Lisinopril Tablets, USP
Lisinopril Information
Company Name: Cardinal Health
Lisinopril (Lisinopril) Description
Lisinopril (Lisinopril) is an oral long-acting angiotensin converting enzyme inhibitor. Lisinopril (Lisinopril) , a synthetic peptide derivative, is chemically described as (S)-1-[N-(1-Carboxy-3-phenyl-propyl)-L-lysyl]-L-proline dihydrate. Its empirical formula is CHNO·2HO and its structural formula is:
Lisinopril (Lisinopril) is a white to off-white crystalline powder, with a molecular weight of 441.53. It is soluble in water and sparingly soluble in methanol and practically insoluble in ethanol.
Lisinopril (Lisinopril) tablet is supplied as 2.5 mg, 5 mg, 10 mg, 20 mg and 40 mg tablets for oral administration.
Inactive Ingredients:
2.5 mg, 5 mg, 10 mg tablets - dibasic calcium phosphate dihydrate, povidone, pregelatinized starch, mannitol, colloidal silicon dioxide, com starch, magnesium stearate.
20 mg, 30 mg, 40 mg tablets - dibasic calcium phosphate dihydrate, povidone, pregelatinized starch, mannitol, colloidal silicon dioxide, corn starch, magnesium stearate, ferric oxide yellow (for20 mg), ferric oxide red (for 30 mg) and ferric oxide brown (for 40 mg).
Lisinopril (Lisinopril) Clinical Pharmacology
Lisinopril (Lisinopril) inhibits angiotensin converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. The beneficial effects of Lisinopril (Lisinopril) in hypertension and heart failure appear to result primarily from suppression of the renin-angiotensin-aldosterone system. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with Lisinopril (Lisinopril) tablet alone for up to 24 weeks, the mean increase in serum potassium was approximately 0.1 mEq/L; however, approximately 15% of patients had increases greater than 0.5 mEq/L and approximately 6% had a decrease greater than 0.5 mEq/L. In the same study, patients treated with Lisinopril (Lisinopril) and hydrochlorothiazide for up to 24 weeks had a mean decrease in serum potassium of 0.1 mEq/L; approximately 4% of patients had increases greater than 0.5 mEq/L and approximately 12% had a decrease greater than 0.5 mEq/L. (See .) Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lisinopril (Lisinopril) tablet remains to be elucidated.
While the mechanism through which Lisinopril (Lisinopril) tablet lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Lisinopril (Lisinopril) tablet is antihypertensive even in patients with low-renin hypertension. Although Lisinopril (Lisinopril) tablet was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than nonblack patients.
Concomitant administration of Lisinopril (Lisinopril) tablet and hydrochlorothiazide further reduced blood pressure in black and non-black patients and any racial differences in blood pressure response were no longer evident.
Adult Patients:
Lisinopril (Lisinopril) does not appear to be bound to other serum proteins. Lisinopril (Lisinopril) does not undergo metabolism and is excreted unchanged entirely in the urine. Based on urinary recovery, the mean extent of absorption of Lisinopril (Lisinopril) is approximately 25%, with large intersubject variability (6%-60%) at all doses tested (5-80 mg). Lisinopril (Lisinopril) absorption is not influenced by the presence of food in the gastrointestinal tract. The absolute bioavailability of Lisinopril (Lisinopril) is reduced to 16% in patients with stable NYHA Class II-IV congestive heart failure, and the volume of distribution appears to be slightly smaller than that in normal subjects. The oral bioavailability of Lisinopril (Lisinopril) in patients with acute myocardial infarction is similar to that in healthy volunteers.
Upon multiple dosing, Lisinopril (Lisinopril) exhibits an effective half-life of accumulation of 12 hours.
Impaired renal function decreases elimination of Lisinopril (Lisinopril) , which is excreted principally through the kidneys, but this decrease becomes clinically important only when the glomerular filtration rate is below 30 mL/min. Above this glomerular filtration rate, the elimination half-life is little changed. With greater impairment, however, peak and trough Lisinopril (Lisinopril) levels increase, time to peak concentration increases and time to attain steady state is prolonged. Older patients, on average, have (approximately doubled) higher blood levels and the area under the plasma concentration time curve (AUC) than younger patients. (See .) Lisinopril (Lisinopril) can be removed by hemodialysis.
