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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.
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 table 1 below:
Table 1 : Percent of
Patients in Controlled Studies
(n=1349) Incidence (discontinuatio n)
|PRINIVIL/ Hydrochlorothiazi de
(n=629) Incidence (discontinuation)
(n=207) Incidence (discontinuatio n)
|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)|
|Hypotension||1.2 (0.5)||1.6 (0.5)||0.5 (0.5)|
|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)|
|Muscle Cramps||0.5 (0.0)||2.9 (0.8)||0.5 (0.0)|
|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)|
|Cough||3.5 (0.7)||4.6 (0.8)||1.0 (0.0)|
|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)|
|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 PRINIVIL.
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.
Table 2 : Controlled Trials
(n=407) Incidence (discontinuation)
(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)|
|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 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.
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).
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, Stevens-Johnson syndrome and cutaneous pseudolymphoma) have been reported rarely; 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 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 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
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.
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.
Read the Prinivil (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 PRINIVIL. The possibility of hypotensive effects with PRINIVIL can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with PRINIVIL. If it is necessary to continue the diuretic, initiate therapy with PRINIVIL 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 PRINIVIL, 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 (COX-2) Inhibitors
Reports suggest that NSAIDs including selective COX-2 inhibitors may diminish the antihypertensive effect of ACE inhibitors, including lisinopril. This interaction should be given consideration in patients taking NSAIDs or selective COX-2 inhibitors concomitantly with ACE inhibitors.
In a study in 36 patients with mild to moderate hypertension where the antihypertensive effects of PRINIVIL alone were compared to PRINIVIL given concomitantly with indomethacin, the use of indomethacin was associated with a reduced antihypertensive effect, although the difference between the two regimens was not significant.
In some patients with compromised renal function (e.g., elderly patients or patients who are volume-depleted including those on diuretic therapy) who are being treated with non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors, the co-administration of angiotensin II receptor antagonists or ACE inhibitors may result in a further deterioration of renal function, including possible acute renal failure. These effects are usually reversible.
These interactions should be considered in patients taking NSAIDS including selective COX-2 inhibitors concomitantly with diuretics and angiotensin II antagonists or ACE inhibitors. Therefore, monitor effects on blood pressure and renal function when administering the combination, especially in the elderly.
Dual Blockade of the Renin-angiotensin-aldosterone System
Dual blockade of the renin-angiotensinaldosterone system (RAAS) with angiotensin receptor blockers, ACE inhibitors, or direct renin inhibitors (such as aliskiren) is associated with increased risks of hypotension, syncope, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function, and electrolytes in patients on PRINIVIL and other agents that affect the RAAS. Do not coadminister aliskiren with PRINIVIL in patients with diabetes. Avoid use of aliskiren with PRINIVIL in patients with renal impairment (GFR < 60ml/min).
PRINIVIL 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 PRINIVIL was used concomitantly with propranolol or hydrochlorothiazide. The presence of food in the stomach does not alter the bioavailability of PRINIVIL.
Agents Increasing Serum Potassium
PRINIVIL attenuates potassium loss caused by thiazide-type diuretics. Use of PRINIVIL 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 PRINIVIL.
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 PRINIVIL 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 PRINIVIL.
Read the Prinivil Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 3/20/2013
This monograph has been modified to include the generic and brand name in many instances.
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