"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
Mechanism of Action
The two components of LEXXEL (enalapril maleate-felodipine) have complementary antihypertensive actions. Enalapril is a pro-drug; following oral administration, it is bioactivated by hydrolysis of the ethyl ester to enalaprilat, which is the active angiotensin converting enzyme (ACE) inhibitor. Enalaprilat inhibits angiotensin-converting enzyme in humans 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 enalapril in hypertension 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. Although the latter decrease is small, it results in small increases of serum potassium. In hypertensive patients treated with enalapril maleate alone for up to 48 weeks, mean increases in serum potassium of approximately 0.2 mEq/L were observed. In patients treated with enalapril maleate plus a thiazide diuretic, there was essentially no change in serum potassium. (See PRECAUTIONS.) 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 enalapril maleate remains to be elucidated.
While the mechanism through which enalapril lowers blood pressure is believed to be primarily suppression of the renin- angiotensin-aldosterone system, enalapril is antihypertensive even in patients with low-renin hypertension. Although enalapril was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to enalapril monotherapy than non-black patients.
Felodipine is a dihydropyridine calcium channel blocker that reduces the influx of Ca++ by an effect on the voltage dependent L-channels in vascular smooth muscle and cultured rabbit atrial cells, and blocks potassium-induced contracture of the rat portal vein.
Pharmacologic studies show that the effects of felodipine on contractile processes are selective, with greater effects on vascular smooth muscle than cardiac muscle. Negative inotropic effects can be detected in vitro, but such effects have not been seen in intact animals.
The consequences of vasodilation produced by felodipine include a modest, short-lived reflex increase in heart rate. A mild diuretic effect is seen in several animal species and man, but most of the effects of felodipine are accounted for by its effects on peripheral vascular resistance.
Pharmacokinetics and Metabolism
Concomitant administration of enalapril and felodipine as an extended-release formulation has little effect on the bioavailability of either compound. The rate and extent of absorption of enalapril from LEXXEL (enalapril maleate-felodipine) is not significantly different from that of enalapril in VASOTEC* (enalapril maleate). The rate and extent of absorption of felodipine from LEXXEL (enalapril maleate-felodipine) has not been directly compared to the extended- release formulation of felodipine in PLENDIL** (felodipine).
Following oral administration of LEXXEL (enalapril maleate-felodipine) , peak concentrations of enalapril occur within about one hour. Enalapril is hydrolyzed to enalaprilat, which is a more potent angiotensin converting enzyme inhibitor than enalapril. Peak serum concentrations of enalaprilat occur about three hours after an oral dose of LEXXEL (enalapril maleate-felodipine) . Based on urinary recovery, the extent of absorption of enalapril is approximately 60%.
Peak concentrations of the isomers of felodipine are generally seen at 3-6 hours after administration of LEXXEL (enalapril maleate-felodipine) . Following oral administration, felodipine is almost completely absorbed and undergoes extensive first-pass metabolism; the systemic bioavailability of felodipine ER is approximately 20%.
When LEXXEL (enalapril maleate-felodipine) is taken with food (a substantial meal of 650 kcal or greater), some of the pharmacokinetics of its components are changed. Although the AUC(0-48 hr) of felodipine is not changed, the peak concentration of its isomers is almost doubled, and the trough concentration is approximately halved. The bioavailability of enalapril, as measured by total urinary recovery of enalaprilat, is slightly reduced. As with other dihydropyridine calcium channel blockers, the bioavailability of felodipine was increased when taken with grapefruit juice, compared to when taken with water or orange juice.
The systemic plasma clearance of felodipine in young healthy subjects is about 0.8 L/min, and the apparent volume of distribution is 10 L/kg. Approximately 99% of felodipine is bound to plasma proteins.
Following administration of 14C-labeled intravenous or immediate-release oral felodipine in man, about 70% of the dose of radioactivity was recovered in urine and 10% in the feces. A negligible amount of intact felodipine was recovered in the urine and feces ( < 0.5%). Six metabolites, which account for 23% of the oral dose, have been identified; none has significant vasodilating activity. Following oral administration of the immediate-release formulation, the plasma levels of felodipine declined polyexponentially with a mean terminal half-life of 11 to 16 hours.
Excretion of enalaprilat and enalapril is primarily renal. Approximately 94% of the dose is recovered in the urine and feces as enalaprilat or enalapril. The principal components in urine are enalaprilat, accounting for about 40% of the dose, and intact enalapril. There is no evidence of metabolites of enalapril, other than enalaprilat. The serum concentration profile of enalaprilat exhibits a prolonged terminal phase, apparently representing a small fraction of the administered dose that has been bound to ACE. The amount bound does not increase with dose, indicating a saturable site of binding. The effective half-life for accumulation of enalaprilat following multiple doses of enalapril maleate is 11 hours.