Studies in rats indicate that Lisinopril (Lisinopril) crosses the blood-brain barrier poorly. Multiple doses of Lisinopril (Lisinopril) in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of C Lisinopril (Lisinopril) . By whole body autoradiography, radioactivity was found in the placenta following administration of labeled drug to pregnant rats, but none was found in the fetuses.
Pediatric Patients:
2
Adult Patients:
WARNINGS
In most patients studied, onset of antihypertensive activity was seen at one hour after oral administration of an individual dose of Lisinopril (Lisinopril) tablet, with peak reduction of blood pressure achieved by 6 hours. Although an antihypertensive effect was observed 24 hours after dosing with recommended single daily doses, the effect was more consistent and the mean effect was considerably larger in some studies with doses of 20 mg or more than with lower doses. However, at all doses studied, the mean antihypertensive effect was substantially smaller 24 hours after dosing than it was 6 hours after dosing.
In some patients achievement of optimal blood pressure reduction may require two to four weeks of therapy.
The antihypertensive effects of Lisinopril (Lisinopril) tablet are maintained during longterm therapy. Abrupt withdrawal of Lisinopril (Lisinopril) has not been associated with a rapid increase in blood pressure, or a significant increase in blood pressure compared to pretreatment levels.
Two dose-response studies utilizing a once daily regimen were conducted in 438 mild to moderate hypertensive patients not on a diuretic. Blood pressure was measured 24 hours after dosing. An antihypertensive effect of Lisinopril (Lisinopril) tablet was seen with 5 mg in some patients. However, in both studies blood pressure reduction occurred sooner and was greater in patients treated with 10, 20 or 80 mg of Lisinopril (Lisinopril) tablet. In controlled clinical studies, Lisinopril (Lisinopril) tablet 20-80 mg has been compared in patients with mild to moderate hypertension to hydrochlorothiazide 12.5-50 mg and with atenolol 50-200 mg; and in patients with moderate to severe hypertension to metoprolol 100-200 mg. It was superior to hydrochlorothiazide in effects on systolic and diastolic pressure in a population that was 3/4 caucasian. Lisinopril (Lisinopril) were approximately equivalent to atenolol and metoprolol in effects on diastolic blood pressure, and had somewhat greater effects on systolic blood pressure.
Lisinopril (Lisinopril) tablet had similar effectiveness and adverse effects in younger and older (>65 years) patients. They were less effective in Blacks than in Caucasians.
In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with little or no change in cardiac output and in heart rate. In a study in nine hypertensive patients, following administration of Lisinopril (Lisinopril) , there was an increase in mean renal blood flow that was not significant. Data from several small studies are inconsistent with respect to the effect of Lisinopril (Lisinopril) on glomerular filtration rate in hypertensive patients with normal renal function, but suggest that changes, if any, are not large.
In patients with renovascular hypertension Lisinopril (Lisinopril) tablet have been shown to be well tolerated and effective in controlling blood pressure. (See .)
Pediatric Patients:
In the above pediatric studies, Lisinopril (Lisinopril) was given either as tablets or in a suspension for those children and infants who were unable to swallow tablets or who required a lower dose than is available in tablet form (see ).
During baseline-controlled clinical trials, in patients receiving digitalis and diuretics, single doses of Lisinopril (Lisinopril) resulted in decreases in pulmonary capillary wedge pressure, systemic vascular resistance and blood pressure accompanied by an increase in cardiac output and no change in heart rate.
