Information for the Patient
Prinivil
Pharmacology
Following oral administration of lisinopril, peak serum concentrations of lisinopril occur within about 7 hours, although patients with recent myocardial infarction have demonstrated an increase in time to peak serum concentration to about 8 to 10 hours. Declining serum concentrations exhibit a prolonged terminal phase which does not contribute to drug accumulation. This terminal phase probably represents saturable binding to ACE and is not proportional to dose. Lisinopril does not bind serum proteins other than ACE.
Lisinopril does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the extent of absorption of lisinopril is approximately 25%, with large intersubject variability (6 to 60%) at all doses tested (5 to 80 mg). Lisinopril absorption is not influenced by the presence of food in the gastrointestinal tract.
Following multiple doses of lisinopril, the effective half-life of accumulation is 12 hours.
In a study in elderly healthy subjects (65 years and above), a single dose of lisinopril 20 mg produced higher serum concentrations than those seen in young healthy adults given a similar dose. In another study, single daily doses of lisinopril 5 mg were given for 7 consecutive days to young and elderly healthy volunteers and to elderly patients with congestive heart failure. Maximum serum concentrations of lisinopril on Day 7 were higher in the elderly volunteers than in the young, and still higher in the elderly patients with congestive heart failure. Renal clearance of lisinopril was decreased in the elderly, particularly in the presence of congestive heart failure.
The elimination of lisinopril in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is 30 mL/min or less. With renal function ≤30 mL/min, peak and trough lisinopril levels increase, time to peak concentration increases and time to steady-state is prolonged (see Dosage).
Studies in rats indicate that lisinopril crosses the blood-brain barrier poorly.
Indications
Hypertension: In the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with thiazide diuretics. A great majority of patients (>80%) with severe hypertension required combination therapy. Lisinopril has been used concomitantly with beta-blockers and calcium antagonists, but the data on such use are limited.
Heart Failure: Lisinopril is indicated in the management of symptomatic congestive heart failure as adjunctive treatment with diuretics and, where appropriate, digitalis. Treatment with lisinopril should be initiated under close medical supervision, usually in a hospital.
Treatment Following Acute Myocardial Infarction: Lisinopril is indicated in the treatment of hemodynamically stable patients as early as within 24 hours following acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, ASA and beta-blocker(s).
Therapy with lisinopril should be reassessed after 6 weeks. If there is no evidence of symptomatic or asymptomatic left ventricular dysfunction, treatment with lisinopril can be stopped.
Lisinopril should not be used if systolic blood pressure is less than 100 mmHg, if clinically relevant renal failure is present, if there is a history of bilateral stenosis of the renal arteries (see Precautions, Hypotension Following Acute Myocardial Infarction, Renal Impairment).
In using lisinopril, attention should be given to the risk of angioedema (see Warnings).
Precautions
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 lisinopril. The possibility of symptomatic hypotension with lisinopril can be minimized by discontinuing the diuretic prior to initiation of treatment with lisinopril and/or lowering the initial dose of lisinopril (see Warnings, Hypotension and Dosage).
Agents Increasing Serum Potassium: Since lisinopril decreases aldosterone production, elevation of serum potassium may occur. Potassium-sparing diuretics, such as spironolactone, triamterene or amiloride, or potassium supplements should be given only for documented hypokalemia and with caution and with frequent monitoring of serum potassium since they may lead to a significant increase in serum potassium. Potassium-containing salt substitutes should also be used with caution (see also Precautions, Hyperkalemia).
Gold: 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 lisinopril.
Agents Causing Renin Release: The antihypertensive effect of lisinopril is augmented by antihypertensive agents that cause renin release (e.g., diuretics).
Agents Affecting Sympathetic Activity: Agents affecting sympathetic activity (e.g., ganglionic blocking agents or adrenergic neuron blocking agents) may be used with caution. Beta-adrenergic blocking drugs add some further antihypertensive effect to lisinopril.
NSAIDs: Non-steroidal anti-inflammatory drugs (NSAIDs) including selective cyclooxygenase-2 inhibitors (COX-2 inhibitors) may reduce the effect of diuretics and other antihypertensive drugs. Therefore, the antihypertensive effect of ACE inhibitors may be attenuated by NSAIDs including selective COX-2 inhibitors.
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 cyclooxygenase-2 inhibitors, the co-administration of ACE inhibitors or angiotensin II receptor antagonists may result in further deterioration of renal function.
Indomethacin may diminish the antihypertensive efficacy of concomitantly administered lisinopril.
Lithium Salts: As with other drugs which eliminate sodium, the lithium elimination may be reduced. Therefore, the serum lithium levels should be monitored carefully if lithium salts are to be administered.
In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution (see Dosage).
Safety and effectiveness in children have not been established.
