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Amturnide

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Amturnide




CLINICAL PHARMACOLOGY

Mechanism Of Action

Amturnide

The effects of combined treatment of aliskiren, amlodipine and HCTZ arise from the actions of these 3 agents on different but complementary mechanisms that regulate blood pressure. Together, inhibition of the RAAS, inhibition of calcium channel-mediated vasoconstriction, and increase of sodium chloride excretion lowers blood pressure to a greater degree than the individual components.

Aliskiren

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 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

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.

HCTZ

The mechanism of action of the antihypertensive effect of thiazides is unknown.

HCTZ is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of HCTZ reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of agents that block the production or function of angiotensin II tends to reverse the potassium loss associated with these diuretics.

Pharmacodynamics

Amturnide

In an active-controlled trial which established the clinical efficacy of Amturnide in hypertensive patients, Amturnide was associated with a 34% reduction in PRA compared to a 63% reduction with aliskiren/amlodipine, 64% reduction with aliskiren/HCTZ and a 170% elevation with amlodipine/HCTZ.

Aliskiren

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.

Amlodipine

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 coadministered 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 H-V 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.

HCTZ

After oral administration of HCTZ, diuresis begins within 2 hours, peaks in about 4 hours, and lasts about 6 to 12 hours.

Drug Interactions

Hydrochlorothiazide (HCTZ)

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal muscle relaxants: Possible increased responsiveness to muscle relaxants such as curare derivatives.

Digitalis glycosides: Thiazide-induced hypokalemia or hypomagnesemia may predispose the patient to digoxin toxicity.

Pharmacokinetics

Absorption and Distribution

Amturnide

Following oral administration of the fixed combination of aliskiren, amlodipine, and HCTZ, peak concentrations were achieved within 1 to 2 hours, 6 to 12 hours, and 1 to 4 hours for aliskiren, amlodipine and HCTZ, respectively. The rate and extent of absorption of aliskiren, amlodipine, and HCTZ following administration of the fixed combination are similar to when they are administered as individual dosage forms.

When Amturnide is taken with food, mean AUC and Cmax of aliskiren are decreased by 78% and 89%, respectively. There is no impact of food on the exposures of amlodipine and HCTZ.

Aliskiren

Aliskiren is poorly absorbed (bioavailability about 2.5%). 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 of aliskiren, it was administered without requiring a fixed relation of administration to meals.

Amlodipine

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.

HCTZ

The estimated absolute bioavailability of HCTZ after oral administration is about 70%. Peak plasma HCTZ concentrations (Cmax) are reached within 2 to 5 hours after oral administration. There is no clinically significant effect of food on the bioavailability of HCTZ.

HCTZ binds to albumin (40% to 70%) and distributes into erythrocytes. Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Metabolism and Elimination

Aliskiren

The effective half-life for aliskiren is 24 hours. Steady state blood levels are reached in about 7 to 8 days. 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.

Transporters: Pgp (MDR1/Mdr1a/1b) was found to be the major efflux system involved in absorption and disposition 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.

Amlodipine

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.

HCTZ

About 70% of an orally administered dose of HCTZ is eliminated in the urine as unchanged drug.

Drug Interactions

Aliskiren

The effects 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 1 (impact of coadministered drugs on aliskiren) and Figure 2 (impact of aliskiren on coadministered drugs).

Figure 1: The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren

The Impact of Coadministered Drugs on the Pharmacokinetics of Aliskiren - Illustration

*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 2: The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs

The Impact of Aliskiren on the Pharmacokinetics of Coadministered Drugs - Illustration

*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: 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

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine: Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit juice: 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.

Maalox® (antacid): Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil: 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.

Atorvastatin: 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.

Digoxin: Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol): Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin: Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Simvastatin: 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.

CYP3A inhibitors: 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.

Hydrochlorothiazide (HCTZ)

Drugs that alter gastrointestinal motility: The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate. Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.

Cholestyramine: In a dedicated drug interaction study, administration of cholestyramine 2 hours before HCTZ resulted in a 70% reduction in exposure to HCTZ. Further, administration of HCTZ 2 hours before cholestyramine, resulted in 35% reduction in exposure to hydrochlorothiazide.

Antineoplastic agents (e.g., cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Special Populations

Pediatric Patients

The pharmacokinetics of Amturnide have not been investigated in patients younger than 18 years of age.

Geriatric Patients

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 (65 years and older) 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. Limited data suggest that the systemic clearance of HCTZ is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers [see Use in Specific Populations].

Race

With Amturnide, pharmacokinetic differences due to race have not been studied. The pharmacokinetic differences among blacks, Caucasians, and Japanese are minimal with aliskiren therapy.

Hepatic Impairment

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 WARNINGS AND PRECAUTIONS and Use in Specific Populations].

Renal Impairment

The pharmacokinetics of aliskiren were 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 matched 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.

The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.