In two placebo controlled, 12-week clinical studies using doses of Lisinopril (Lisinopril) tablet up to 20 mg, Lisinopril (Lisinopril) tablet as adjunctive therapy to digitalis and diuretics improved the following signs and symptoms due to congestive heart failure: edema, rales, paroxysmal nocturnal dyspnea, and jugular venous distention. In one of the studies, beneficial response was also noted for: orthopnea, presence of third heart sound and the number of patients classified as NYHA Class III and IV. Exercise tolerance was also improved in this study. The effect of Lisinopril (Lisinopril) on mortality in patients with heart failure has not been evaluated. The once daily dosing for the treatment of congestive heart failure was the only dosage regimen used during clinical trial development and was determined by the measurement of hemodynamic response. A large (over 3000 patients) survival study, the ATLAS Trial, comparing 2.5 and 35 mg of Lisinopril (Lisinopril) in patients with heart failure, showed that the higher dose of Lisinopril (Lisinopril) had outcomes at least as favorable as the lower dose.
The Gruppo Italiano per lo Studio della Sopravvienza nell'Infarto Miocardico (GISSI-3) study was a multicenter, controlled, randomized, unblinded clinical trial conducted in 19,394 patients with acute myocardial infarction admitted to a coronary care unit. It was designed to examine the effects of short-term (6 week) treatment with Lisinopril (Lisinopril) , nitrates, their combination, or no therapy on short-term (6 week) mortality and on longer-term death and markedly impaired cardiac function. Patients presenting within 24 hours of the onset of symptoms who were hemodynamically stable were randomized, in a 2x2 factorial design, to six weeks of either 1) Lisinopril (Lisinopril) alone (n=4841), 2) nitrates alone (n=4869), 3) Lisinopril (Lisinopril) plus nitrates (n=4841), or 4) open control (n=4843). All patients received routine therapies, including thrombolytics (72%), aspirin (84%), and a beta-blocker (31%), as appropriate, normally utilized in acute myocardial infarction (MI) patients.
The protocol excluded patients with hypotension (systolic blood pressure ≤100 mmHg), severe heart failure, cardiogenic shock, and renal dysfunction (serum creatinine >2 mg/dL and/or proteinuria >500 mg/24 h). Doses of Lisinopril (Lisinopril) tablet were adjusted as necessary according to protocol (see ).
Study treatment was withdrawn at six weeks except where clinical conditions indicated continuation of treatment.
The primary outcomes of the trial were the overall mortality at 6 weeks and a combined endpoint at 6 months after the myocardial infarction, consisting of the number of patients who died, had late (day 4) clinical congestive heart failure, or had extensive left ventricular damage defined as ejection fraction ≤35% or an akinetic-dyskinetic [A-D] score ≥45%. Patients receiving Lisinopril (Lisinopril) (n=9646), alone or with nitrates, had an 11% lower risk of death (2p [two-tailed] = 0.04) compared to patients receiving no Lisinopril (Lisinopril) (n=9672) (6.4% vs. 7.2%, respectively) at 6 weeks. Although patients randomized to receive Lisinopril (Lisinopril) for up to 6 weeks also fared numerically better on the combined end-point at 6 months, the open nature of the assessment of heart failure, substantial loss to follow-up echocardiography, and substantial excess use of Lisinopril (Lisinopril) between 6 weeks and 6 months in the group randomized to 6 weeks of Lisinopril (Lisinopril) , preclude any conclusion about this endpoint.
Patients with acute myocardial infarction, treated with Lisinopril (Lisinopril) , had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure
Lisinopril (Lisinopril) Indications And Usage
Lisinopril (Lisinopril) tablet is indicated for the treatment of hemodynamically stable patients within 24 hours of acute myocardial infarction, to improve survival. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers.
In using Lisinopril (Lisinopril) tablet, consideration should be given to the fact that another angiotensin converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease, and that available data are insufficient to show that Lisinopril (Lisinopril) tablet does not have a similar risk. (See .)
In considering the use of Lisinopril (Lisinopril) tablet, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors have been associated with a higher rate of angioedema in Black than in non-Black patients (see , ).
Lisinopril (Lisinopril) Contraindications
Lisinopril (Lisinopril) tablet is contraindicated in patients who are hypersensitive to this product and in patients with a history of angioedema related to previous treatment with an angiotensin converting enzyme inhibitor and in patients with hereditary or idiopathic angioedema.
Lisinopril (Lisinopril) Warnings
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CTscan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see also and ).
Excessive hypotension is rare in patients with uncomplicated hypertension treated with Lisinopril (Lisinopril) tablet alone.
