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The study shows that within hours of drinking it, beet juice lowered systolic blood pressure (the top n"...
Mechanism Of Action
Renin is secreted by the kidney in response to decreases in blood volume and renal perfusion. Renin cleaves angiotensinogen to form the inactive decapeptide angiotensin I (Ang I). Ang I is converted to the active octapeptide angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) and non-ACE pathways. Ang II is a powerful vasoconstrictor and leads to the release of catecholamines from the adrenal medulla and prejunctional nerve endings. It also promotes aldosterone secretion and sodium reabsorption. Together, these effects increase blood pressure. Ang II also inhibits renin release, thus providing a negative feedback to the system. This cycle, from renin through angiotensin to aldosterone and its associated negative feedback loop, is known as the renin-angiotensin-aldosterone system (RAAS). Aliskiren is a direct renin inhibitor, decreasing plasma renin activity (PRA) and inhibiting the conversion of angiotensinogen to Ang I. Whether aliskiren affects other RAAS components, e.g., ACE or non-ACE pathways, is not known.
All agents that inhibit the RAAS, including renin inhibitors, suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. When this rise occurs during treatment with ACEIs and ARBs, the result is increased levels of PRA. During treatment with aliskiren, however, the effect of increased renin levels is blocked, so that PRA, Ang I and Ang II are all reduced, whether aliskiren is used as monotherapy or in combination with other antihypertensive agents.
Amlodipine is a dihydropyridine calcium channel blocker that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.
The effects of combined treatment of aliskiren and amlodipine arise from the actions of these 2 agents on different, but complementary mechanisms that regulate blood pressure, calcium channel-mediated vasoconstriction and RAAS-mediated effects on vascular tone and sodium excretion.
PRA reductions in clinical trials ranged from approximately 50% to 80%, were not dose-related and did not correlate with blood pressure reductions. The clinical implications of the differences in effect on PRA are not known.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.
With chronic once daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105 mmHg to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 mmHg to 104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In patients with chronic stable angina, intravenous administration of 10 mg did not significantly alter A-H and HV conduction and sinus node recovery time after pacing. Similar results were obtained in patients receiving amlodipine and concomitant beta-blockers. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects of electrocardiographic parameters were observed. In clinical trials with angina patients alone, amlodipine therapy did not alter electrocardiographic intervals or produce higher degrees of AV blocks.
Amlodipine has indications other than hypertension which can be found in the Norvasc® package insert.
In a placebo-controlled study in hypertensive patients, amlodipine was associated with an increase in PRA (59% to 73% increase) whereas aliskiren monotherapy was associated with a 61% to 68% reduction in PRA. Aliskiren in combination with amlodipine reduced PRA (55% to 68% reduction).
Absorption And Distribution
Following oral administration of the aliskiren/amlodipine combination tablets, the median peak plasma concentration times are within 3 hours for aliskiren and 8 hours for amlodipine. The rate and extent of absorption of aliskiren and amlodipine from Tekamlo are the same as when administered as individual tablets. When taken with food, mean AUC and Cmax of aliskiren are decreased by 79% and 90%, respectively, while there is no impact of food on the AUC and Cmax of amlodipine.
Aliskiren is poorly absorbed (bioavailability about 2.5%) with an accumulation half-life of about 24 hours. Steady state blood levels are reached in about 7 to 8 days. Following oral administration, peak plasma concentrations of aliskiren are reached within 1 to 3 hours. When taken with a high fat meal, mean AUC and Cmax of aliskiren are decreased by 71% and 85% respectively. In the clinical trials, aliskiren was administered without a fixed relation to meals.
Peak plasma concentrations of amlodipine are reached 6 to 12 hours after an oral administration of amlodipine. Absolute bioavailability has been estimated to be between 64% and 90%. The bioavailability of amlodipine is not altered by the presence of food.
The apparent volume of distribution of amlodipine is about 21 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.
Metabolism And Elimination
About one-fourth of the absorbed dose appears in the urine as parent drug. How much of the absorbed dose is metabolized is unknown. Based on the in vitro studies, the major enzyme responsible for aliskiren metabolism appears to be CYP3A4. Aliskiren does not inhibit the CYP450 isoenzymes (CYP 1A2, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A) or induce CYP3A4.
Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in intestinal absorption and elimination via biliary excretion of aliskiren in preclinical studies. The potential for drug interactions at the Pgp site will likely depend on the degree of inhibition of this transporter.
