Ramipril Information
Ramipril ()
Ramipril () Dosage And Administration
Generally, swallow Ramipril () capsules whole. The Ramipril () capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that Ramipril () is not lost when such a mixture is used, the mixture should be consumed in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of Ramipril () with potassium supplements, potassium salt substitutes, or potassiumÂsparing diuretics can lead to increases of serum potassium [see (5.8)].
Ramipril () Dosage Forms And Strengths
Ramipril () Capsules USP are supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg and 10 mg of Ramipril () .
Ramipril () Contraindications
Ramipril () Capsules USP are contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).
Ramipril () Warnings And Precautions
Rarely, ACE inhibitors, including Ramipril () , have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue Ramipril () if patient develops jaundice or marked elevations of hepatic enzymes.
As Ramipril () is primarily metabolized by hepatic esterases to its active moiety, Ramipril () at, patients with impaired liver function could develop markedly elevated plasma levels of Ramipril () . No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.
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 ACE inhibitors, including Ramipril () , may be associated with oliguria or progressive azotemia and rarely with acute renal failure 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 ACE inhibitor suggests that these increases would be reversible upon discontinuation of Ramipril () and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Ramipril () has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Ramipril () and/or discontinuation of the diuretic may be required.
Angiotensin converting enzyme 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, discontinue ACE inhibitors 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; 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 caused by the ACE inhibitor exposure.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been confirmed.
Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin-aldosterone system will be found. In these rare cases, inform mothers about the potential hazards to their fetuses, and perform serial ultrasound examinations to assess the intraamniotic environment.
If oligohydramnios is observed, discontinue Ramipril () unless it is considered lifeÂsaving for the mother. Contraction stress testing, a nonÂstress test, or biophysical profiling 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.
Closely observe infants with histories of exposure to ACE inhibitors for hypotension, oliguria, and hyperkalemia. If oliguria occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril () , which crosses the placenta can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.
Ramipril () Drug Interactions
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Ramipril () . The possibility of hypotensive effects with Ramipril () can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Ramipril () . If this is not possible, reduce the starting dose [see (2)].
Ramipril () can attenuate potassium loss caused by thiazide diuretics. PotassiumÂsparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
Limited experience in controlled and uncontrolled trials combining Ramipril () with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
The combination of Ramipril () and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
In a large-scale, long-term clinical efficacy study, the combination of telmisartan and Ramipril () resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and Ramipril () is not recommended [see (5.7)].
Neither Ramipril () nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of Ramipril () and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, coÂadministration of Ramipril () with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients’ state of anticoagulation.
Rarely, concomitant treatment with ACE inhibitors and nonsteroidal anti-inflammatory agents have been associated with worsening of renal failure and an increase in serum potassium.
Ramipril () Use In Specific Populations
Of the total number of patients who received Ramipril () in US clinical studies of Ramipril () 11% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak Ramipril () at levels and area under the plasma concentration-time curve (AUC) for Ramipril () at are higher in older patients.
Ramipril () Overdosage
Single oral doses of Ramipril () in rats and mice of 10 g/kg to 11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of Ramipril () and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of Ramipril () overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of Ramipril () and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonistÂantidote in the setting of Ramipril () overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of Ramipril () is achieved through vasodilation and effective hypovolemia, it is reasonable to treat Ramipril () overdose by infusion of normal saline solution.
Ramipril () Description
Ramipril () is a 2ÂazaÂbicyclo [3.3.0]ÂoctaneÂ3Âcarboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril () melts between 105°C to 112°C.
Ramipril () 's chemical name is (2)Â1-[()Â[()Â1-CarboxyÂ3Âphenylpropyl] alanyl] octahydrocyclopenta []pyrroleÂ2Âcarboxylic acid, 1Âethyl ester.
The inactive ingredients present are pregelatinized starch, gelatin, and titanium dioxide. In addition to the ingredients listed above, the 1.25 mg capsule shell contains D&C yellow #10 and FD&C yellow #6, the 2.5 mg capsule shell contains FD&C yellow #6, the 5 mg capsule shell contains D&C red #28, FD&C blue #1 and FD&C yellow #6, and the 10 mg capsule shell contains D&C red #28 and FD&C blue #1. The ink contains ethanol, FD&C blue #2, FD&C red #40, FD&C yellow#6, iron oxide black, n-butyl alcohol, propylene glycol, and shellac glaze.
The structural formula for Ramipril () is:
Its molecular formula is CHNO, and its molecular weight is 416.51.
Ramipril () at, the diacid metabolite of Ramipril () , is a nonÂsulfhydryl ACE inhibitor. Ramipril () is converted to Ramipril () at by hepatic cleavage of the ester group.
Ramipril () Clinical Pharmacology
Ramipril () and Ramipril () at inhibit ACE in human subjects and animals. Angiotensin converting enzyme 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. 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 Ramipril () alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with Ramipril () and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
The effect of Ramipril () on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.
Angiotensin converting enzyme 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 Ramipril () remains to be elucidated.
While the mechanism through which Ramipril () lowers blood pressure is believed to be primarily suppression of the reninÂangiotensinÂaldosterone system, Ramipril () has an antihypertensive effect even in patients with lowÂrenin hypertension. Although Ramipril () was antihypertensive in all races studied, Black hypertensive patients (usually a lowÂrenin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than nonÂBlack patients.
Ramipril () How Supplied/storage And Handling
Ramipril () Capsules USP are available in potencies of 1.25 mg, 2.5 mg, 5 mg, and 10 mg in hard gelatin capsules.
Ramipril () Capsules USP, 1.25 mg are supplied as yellow opaque capsules with "54 328" printed in black ink.
Ramipril () Capsules USP, 2.5 mg are supplied as orange opaque capsules with "54 794" printed in black ink.
Ramipril () Capsules USP, 5 mg are supplied as red opaque capsules with "54 145" printed in black ink.
Ramipril () Capsules USP, 10 mg are supplied as blue opaque capsules with "54 602" printed in black ink.
Ramipril () Patient Counseling Information
Inform patients that lightheadedness can occur, especially during the first days of therapy, and it should be reported. Advise patients to discontinue Ramipril () if syncope (fainting) occurs, and to follow up with their health care providers.
Inform patients that inadequate fluid intake or excessive perspiration, diarrhea, or vomiting while taking Ramipril () can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.
Advise patients not to use salt substitutes containing potassium without consulting their physician.
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10004223/05
Revised February 2011
© RLI, 2011
Ramipril () Principal Display Panel
Roxane Laboratories, Inc.
Ramipril () Capsules USP, 1.25 mg
NDC 0054-0106-25
Ramipril () Principal Display Panel
Roxane Laboratories, Inc.
Ramipril () Capsules USP, 2.5 mg
NDC 0054-0107-25
Ramipril () Principal Display Panel
Roxane Laboratories, Inc.
Ramipril () Capsules USP, 5 mg
NDC 0054-0108-25
Ramipril () Principal Display Panel
Roxane Laboratories, Inc.
Ramipril () Capsules USP, 10 mg
NDC 0054-0109-25