Patients with heart failure given Lisinopril (Lisinopril) tablet commonly have some reduction in blood pressure, with peak blood pressure reduction occurring 6 to 8 hours post dose. Evidence from the two-dose ATLAS trial suggested that incidence of hypotension may increase with Lisinopril (Lisinopril) in heart failure patients. Discontinuation of therapy because of continuing symptomatic hypotension usually is not necessary when dosing instructions are followed; caution should be observed when initiating therapy. (See .)
Patients at risk of excessive hypotension, sometimes associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death, include those with the following conditions or characteristics: heart failure with systolic blood pressure below 100 mmHg, hyponatremia, high dose diuretic therapy, recent intensive diuresis or increase in diuretic dose, renal dialysis, or severe volume and/or salt depletion of any etiology. It may be advisable to eliminate the diuretic (except in patients with heart failure), reduce the diuretic dose or increase salt intake cautiously before initiating therapy with Lisinopril (Lisinopril) in patients at risk for excessive hypotension who are able to tolerate such adjustments. (See , and .)
Patients with acute myocardial infarction in the GISSI-3 trial had a higher (9.0% versus 3.7%) incidence of persistent hypotension (systolic blood pressure
In patients at risk of excessive hypotension, therapy should be started under very close medical supervision and such patients should be followed closely for the first two weeks of treatment and whenever the dose of Lisinopril (Lisinopril) tablet and/or diuretic is increased. Similar considerations may apply to patients with ischemic heart or cerebrovascular disease, or in patients with acute myocardial infarction, in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, receive an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further doses of Lisinopril (Lisinopril) tablet which usually can be given without difficulty once the blood pressure has stabilized. If symptomatic hypotension develops, a dose reduction or discontinuation of Lisinopril (Lisinopril) tablet or concomitant diuretic may be necessary.
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, ACE inhibitors should be discontinued as soon as possible.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor drug during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergqne first trimester exposure to ACE inhibitor drugs. Tile number of cases of birth defects is small and tile findings ofthis study have not yet been repeated.
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; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE-inhibitor exposure.
These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of Lisinopril (Lisinopril) tablet as soon as possible.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intraamniotic environment.
If oligohydramnios is observed, Lisinopril (Lisinopril) should be discontinued unless it is considered lifesaving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of 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 means of reversing hypotension and/or substituting for disordered renal function. Lisinopril (Lisinopril) , which crosses the placenta, has been removed from neonatal circulation by peritoneal dialysis with some clinical benefit, and theoretically may be removed by exchange transfusion, although there is no experience with the latter procedure.
No teratogenic effects of Lisinopril (Lisinopril) were seen in studies of pregnant rats, mice, and rabbits. On a mg/kg basis, the doses used were up to 625 times (in mice), 188 times (in rats), and 0.6 times (in rabbits) the maximum recommended human dose.
Lisinopril (Lisinopril) Precautions
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin converting enzyme inhibitors, including Lisinopril (Lisinopril) , may be associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another angiotensin converting enzyme inhibitor suggests that these increases are usually reversible upon discontinuation of Lisinopril (Lisinopril) and/or diuretic therapy. In such patients, renal function should be monitored during the first few weeks of therapy.
Some patients with hypertension or heart failure with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Lisinopril (Lisinopril) tablet has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Lisinopril (Lisinopril) may be required.
Patients with acute myocardial infarction in the GISSI-3 trial, treated with Lisinopril (Lisinopril) had a higher (2.4% versus 1.1%) incidence of renal dysfunction in-hospital and at six weeks (increasing creatinine concentration to over 3 mg/dL or a doubling or more of the baseline serum creatinine concentration). In acute myocardial infarction, treatment with Lisinopril (Lisinopril) should be initiated with caution in patients with evidence of renal dysfunction, defined as serum creatinine concentration exceeding 2 mg/dL. If renal dysfunction develops during treatment with Lisinopril (Lisinopril) (serum creatinine concentration exceeding 3 mg/dL or a doubling from the pre-treatment value) then the physician should consider withdrawal of Lisinopril (Lisinopril) tablet.