Anaphylactoid Reactions during Membrane Exposure: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor. Dialysis should be stopped immediately if symptoms such as nausea, abdominal cramps, burning, angioedema, shortness of breath and severe hypotension occur. Symptoms are not relieved by antihistamines. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Anaphylactoid Reactions during LDL Apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (LDL) apheresis with dextran sulfate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactoid Reactions during Hymenoptera Desensitization: There have been isolated reports of patients experiencing sustained life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitizing treatment with hymenoptera (bees, wasps) venom. In the same patients, these reactions have been avoided when ACE inhibitors were temporarily withheld for at least 24 hours, but they have reappeared upon inadvertent rechallenge.
Angioedema: Angioedema, including laryngeal edema, may occur especially following the first dose of lisinopril. Patients should be so advised and told to report immediately any signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, difficulty in breathing) and to take no more drug until they have consulted with the prescribing physician.
Hypotension: Patients should be cautioned to report lightheadedness especially during the first few days of therapy. If actual syncope occurs, the patients should be told to discontinue the drug until they have consulted with the prescribing physician.
All patients should be cautioned that excessive perspiration and dehydration may lead to an excessive fall in blood pressure because of reduction in fluid volume. Other causes of volume-depletion such as vomiting or diarrhea may also lead to a fall in blood pressure; patients should be advised to consult with their physician.
Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which may be a sign of neutropenia.
Impaired Liver Function: Patients should be advised to return to the physician if he/she experiences any symptoms possibly related to liver dysfunction. This would include “viral-like symptoms” in the first weeks to months of therapy (such as fever, malaise, muscle pain, rash or adenopathy which are possible indicators of hypersensitivity reactions), or if abdominal pain, nausea or vomiting, loss of appetite, jaundice, itching or any other unexplained symptoms occur during therapy.
Hyperkalemia: Patients should be told not to use salt substitutes containing potassium without consulting their physician.
Pregnancy: Patients should be advised to stop taking the medication and to report promptly to their physician if they become pregnant, since the use of Prinivil during pregnancy can cause injury and even death of the developing fetus.
Lactation: Patients should be advised not to breast-feed while taking Prinivil, as it is possible that Prinivil passes into breast milk.
Note: As with many other drugs, certain advice to patients being treated with Prinivil is warranted. This information is intended to aid in the safe and effective use of this medication. It is not a disclosure of all possible adverse or intended effects.
Supplied
Each white, oval-shaped, compressed tablet, with code MSD 19 on one side and scored on the other, contains: lisinopril 5 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, magnesium stearate and mannitol. Bottles of 100. Blister packages of 28.
Each peach, oval-shaped, compressed tablet, engraved MSD 207 on one side and scored on the other, contains: lisinopril 20 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, iron oxide, magnesium stearate and mannitol. Bottles of 100. Blister packages of 28.
The splitting of Prinivil tablets is not advised. Store at room temperature (15 to 30°C).
Each light yellow, oval-shaped, compressed tablet, engraved MSD 106 on one side and scored on the other, contains: lisinopril 10 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, iron oxide, magnesium stearate and mannitol. Blister packages of 28.
Contraindications
In patients who are hypersensitive to any component of this product; have a history of angioneurotic edema relating to previous treatment with an angiotensin converting enzyme inhibitor; have hereditary or idiopathic angioedema.
Warnings
The presence of concentrations of ACE inhibitor have been reported in human milk. Use of ACE inhibitors is not recommended during breast-feeding.
ACE inhibitors can cause fetal and neonatal morbidity and mortality when administered to pregnant women. When pregnancy is detected, lisinopril should be discontinued as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function, associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development.
Prematurity, and patent ductus arteriosus and other structural cardiac malformations, as well as neurologic malformations, have also been reported following exposure in the first trimester of pregnancy.
Infants with a history of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for impaired renal function; however, limited experience with those procedures has not been associated with significant clinical benefit.
Lisinopril has been removed from the neonatal circulation by peritoneal dialysis with some clinical benefit and may, theoretically, be removed by exchange transfusion, although there is no experience with the latter procedure.
Animal Data: Lisinopril was not teratogenic in mice treated on days 6 to 15 of gestation with up to 1000 mg/kg/day (625 times the maximum recommended human dose). There was an increase in fetal resorptions at doses down to 100 mg/kg; at doses of 1000 mg/kg this was prevented by saline supplementation. There was no fetotoxicity or teratogenicity in rats treated with up to 300 mg/kg/day (188 times the maximum recommended dose) of lisinopril at days 6 to 17 of gestation. In rats receiving lisinopril from day 15 of gestation through day 21 postpartum, there was an increased incidence in pup deaths on days 2 to 7 postpartum and a lower average body weight of pups on day 21 postpartum. The increase in pup deaths and decrease in pup weight did not occur with maternal saline supplementation.
