Lisinopril (Page 5 of 8)

8.2 Lactation

Risk Summary

No data are available regarding the presence of lisinopril in human milk or the effects of lisinopril on the breast fed infant or on milk production. Lisinopril is present in rat milk. Because of the potential for severe adverse reactions in the breastfed infant, advise women not to breastfeed during treatment with lisinopril tablets.

8.4 Pediatric Use

Antihypertensive effects and safety of lisinopril tablets have been established in pediatric patients aged 6 to 16 years [see Dosage and Administration (2.1) and Clinical Studies (14.1)] . No relevant differences between the adverse reaction profile for pediatric patients and adult patients were identified.

Safety and effectiveness of lisinopril tablets have not been established in pediatric patients under the age 6 or in pediatric patients with glomerular filtration rate < 30 mL/min/1.73 m 2 [see Dosage and Administration (2.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)] .

Neonates with a History of in utero Exposure to Lisinopril

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.

8.5 Geriatric Use

No dosage adjustment with lisinopril tablets is necessary in elderly patients. In a clinical study of lisinopril tablets in patients with myocardial infarctions (GISSI-3 Trial) 4,413 (47%) were 65 and over, while 1,656 (18%) were 75 and over. In this study, 4.8% of patients aged 75 years and older discontinued lisinopril tablets treatment because of renal dysfunction vs. 1.3% of patients younger than 75 years. No other differences in safety or effectiveness were observed between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

8.6 Race

ACE inhibitors, including lisinopril, have an effect on blood pressure that is less in black patients than in non blacks.

8.7 Renal Impairment

Dose adjustment of lisinopril tablets is required in patients undergoing hemodialysis or whose creatinine clearance is ≤ 30 mL/min. No dose adjustment of lisinopril tablets is required in patients with creatinine clearance > 30 mL/min [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)] .

10 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 can be removed by hemodialysis [see Clinical Pharmacology (12.3)] .

11 DESCRIPTION

Lisinopril is an oral long-acting angiotensin converting enzyme (ACE) inhibitor. Lisinopril, a synthetic peptide derivative, is chemically described as (S)-1-[ N 2 -(1-carboxy-3-phenylpropyl)-L-lysyl]-L-proline dihydrate. Its molecular formula is C 21 H 31 N 3 O 5 • 2H 2 O and its structural formula is:

Lisinopril Structural Formula
(click image for full-size original)

Lisinopril, USP 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 tablets, USP are supplied as 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg or 40 mg tablets for oral administration. Each tablet contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate dihydrate, magnesium stearate, mannitol, povidone, pregelatinized starch (corn) and sodium lauryl sulfate. In addition, the 2.5 mg tablets contain FD&C Blue No. 2 Aluminum Lake, the 5 mg tablets contain FD&C Yellow No. 6 Aluminum Lake, the 20 mg tablets contain D&C Yellow No. 10 Aluminum Lake, the 30 mg tablets contain FD&C Blue No. 2 Aluminum Lake, and the 40 mg tablets contain D&C Yellow No. 10 Aluminum Lake and FD&C Blue No. 2 Aluminum Lake.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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 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 tablets 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 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 Clinical Studies (14.1)] . 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 tablets remains to be elucidated.

While the mechanism through which lisinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, lisinopril is antihypertensive even in patients with low-renin hypertension. Although lisinopril was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non Black patients.

Concomitant administration of lisinopril and hydrochlorothiazide further reduced blood pressure in Black and non-Black patients and any racial differences in blood pressure response were no longer evident.

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