The effect of coadministered drugs on the pharmacokinetics of aliskiren and vice versa, were studied in several single and multiple dose studies. Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 5 (impact of coadministered drugs on aliskiren) and Figure 6 (impact of aliskiren on coadministered drugs).
Figure 5: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren
*Ketoconazole : A 400 mg once daily dose was not studied, but would be expected to increase aliskiren blood levels further.
**Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see DRUG INTERACTIONS]. Warfarin: There was no clinically significant effect of a single dose of warfarin 25 mg on the pharmacokinetics of aliskiren.
Figure 6: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs
*Furosemide: Patients receiving furosemide may find its effects diminished after starting aliskiren. In patients with heart failure, coadministration of aliskiren (300 mg/day) reduced plasma AUC and Cmax of oral furosemide (60 mg/day) by 17% and 27%, respectively, and reduced 24 hour urinary furosemide excretion by 29%. This change in exposure did not result in statistically significant difference in total urine volume and urinary sodium excretion over 24 hours. However, a transient decrease in urinary sodium excretion and urine volume effects up to 12 hours were observed when furosemide was coadministered with aliskiren 300 mg/day. **Ramipril, valsartan, irbesartan: In general, avoid combined use of aliskiren with ACE inhibitors or ARBs, particularly in patients with CrCl less than 60 mL/min [see DRUG INTERACTIONS].
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination of amlodipine from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Steady state plasma levels are reached after once-daily dosing for 7 to 8 days.
Aliskiren exposure is increased slightly (AUC increased 29%) when aliskiren is coadministered with amlodipine, while amlodipine exposure remains unchanged when coadministered with aliskiren. The slight exposure increase of aliskiren in the presence of amlodipine is not clinically relevant.
In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.
Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.
Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.
The pharmacokinetics of Tekamlo have not been investigated in patients younger than 18 years of age.
Impact of aging on aliskiren pharmacokinetics has been assessed. When compared to young adults (18 to 40 years), aliskiren mean AUC and Cmax in elderly subjects (older than 65 years) are increased by 57% and 28%, respectively. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve [see Use In Specific Populations].
With Tekamlo, pharmacokinetic differences due to race have not been studied. The pharmacokinetic differences among blacks, Caucasians, and Japanese are minimal with aliskiren therapy.
The pharmacokinetics of aliskiren is not significantly affected in patients with mild-to-severe liver disease. Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40% to 60% [see Use In Specific Populations].
The pharmacokinetics of aliskiren was evaluated in patients with varying degrees of renal impairment. Rate and extent of exposure (AUC and Cmax) of aliskiren in subjects with renal impairment did not show a consistent correlation with the severity of renal impairment.
The pharmacokinetics of aliskiren following administration of a single oral dose of 300 mg was evaluated in patients with End Stage Renal Disease (ESRD) undergoing hemodialysis. When compared to healthy subjects, changes in the rate and extent of aliskiren exposure (Cmax and AUC) in ESRD patients undergoing hemodialysis were not clinically significant. Timing of hemodialysis did not significantly alter the pharmacokinetics of aliskiren in ESRD patients.
Animal Toxicology And/Or Pharmacology
Preclinical safety studies have demonstrated that the combination of aliskiren hemifumarate and amlodipine besylate was well tolerated in rats. The findings from the 2-and 13-week oral toxicity studies in rats were consistent with those of aliskiren hemifumarate and amlodipine besylate when both drugs were administered alone. There were no new toxicities or increased severity of the toxicities which were associated with either component.
Animal reproductive and developmental toxicology findings are described elsewhere [see Use In Specific Populations].
Juvenile toxicity studies indicated increased systemic exposure to aliskiren 85-to 385-fold in 14 day and 8 day old rats respectively, compared with adult rats. The mdr1 gene expression in juvenile rats was also significantly lower when compared to adult rats. The increased aliskiren exposure in juvenile rats appears to be mainly attributed to lack of maturation of P-gp. The overexposure in juvenile rats was associated with high mortality [see Use In Specific Populations].
Tekamlo was studied in a total of 5549 patients with mild to moderate hypertension (diastolic blood pressure between 90 mmHg and 109 mmHg).