Lisinopril, at doses up to 1 mg/kg/day, was not teratogenic when given throughout the organogenic period in saline supplemented rabbits. Saline supplementation (physiologic saline in place of tap water) was used to eliminate maternotoxic effects and enable evaluation of the teratogenic potential at the highest possible dosage level. The rabbit has been shown to be extremely sensitive to angiotensin converting enzyme inhibitors (captopril and enalapril) with maternal and fetotoxic effects apparent at or below the recommended therapeutic dosage levels in man.
Fetotoxicity was demonstrated in rabbits by an increased incidence of fetal resorptions at an oral dose of lisinopril of 1 mg/kg/day and by an increased incidence of incomplete ossification at the lowest dose tested (0.1 mg/kg/day). A single i.v. dose of 15 mg/kg of lisinopril administered to pregnant rabbits on gestation days 16, 21 or 26 resulted in 88 to 100% fetal death.
By whole body autoradiography, radioactivity was found in the placenta following administration of labelled lisinopril to pregnant rats, but none was found in the fetuses.
Adverse Effects
mental confusion, mood alterations, paresthesia, vertigo.
abdominal pain and indigestion, dry mouth, pancreatitis, vomiting.
Serum Electrolytes: Hyperkalemia and hyponatremia have occurred (see Precautions).
Creatinine, Blood Urea Nitrogen: Increases in blood urea nitrogen and serum creatinine, usually reversible upon discontinuation of therapy, were observed in 1.1 and 1.6% of patients, respectively, with essential hypertension treated with lisinopril alone. Increases were more common in patients receiving concomitant diuretics and in patients with renal artery stenosis (see Precautions). Reversible increases in blood urea nitrogen (14.5%) and serum creatinine (11.2%) were observed in approximately 12.0% of patients with congestive heart failure on concomitant diuretic therapy. Frequently, these abnormalities resolved when the dosage of the diuretic was decreased.
Hematology: Decreases in hemoglobin and hematocrit (mean decreases of approximately 0.9 g % and 0.6 vol % respectively) occurred frequently in patients treated with lisinopril but were rarely of clinical importance in patients without some other cause of anemia.
Rarely, hemolytic anemia has been reported.
Agranulocytosis and bone marrow depression, manifested as anemia, thrombocytopenia or leukopenia, have been caused by angiotensin converting enzyme inhibitors, including lisinopril. Several cases of agranulocytosis and neutropenia have been reported in which a causal relationship to lisinopril cannot be excluded (see Warnings, Neutropenia/Agranulocytosis).
Hepatic: Elevations of liver enzymes and/or serum bilirubin have occurred (see Precautions).
syndrome of inappropriate antidiuretic hormone secretion (SIADH).
bronchospasm, rhinitis, sinusitis.
Cases of hypoglycemia in diabetic patients on oral antidiabetic agents or insulin have been reported (see Drug Interactions).
erythema multiforme, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis, cutaneous pseudolymphoma.
acute renal failure, impotence, oliguria/anuria, renal dysfunction, uremia.
A symptom complex has been reported which may include fever, vasculitis, myalgia, arthralgia/arthritis, a positive ANA, elevated ESR, eosinophilia and leukocytosis. Rash, photosensitivity or other dermatologic manifestations may also occur.
Other Events in Controlled Clinical Trials or Postmarketing Experience: Additional adverse reactions which were reported rarely, either during controlled clinical trials or after the drug was marketed, include:
Overall, 1% of patients discontinued therapy due to laboratory adverse experiences, principally elevations in blood urea nitrogen (0.8%), serum creatinine (0.1%) and serum potassium (0.1%).
alopecia, diaphoresis, pruritus, urticaria.
hepatitis, jaundice (hepatocellular and/or cholestatic), liver function abnormalities, hepatic failure.
myocardial infarction or cerebrovascular accident possibly secondary to excessive hypotension in high-risk patients (see Warnings, Hypotension), tachycardia.
Overdose
The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be i.v. infusion of normal saline solution. If available, angiotensin II may be beneficial.
Lisinopril may be removed from the general circulation by hemodialysis (see Precautions, Anaphylactoid Reactions during Membrane Exposure).
Dosage
Since absorption of lisinopril is not affected by food, the tablets may be administered before, during or after meals. Lisinopril should be administered in a single daily dose. Lisinopril should be taken at the same time each day. The splitting of Prinivil tablets is not advised.
Dosage must be individualized.