Evaluation of patients with hypertension, heart failure, or myocardial infarction should always include assessment of renal function. (See .)
Patients should be cautioned to report lightheadedness, especially during the first few days of therapy. If actual syncope occurs, the patient 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.
Female patients of childbearing age should be told about the consequences of second- and third-trimester exposure to ACE inhibitors during pregnancy. These patients should be asked to report pregnancies to their physicians as soon as possible.
NOTE:
There was no evidence of a tumorigenic effect when Lisinopril (Lisinopril) was administered for 105 weeks to male and female rats at doses up to 90 mg/kg/day (about 56 or 9 times* the maximum recommended daily human dose, based on body weight and body surface area, respectively). There was no evidence of carcinogenicity when Lisinopril (Lisinopril) was administered for 92 weeks to (male and female) mice at doses up to 135 mg/kg/day (about 84 times* the maximum recommended daily human dose). This dose was 6.8 times the maximum human dose based on body surface area in mice.
Lisinopril (Lisinopril) was not mutagenic in the Ames microbial mutagen test with or without metabolic activation. It was also negative in a forward mutation assay using Chinese hamster lung cells. Lisinopril (Lisinopril) did not produce single strand DNA breaks in an alkaline elution rat hepatocyte assay. In addition, Lisinopril (Lisinopril) did not produce increases in chromosomal aberrations in an vitrotest in Chinese hamster ovary cells or in an study in mouse bone marrow.
There were no adverse effects on reproductive performance in male and female rats treated with up to 300 mg/kg/day of Lisinopril (Lisinopril) . This dose is 188 times and 30 times the maximum human dose when based on mg/kg and mg/m, respectively.
Lisinopril (Lisinopril) Adverse Reactions
Lisinopril (Lisinopril) tablet 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 (Lisinopril) , 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 (Lisinopril) tablet or Lisinopril (Lisinopril) tablet plus hydrochlorothiazide in controlled clinical trials, and more frequently with Lisinopril (Lisinopril) tablet and/or Lisinopril (Lisinopril) tablet plus hydrochlorothiazide than placebo, comparative incidence data are listed in the table below:
Chest pain and back pain were also seen, but were more common on placebo than Lisinopril (Lisinopril) tablet.
In patients with heart failure treated with Lisinopril (Lisinopril) tablet 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 (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 (Lisinopril) or placebo for up to 12 weeks in controlled clinical trials, and more frequently on Lisinopril (Lisinopril) tablet than placebo.
Also observed at >1% with Lisinopril (Lisinopril) tablet but more frequent or as frequent on placebo than Lisinopril (Lisinopril) 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 (Lisinopril) tablet.
In the two-dose ATLAS trial in heart failure patients, withdrawals due to adverse events were not different between the tow and high groups, either in total number of discontinuation (17-18%) or in rare specific events (
In the GISSI-3 trial, in patients treated with Lisinopril (Lisinopril) for six weeks following acute myocardial infarction, discontinuation of therapy occurred in 17.6% of patients.
Patients treated with Lisinopril (Lisinopril) tablet had a significantly higher incidence of hypotension and renal dysfunction compared with patients not taking Lisinopril (Lisinopril) .
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 (Lisinopril) , 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 (Lisinopril) 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:
Angioedema has been reported in patients receiving Lisinopril (Lisinopril) (0.1%). Angioedema associated with laryngeal edema may be fatal. If angioedema of the face, extremities, lips, tongue, glottis and/or larynx occurs, treatment with Lisinopril (Lisinopril) should be discontinued and appropriate therapy instituted immediately. (See .)
In rare cases, intestinal angioedema has been reported in post marketing experience.
Serum Electrolytes:
PRECAUTIONS
Rarely, elevations of liver enzymes and/or serum bilirubin have occurred. (See , .)
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 Lisinopril (Lisinopril) 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.
Lisinopril (Lisinopril) Overdosage
Following a single oral dose of 20 g/kg no lethality occurred in rats, and death occurred in one of 20 mice receiving the same dose. The most likely manifestation of overdosage would be hypotension, for which the usual treatment would be intravenous infusion of normal saline solution.
