0.2)2.7 (0.3)2.4 (0.0)Nausea2.0 (0.4)2.5 (0.2)2.4 (0.0)Vomiting1.1 (0.2)1.4 (0.1)0.5 (0.0)Dyspepsia0.9 (0.0)1.9 (0.0)0.0 (0.0)MuscoloskeletalMuscle Cramps0.5 (0.0)2.9 (0.8)0.5 (0.0)Nervous/PsychiatricHeadache5.7 (0.2)4.5 (0.5)1.9 (0.0)Dizziness5.4 (0.4)9.2 (1.0)1.9 (0.0)Paresthesia0.8 (0.1)2.1 (0.2)0.0 (0.0)Decreased Libido0.4 (0.1)1.3 (0.1)0.0 (0.0)Vertigo0.2 (0.1)1.1 (0.2)0.0 (0.0)RespiratoryCough3.5 (0.7)4.6 (0.8)1.0 (0.0)Upper Respiratory Infection2.1 (0.1)2.7 (0 1)0.0 (0.0)Common Cold1.1 (0.1)1.3 (0.1)0.0 (0.0)Nasal Congestion0.4 (0.1)1.3 (0.1)0.0 (0.0)Influenza0.3 (0.1)1.1 (0.1)0.0 (0.0)SkinRash1.3 (0.4)1.6 (0.2)0.5 (0.5)UrogenitalImpotence1.0 (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 lisinopril.
In patients with heart failure treated with lisinopril 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 lisinopril 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 lisinopril or placebo for up to 12 weeks in controlled clinical trials, and more frequently on lisinopril than placebo.
Controlled TrialsLISINOPRILPlacebo(n=407)(n-155)IncidenceIncidence(discontinuation)(discontinuation)12 weeks12 weeksBody as a WholeChest Pain3.4 (0.2)1.3 (0.0)Abdominal Pain2.2 (0.7)1.9 (0.0)CardiovascularHypotension4.4 (1.7)0.6 (0.6)DigestiveDiarrhea3.7 (0.5)1.9 (0.0)Nervous/PsychiatricDizziness11.8 (1.24.5 (1.3)Headache4.4 (0.2)3.9 (0.0)RespiratoryUpper Respiratory Infection1.5 (0.0)1.3 (0.0)SkinRash1.7 (0.5)0.6 (0.6)Also observed at > 1% with Lisinopril Tablets but more frequent or as frequent on placebo than Lisinopril Tablets 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 Lisinopril Tablets.
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 EventsHigh Dose (N=1568)Low Dose (N=1596)Dizziness18.912.1Hypotension10.86.7Creatinine increased9.97.0Hyperkalemia6.43.5NPNi increased9.26.5Syncope7.05.1i NPN = non-protein nitrogen
Acute Myocardial Infarction:
In the GISSI-3 trial, in patients treated with Lisinopril Tablets for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
Patients treated with Lisinopril Tablets had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking Lisinopril Tablets.
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 Lisinopril Tablets, 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 Lisinopril Tablets 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.
Pancreatitis, hepatitis (hepatocellular or cholestatic jaundice) (seeWARNINGS, Hepatic Failure
), vomiting, gastritis, dyspepsia, heartburn, gastrointestinal cramps, constipation, flatulence, dry mouth.
Rare cases of bone marrow depression, hemolytic anemia, leukopenia/neutropenia and thrombocytopenia.
Diabetes mellitus, inappropriate antidiuretic hormone secretion.
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
Arthritis, arthralgia, neck pain, hip pain, low back pain, joint pain, leg pain, knee pain, shoulder pain, arm pain, lumbago.
Stroke, ataxia, memory impairment, tremor, peripheral neuropathy (e.g., dysesthesia), spasm, paresthesia, confusion, insomnia, somnolence, hypersomnia, irritability, nervousness and mood alterations (including depressive symptoms).
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.
Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances, olfactory disturbance.
Acute renal failure, oliguria, anuria, uremia, progressive azotemia, renal dysfunction, (see
DOSAGE AND ADMINISTRATION
), pyelonephritis, dysuria, urinary tract infection, breast pain.
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 has been reported in patients receiving Lisinopril Tablets 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 Lisinopril Tablets should be discontinued and appropriate therapy instituted immediately. (See
In rare cases, intestinal angioedema has been reported in post marketing experience.
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 Lisinopril Tablets for six weeks after acute myocardial infarction, hypotension (systolic blood pressuremmHg) resulted in discontinuation of therapy in 9.7% of the patients. (See
Fetal/Neonatal Morbidity and Mortality:
WARNINGS, Fetal/Neonatal Morbidity and Mortality
PRECAUTIONS - Cough
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 Lisinopril Tablets alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis. (See
.) 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.
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%).
To report SUSPECTED ADVERSE REACTIONS, contact West-ward Pharmaceutical Corp. at 1-877-233 2001 or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.