Essential Hypertension: In patients with essential hypertension, not on diuretic therapy, the usual recommended starting dose is 10 mg once a day. Dosage should be adjusted according to blood pressure response: the usual dosage range is 10 to 40 mg/day, administered in a single daily dose. In some patients, achievement of optimal blood pressure reduction may require 2 to 4 weeks of therapy. The antihypertensive effect may diminish toward the end of the dosing interval regardless of the administered dose, but most commonly with a dose of 10 mg daily. This can be evaluated by measuring blood pressure just prior to dosing to determine whether satisfactory control is being maintained for 24 hours. If it is not, an increase in dose should be considered. The maximum dose used in long-term controlled clinical trials was 80 mg/day. If blood pressure is not controlled with lisinopril alone, a low dose of a diuretic may be added. Hydrochlorothiazide 12.5 mg has been shown to provide an additive effect. After the addition of a diuretic, it may be possible to reduce the dose of lisinopril.
Diuretic Treated Patients: In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of lisinopril. The diuretic should be discontinued, if possible, for 2 to 3 days before beginning therapy with lisinopril to reduce the likelihood of hypotension (see Warnings). The dosage of lisinopril should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with lisinopril alone, diuretic therapy may be resumed as described above.
If the diuretic cannot be discontinued, an initial dose of 5 mg should be used under medical supervision for at least 2 hours and until blood pressure has stabilized for at least an additional hour (see Warnings, Hypotension and Precautions, Drug Interactions).
A lower starting dose is required in the presence of renal impairment, in patients in whom diuretic therapy cannot be discontinued, in patients who are volume and/or salt-depleted for any reason, and in patients with renovascular hypertension.
Dosage Adjustment in Renal Impairment: Dosage in patients with renal impairment should be based on creatinine clearance as outlined in Table 3.
Table 3: PrinivilDosage Adjustment in Renal Impairment | Creatinine Clearance | Starting Dose |
| ≤70 ≥30 mL/min (≤1.17 ≥0.5 mL/s) | 5.0–10.0 mg/day |
| ≤30 ≥10 mL/min (≤0.5 ≥0.17 mL/s) | 2.5–5.0 mg/day |
| <10 mL/min (<0.17 mL/s) | 2.5 mg/daya (including patients on dialysis) |
a. Dosage and/or frequency of administration should be adjusted depending on the blood pressure response.
The dosage may be titrated upward until blood pressure is controlled or to a maximum of 40 mg daily.
Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g., polyacrylonitrile [PAN]) and treated concomitantly with an ACE inhibitor (see Precautions, Anaphylactoid Reactions during Membrane Exposure).
Geriatrics: In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of lisinopril. Pharmacokinetic studies, however, indicate that maximum blood levels and area under the plasma concentration time curve (AUC) are doubled in older patients so that dosage adjustments should be made with particular caution.
Renovascular Hypertension: Some patients with renovascular hypertension, especially those with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, may develop an exaggerated response to the first dose of lisinopril. Therefore, a lower starting dose of 2.5 or 5 mg is recommended. Thereafter, the dosage may be adjusted according to the blood pressure response.
Congestive Heart Failure: Lisinopril is to be used in conjunction with a diuretic and, where appropriate, digitalis. Therapy must be initiated under close medical supervision, usually in a hospital. Blood pressure and renal function should be monitored, both before and during treatment with lisinopril, because severe hypotension and, more rarely, consequent renal failure have been reported (see Warnings, Hypotension and Precautions, Renal Impairment).
Initiation of therapy requires consideration of recent diuretic therapy and the possibility of severe salt-/volume-depletion. If possible, the dose of diuretic should be reduced before beginning treatment.
The recommended initial dose is 2.5 mg/day. If required, the dose should be increased gradually, depending on the patient response. The usual effective dosage range is 5-20 mg/day administered in a single daily dose. Dose titration may be performed over a 2-4 week period, or more rapidly if indicated by the presence of residual signs and symptoms of heart failure.
Treatment Following Acute Myocardial Infarction: Treatment of hemodynamically stable patients may be started as early as within 24 hours following the onset of symptoms of myocardial infarction. Patients should receive, as appropriate, standard recommended treatments (see Indications, Treatment Following Acute Myocardial Infarction).
The first dose of lisinopril is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg once daily thereafter.
Patients with a low systolic blood pressure (between 100 and 120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower dose, 2.5 mg orally. (Treatment with lisinopril must not be initiated in patients who are at risk of serious hemodynamic deterioration [see Precautions, Hypotension Following Acute Myocardial Infarction.]) After 3 days if hypotension occurs (systolic blood pressure less than or equal to 100 mmHg), a daily maintenance dose of 5 mg may be given with temporary reductions to 2.5 mg if needed. If prolonged hypotension occurs (systolic blood pressure less than 90 mmHg for more than 1 hour), lisinopril should be withdrawn.
Renal function should be assessed before and during therapy with lisinopril (see Precautions, Renal Impairment).
Dosing should normally continue for 6 weeks. At that time, patients with signs or symptoms of heart failure should continue with lisinopril (see Congestive Heart Failure).
Lisinopril is compatible with i.v. or transdermal glyceryl trinitrate.