Lisinopril (Lisinopril) can be removed by hemodialysis. (See .)
Lisinopril (Lisinopril) Dosage And Administration
In hypertensive patients who are currently being treated with a diuretic, symptomatic hypotension may occur occasionally following the initial dose of Lisinopril (Lisinopril) tablet. The diuretic should be discontinued, if possible, for two to three days before beginning therapy with Lisinopril (Lisinopril) tablet to reduce the likelihood of hypotension. (See .) The dosage of Lisinopril (Lisinopril) tablet should be adjusted according to blood pressure response. If the patient's blood pressure is not controlled with Lisinopril (Lisinopril) tablet 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 two hours and until blood pressure has stabilized for at least an additional hour. (See and , .)
Concomitant administration of Lisinopril (Lisinopril) tablet with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics may lead to increases of serum potassium. (See .)
Lisinopril (Lisinopril) tablet is indicated as adjunctive therapy with diuretics and (usually) digitalis. The recommended starting dose is 5 mg once a day. When initiating treatment with Lisinopril (Lisinopril) in patients with heart failure, the initial dose should be administered under medical observation, especially in those patients with low blood pressure (systolic blood pressure below 100 mmHg). The mean peak blood pressure lowering occurs six to eight hours after dosing. Observation should continue until blood pressure is stable. The concomitant diuretic dose should be reduced, if possible, to help minimize hypovolemia which may contribute to hypotension. (See and , .) The appearance of hypotension after the initial dose of Lisinopril (Lisinopril) tablet does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension.
The usual effective dosage range is 5 to 40 mg per day administered as a single daily dose. The dose of Lisinopril (Lisinopril) tablet can be increased by increments of no greater than 10 mg, at intervals of no less than 2 weeks to the highest tolerated dose, up to a maximum of 40 mg daily. Dose adjustment should be based on the clinical response of individual patients.
In hemodynamically stable patients within 24 hours of the onset of symptoms of acute myocardial infarction, the first dose of Lisinopril (Lisinopril) tablet is 5 mg given orally, followed by 5 mg after 24 hours, 10 mg after 48 hours and then 10 mg of Lisinopril (Lisinopril) tablet once daily. Dosing should continue for six weeks. Patients should receive, as appropriate, the standard recommended treatments such as thrombolytics, aspirin, and beta-blockers.
Patients with a low systolic blood pressure (≤120 mmHg) when treatment is started or during the first 3 days after the infarct should be given a lower 2.5 mg oral dose of Lisinopril (Lisinopril) tablet (See ). If hypotension occurs (systolic blood pressure ≤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 ≤90 mmHg for more than 1 hour) Lisinopril (Lisinopril) tablet should be withdrawn. For patients who develop symptoms of heart failure, see , .
In general, blood pressure response and adverse experiences were similar in younger and older patients given similar doses of Lisinopril (Lisinopril) tablet. 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.
The usual recommended starting dose is 0.07 mg/kg once daily (up to 5 mg total). Dosage should be adjusted according to blood pressure response. Doses above 0.61 mg/kg (or in excess of 40 mg) have not been studied in pediatric patients. (See , and .)
Lisinopril (Lisinopril) tablet is not recommend in pediatric patients
Add 10 ml of Purified Water USP to a polyethylene terephthalate (PET) bottle containing ten 20 mg tablets of Lisinopril (Lisinopril) tablet and shake for at least one minute. Add 30 mlof Bicitra diluent and 160 mL of Ora Sweet SFto the concentrate in the PET bottle and gently shake for several seconds to disperse the ingredients. The suspension should be stored at or below 25°C (77°F) and can be stored for up to four weeks. Shake the suspension before each use.
*Registered trademark of Alza Corporation**Trademark of Paddock Laboratories, Inc.
Lisinopril (Lisinopril) How Supplied
Store at a temperature, 20-25°C (68-77°F) [see USP]. Protect from moisture, freezing and excessive heat.
*AN69 is a registered trademark of Hospal Ltd.
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Repackaged by:American Health PackagingColumbus, Ohio 43217
800185/290709