Aliskiren 150 mg and 300 mg and amlodipine besylate 5 mg and 10 mg were studied alone and in combination in an 8-week, randomized, double-blind, placebo-controlled, multifactorial study comparing the combinations 150 mg/5 mg, 150 mg/10 mg, 300 mg/5 mg and 300 mg/10 mg of aliskiren and amlodipine with their components and placebo. The combination of aliskiren and amlodipine resulted in placebo-adjusted decreases in systolic/diastolic blood pressure at trough of 14–17/9–11 mmHg compared to 4–9/3–5 mmHg for aliskiren alone and 9–14/6–8 mmHg for amlodipine alone.
Treatment with Tekamlo resulted overall in significantly greater reductions in diastolic and systolic blood pressure compared to the respective monotherapy components.
The antihypertensive effect of Tekamlo was similar in patients with and without diabetes, obese and non-obese patients, in patients 65 years of age or older and under 65 years of age, and in women and men.
A subgroup of 819 patients was studied with ambulatory blood pressure monitoring. The blood pressure lowering effect in the aliskiren/amlodipine group was maintained throughout the 24-hour period (see Figure 7 and Figure 8).
Figure 7: Mean Ambulatory Diastolic Blood Pressure (DBP) at Endpoint by Treatment and Hour
Figure 8: Mean Ambulatory Systolic Blood Pressure (SBP) at Endpoint by Treatment and Hour
Two additional double-blind, active-controlled studies of similar design were conducted in which Tekamlo was administered as initial therapy in patients with moderate to severe hypertension (SBP 160 mmHg to 200 mmHg). Patients were randomized to receive either combination aliskiren/amlodipine or amlodipine monotherapy. The initial dose of aliskiren/amlodipine was 150 mg/5 mg for 1 week with forced titration to 300 mg/10 mg for 7 weeks. The initial dose of amlodipine was 5 mg for 1 week with forced titration to 10 mg for 7 weeks. In one study of 443 black patients, at the primary endpoint of 8 weeks, the treatment difference between aliskiren/amlodipine and amlodipine was 5.2/3.8 mmHg. In the other study of 484 patients, at the primary endpoint of 8 weeks, the treatment difference between aliskiren/amlodipine and amlodipine was 7.1/3.8 mmHg.
The blood pressure lowering effects of Tekamlo are largely attained within 1 to 2 weeks.
There are no trials of the Tekamlo combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but the amlodipine component has demonstrated such benefits.
Aliskiren In Patients With Diabetes Treated With ARB Or ACEI (ALTITUDE Study)
Patients with diabetes with renal disease (defined either by the presence of albuminuria or reduced GFR) were randomized to aliskiren 300 mg daily (n=4296) or placebo (n=4310). All patients were receiving background therapy with an ARB or ACEI. The primary efficacy outcome was the time to the first event of the primary composite endpoint consisting of cardiovascular death, resuscitated sudden death, nonfatal myocardial infarction, nonfatal stroke, unplanned hospitalization for heart failure, onset of end stage renal disease, renal death, and doubling of serum creatinine concentration from baseline sustained for at least 1 month. After a median follow-up of about 32 months, the trial was terminated early for lack of efficacy. Higher risk of renal impairment, hypotension and hyperkalemia was observed in aliskiren compared to placebo treated patients, as shown in the Table 1.
Table 1: Incidence of Selected Adverse Events During the Treatment Phase in ALTITUDE
|Serious Adverse Events* (%)||Adverse Events (%)||Serious Adverse Events* (%)||Adverse Events (%)|
|Renal impairment †||5.7||14.5||4.3||12.4|
|†renal failure, renal failure acute, renal failure chronic, renal impairment
††dizziness, dizziness postural, hypotension, orthostatic hypotension, presyncope, syncope
††† Given the variable baseline potassium levels of patients with renal insufficiency on dual RAAS therapy, the reporting of adverse event of hyperkalemia was at the discretion of the investigator.
* A Serious Adverse Event (SAE) is defined as an event which is fatal or life-threatening, results in persistent or significant disability/incapacity, constitutes a congenital anomaly/birth defect, requires inpatient hospitalization or prolongation of existing hospitalization, or is medically significant (i.e., defined as an event that jeopardizes the patient or may require medical or surgical intervention to prevent one of the outcomes previously listed).
The risk of stroke (3.4% aliskiren versus 2.7% placebo) and death (8.4% aliskiren versus 8.0% placebo) were also numerically higher in aliskiren-treated patients.
Last reviewed on RxList: 1/30/2017
This monograph has been modified to include the generic and brand name in many instances.
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