ADVERSE REACTIONS
PRINIVIL 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 PRINIVIL, discontinuation of therapy due to clinical adverse experiences occurred in 5.7 percent 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 one percent of patients with hypertension treated with PRINIVIL or PRINIVIL plus hydrochlorothiazide in controlled clinical trials and more frequently with PRINIVIL and/or PRINIVIL plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:
| | Percent of Patients
in Controlled Studies |
| |
PRINIVIL
(n = 1349)
Incidence
(discontinuation) | PRINIVIL/
Hydrochlorothiazide
(n = 629)
Incidence
(discontinuation) |
Placebo
(n = 207)
Incidence
(discontinuation) |
Body As A Whole
Fatigue
Asthenia
Orthostatic Effects |
2.5 (0.3)
1.3 (0.5)
1.2 (0.0) |
4.0 (0.5)
2.1 (0.2)
3.5 (0.2) |
1.0 (0.0)
1.0 (0.0)
1.0 (0.0) |
Cardiovascular
Hypotension |
1.2 (0.5) |
1.6 (0.5) |
0.5 (0.5) |
Digestive
Diarrhea
Nausea
Vomiting
Dyspepsia |
2.7 (0.2)
2.0 (0.4)
1.1 (0.2)
0.9 (0.0) |
2.7 (0.3)
2.5 (0.2)
1.4 (0.1)
1.9 (0.0) |
2.4 (0.0)
2.4 (0.0)
0.5 (0.0)
0.0 (0.0) |
Musculoskeletal
Muscle Cramps |
0.5 (0.0) |
2.9 (0.8) |
0.5 (0.0) |
Nervous/Psychiatric
Headache
Dizziness
Paresthesia
Decreased Libido
Vertigo |
5.7 (0.2)
5.4 (0.4)
0.8 (0.1)
0.4 (0.1)
0.2 (0.1) |
4.5 (0.5)
9.2 (1.0)
2.1 (0.2)
1.3 (0.1)
1.1 (0.2) |
1.9 (0.0)
1.9 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0) |
Respiratory
Cough
Upper Respiratory Infection
Common Cold
Nasal Congestion
Influenza |
3.5 (0.7)
2.1 (0.1)
1.1 (0.1)
0.4 (0.1)
0.3 (0.1) |
4.6 (0.8)
2.7 (0.1)
1.3 (0.1)
1.3 (0.1)
1.1 (0.1) |
1.0 (0.0)
0.0 (0.0)
0.0 (0.0)
0.0 (0.0)
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 PRINIVIL.
HEART FAILURE
In patients with heart failure treated with PRINIVIL for up to four years, discontinuation of therapy due to clinical adverse experiences occurred in 11.0 percent of patients. In controlled studies in patients with heart failure, therapy was discontinued in 8.1 percent of patients treated with PRINIVIL for up to 12 weeks, compared to 7.7 percent of patients treated with placebo for 12 weeks.
The following table lists those adverse experiences which occurred in greater than one percent of patients with heart failure treated with PRINIVIL or placebo for up to 12 weeks in controlled clinical trials and more frequently on PRINIVIL than placebo.
| Controlled Trials |
| | PRINIVIL
(n=407)
Incidence
(discontinuation) | Placebo
(n=155)
Incidence
(discontinuation) |
| | 12 weeks | 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 PRINIVIL but more frequent or as frequent on placebo than PRINIVIL 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 PRINIVIL.
ACUTE MYOCARDIAL INFARCTION
In the GISSI - 3 trial, in patients treated with PRINIVIL for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6 percent of patients.
Patients treated with PRINIVIL had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking PRINIVIL.
In the GISSI - 3 trial, hypotension (9.7 percent), renal dysfunction (2.0 percent), cough (0.5 percent), post-infarction angina (0.3 percent), skin rash and generalized edema (0.01 percent), and angioedema (0.01 percent) resulted in withdrawal of treatment. In elderly patients treated with PRINIVIL, discontinuation due to renal dysfunction was 4.2 percent.
Other clinical adverse experiences occurring in 0.3 to 1.0 percent of patients with hypertension or heart failure treated with PRINIVIL in controlled 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.
Metabolic: Weight loss, dehydration, fluid overload, gout, weight gain. Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported (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, and nervousness.
Respiratory System: Malignant lung neoplasms, hemoptysis, pulmonary infiltrates, eosinophilic pneumonitis, bronchospasm, asthma, pleural effusion, pneumonia, 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. Other severe skin reactions (including toxic epidermal necrolysis and Stevens-Johnson syndrome) have been reported rarely; causal relationship has not been established.
Special Senses: Visual loss, diplopia, blurred vision, tinnitus, photophobia, taste disturbances.
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 PRINIVIL (0.1%) 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 PRINIVIL should be discontinued and appropriate therapy instituted immediately. In rare cases, intestinal angioedema has been reported with angiotensin converting enzyme inhibitors including lisinopril. (See WARNINGS.)
Hypotension: In hypertensive patients, hypotension occurred in 1.2 percent and syncope occurred in 0.1 percent of patients. Hypotension or syncope was a cause for discontinuation of therapy in 0.5 percent of hypertensive patients. In patients with heart failure, hypotension occurred in 5.3 percent and syncope occurred in 1.8 percent of patients. These adverse experiences were causes for discontinuation of therapy in 1.8 percent of these patients. In patients treated with PRINIVIL for six weeks after acute myocardial infarction, hypotension (systolic blood pressure ≤100 mmHg) resulted in discontinuation of therapy in 9.7 percent of the patients. (See WARNINGS.)
Fetal/Neonatal Morbidity and Mortality: See WARNINS, 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 percent of patients with essential hypertension treated with PRINIVIL 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 percent 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 percent and 1.3 vol percent, respectively) occurred frequently in patients treated with PRINIVIL but were rarely of clinical importance in patients without some other cause of anemia. In clinical trials, less than 0.1 percent 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 percent discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.6 percent), serum creatinine (0.5 percent) and serum potassium (0.4 percent). In the heart failure trials, 3.4 percent of patients discontinued therapy due to laboratory adverse experiences, 1.8 percent due to elevations in blood urea nitrogen and/or creatinine and 0.6 percent due to elevations in serum potassium. In the myocardial infarction trial, 2.0 percent of patients receiving PRINIVIL 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 percent of patients discontinued therapy due to other laboratory adverse experiences: 0.1 percent with hyperkalemia and less than 0.1 percent with hepatic enzyme alterations.
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