The disposition of enalapril and enalaprilat in patients with renal insufficiency is similar to that in patients with normal renal function until the glomerular filtration rate is reduced to 30 mL/min or less. With glomerular filtration rate ≤ 30 mL/min, peak and trough enalaprilat levels increase, time to peak concentration increases, and time to steady state may be delayed. The effective half-life of enalaprilat following multiple doses of enalapril maleate is prolonged at this level of renal insufficiency. Enalaprilat is dialyzable at a rate of 62 mL/min.
Plasma concentrations of felodipine, after a single dose and at steady state, increase with age. Mean clearance of felodipine in elderly hypertensives (mean age 74) was only 45% of that for young volunteers (mean age 26). At steady state, the mean AUC for young patients was 39% of that for the elderly. Data for intermediate age ranges suggest that the AUCs fall between the extremes of the young and the elderly.
In patients with hepatic disease, the clearance of felodipine was reduced to about 60% of that seen in normal young volunteers.
Blood Brain Barrier and Blood Placental Barrier- Animal studies have shown that felodipine crosses the blood brain barrier. The plasma to brain concentration ratio of felodipine is about 20:1. Felodipine crosses the placenta. Fetal plasma levels of felodipine are similar to maternal plasma levels. Studies in dogs indicate that enalapril crosses the blood brain barrier poorly, if at all; enalaprilat does not enter the brain. Multiple doses of enalapril maleate in rats do not result in accumulation in any tissues. Milk of lactating rats contains radioactivity following administration of 14C enalapril maleate. Radioactivity was found to cross the placenta following administration of labeled drug to pregnant hamsters.
Administration of enalapril maleate to patients with hypertension of severity ranging from mild to severe results in a reduction of both supine and standing blood pressure, usually with no orthostatic component. Symptomatic postural hypotension is infrequent with enalapril alone, although it might be anticipated in volume-depleted patients. (See WARNINGS.) In most patients studied, after oral administration of a single dose of enalapril, onset of antihypertensive activity was seen at one hour, with peak reduction of blood pressure achieved by 4 to 6 hours. At recommended doses, antihypertensive effects have been maintained for at least 24 hours. In some patients the effects may diminish toward the end of the dosing interval.
In most patients, achievement of optimal blood pressure reduction may require several weeks of therapy. The antihypertensive effects of enalapril have continued during long-term therapy. Abrupt withdrawal of enalapril has not been associated with a rapid increase in blood pressure. In hemodynamic studies in patients with essential hypertension, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance with an increase in cardiac output and little or no change in heart rate. Following administration of enalapril maleate, there is an increase in renal blood flow; glomerular filtration rate is usually unchanged. The effects appear to be similar in patients with renovascular hypertension.
In a clinical pharmacology study, indomethacin or sulindac was administered to hypertensive patients receiving enalapril. In this study there was no evidence of a blunting of the antihypertensive action of enalapril. (See PRECAUTIONS: DRUG INTERACTIONS.)
The effect of felodipine on blood pressure is principally a consequence of a dose-related decrease in peripheral vascular resistance. Blood pressure response following administration of felodipine ER to hypertensive patients is correlated with dose and plasma concentrations of felodipine. A reduction in blood pressure generally occurs within 2 to 5 hours. During chronic administration, substantial blood pressure control lasts for 24 hours, with trough reductions in diastolic blood pressure approximately 40-50% of peak reductions. A reflex increase in heart rate frequently occurs during the first week of therapy; this increase attenuates over time. Heart rate increases of 5-10 beats per minute may be seen during chronic dosing. The increase is inhibited by beta-blocking agents.
Felodipine has no significant effect on cardiac conduction (P-R, P-Q, and H-V intervals). In clinical trials in hypertensive patients without clinical evidence of left ventricular dysfunction, no symptoms suggestive of a negative inotropic effect were noted; however, none would be expected in this population.
In an 8-week, fixed-dose, parallel-group, double-blind study, 707 hypertensive patients were randomized among all possible combinations of enalapril (0, 5, or 20 mg), and extended- release felodipine (0, 2.5, 5, or 10 mg), both taken once daily. Each of the non-placebo combinations was significantly more effective than placebo in reducing seated systolic and diastolic blood pressure at peak (3 to 5 hours after dosing) and trough (24 hours after dosing). Enalapril and felodipine contributed additively to the effect, so that each active-active combination was significantly more effective than either of its component monotherapies. Most of the drug effect seen at peak was still present at trough. The efficacy of combination therapy relative to monotherapy was not significantly affected by race, sex, or age.
During chronic dosing with LEXXEL (enalapril maleate-felodipine) , the maximum reduction in blood pressure is generally achieved after one to two weeks. The antihypertensive effects of LEXXEL (enalapril maleate-felodipine) have continued during chronic therapy for at least one year.
Last reviewed on RxList: 10/25/2007
This monograph has been modified to include the generic and brand name in many instances.
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