In a study in individuals with impaired renal function, the mean elimination half-life of HCTZ was doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90 mL/min) and tripled in severe renal impairment (CrCl less than or equal to 30 mL/min), compared to individuals with normal renal function (CrCl greater than 90 mL/min) [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Animal Toxicology And/Or Pharmacology

Reproductive Toxicology Studies

[See Use In Specific Populations]

Clinical Studies

Amturnide

Amturnide was studied in a double-blind, active-controlled study in 1181 treated hypertensive patients, of whom 773 were classified as moderately hypertensive (SBP 160 to 180 mmHg) and 408 as severely hypertensive (SBP 180 to 200 mmHg) at baseline. The mean baseline systolic/diastolic blood pressure for all randomized patients was approximately 173/105 mmHg. A total of 61% of patients were male, 19% were 65 years or older, 84% were Caucasian, and 10% were black.

At study initiation, patients assigned to the dual combination treatments received lower doses of their treatment combination (aliskiren 150 mg plus amlodipine 5 mg, aliskiren 150 mg plus HCTZ 12.5 mg, or amlodipine 5 mg plus HCTZ 12.5 mg), while patients assigned to the Amturnide arm received aliskiren/HCTZ 150/12.5 mg. After 3 days, Amturnide patients were titrated to aliskiren/amlodipine/HCTZ 150/5/12.5 mg, while all other patients continued receiving their initial doses. After 4 weeks, all patients were titrated to their full target doses of aliskiren/amlodipine/HCTZ 300/10/25 mg, aliskiren/amlodipine 300/10, aliskiren/HCTZ 300/25 mg, or amlodipine/HCTZ 10/25 mg.

Amturnide produced greater reductions in blood pressure than did any of the 3 dual combination treatments (p value less than 0.001 for both diastolic and systolic blood pressure reductions). The reductions in systolic/diastolic blood pressure with Amturnide were 9.9/6.3 mmHg greater than with aliskiren/HCTZ, 7.2/3.6 mmHg greater than with amlodipine/HCTZ, and 6.6/2.6 mmHg greater than with aliskiren/amlodipine.

In the severe hypertensive patients, Amturnide produced greater reductions in blood pressure than each of the 3 dual combination treatments (p value less than 0.001 for both diastolic and systolic blood pressure reductions). The reductions in systolic/diastolic blood pressure with Amturnide were 16.3/8.2 mmHg greater than with aliskiren/HCTZ, 9.6/4.8 mmHg greater than with amlodipine/HCTZ, and 11.4/4.9 mmHg greater than with aliskiren/amlodipine.

The distribution of reductions in blood pressure on each treatment are shown in Figure 3 for diastolic blood pressure and in Figure 4 for systolic blood pressure. For example, Figure 3 shows that 50% of patients on Amturnide had more than 20.2 mmHg reduction in diastolic blood pressure compared to 18.7 mmHg on aliskiren/amlodipine combination, 12.7 mmHg on aliskiren/HCTZ combination, and 15.3 mmHg on amlodipine/HCTZ combination. Similarly, Figure 4 shows that 50% of patients on Amturnide had more than 36.3 mmHg reduction in systolic blood pressure compared to 30.8 mmHg on aliskiren/amlodipine combination, 28.3 mmHg on aliskiren/HCTZ combination, and 31.0 mmHg on amlodipine/HCTZ combination. The time course over which blood pressure effects developed is shown in Figures 5 and 6. As the trial had no placebo control, the treatment effects shown in Figures 3–6 include a placebo effect of unknown size.

The antihypertensive effect of Amturnide was similar in patients with and without diabetes, obese and non-obese patients, in patients 65 years of age and older and less than 65 years of age, and in women and men.

Figure 3: Distribution of Diastolic Blood Pressure Responses on Amturnide and Combinations of Two Drugs

Distribution of Diastolic Blood Pressure Responses on Amturnide and Combinations of Two Drugs - Illustration

Figure 4: Distribution of Systolic Blood Pressure Responses on Amturnide and Combinations of Two Drugs

Distribution of Systolic Blood Pressure Responses on Amturnide and Combinations of Two Drugs - Illustration

Figure 5: Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Clock Hour

Mean Ambulatory Diastolic Blood Pressure at Endpoint by Treatment and Clock Hour - Illustration

Figure 6: Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Clock Hour

Mean Ambulatory Systolic Blood Pressure at Endpoint by Treatment and Clock Hour - Illustration

There are no trials of the Amturnide triple combination tablet demonstrating reductions in cardiovascular risk in patients with hypertension, but 2 of the components, amlodipine and HCTZ, have 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 Table 2.

Table 2: Incidence of Selected Adverse Events During the Treatment Phase in ALTITUDE

  Aliskiren
N=4272
Placebo
N=4285
Serious Adverse Events* (%) Adverse Events (%) Serious Adverse Events* (%) Adverse Events (%)
Renal impairment † 5.7 14.5 4.3 12.4
Hypotension †† 2.3 19.9 1.9 16.3
Hyperkalemia††† 1.0 38.9 0.5 28.8
†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: 1/3/2016
This monograph has been modified to include the generic and brand name in many instances.

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