Aliskiren

Pronunciation: (a-lis-KYE-ren)
Class: Direct renin inhibitor

Trade Names

Tekturna
- Tablets 150 mg
- Tablets 300 mg

Pharmacology

Aliskiren is a direct renin inhibitor, decreasing plasma renin activity and inhibiting conversion of angiotensinogen to angiotensin I.

All agents that inhibit the renin-angiotensin system suppress the negative feedback loop, leading to a compensatory rise in plasma renin concentration. Aliskiren blocks the clinical effect of increased renin levels.

Pharmacokinetics

Absorption

Bioavailability about 2.5%. Following oral administration, C _max is reached within 1 to 3 h. High-fat meals decrease AUC and C _max 71% and 85%, respectively. Steady-state blood levels are reached in approximately 7 to 8 days. Accumulation half-life is approximately 24 h.

Metabolism

Major enzyme responsible for aliskiren metabolism appears to be CYP3A4.

Elimination

Approximately 25% of the absorbed dose of the parent drug appears to be excreted in the urine.

Special Populations

Renal Function Impairment

Rate and extent of exposure did not show a consistent correlation with severity of renal function. Adjustment of the starting dose is not required.

Hepatic Function Impairment

Pharmacokinetics were not significantly affected in patients with mild to severe disease. Adjustment of the starting dose is not required.

Elderly

AUC is increased in elderly patients 65 yr of age and older. Adjustment of the starting dose is not required.

Race

Pharmacokinetic differences among black, white, and Japanese patients are minimal.

Indications and Usage

Treatment of hypertension, either alone or in combination with other antihypertensive agents.

Contraindications

None well documented.

Dosage and Administration

Adults

PO Initial dosage is 150 mg once daily. The daily dose may be increased to 300 mg in patients whose BP is not adequately controlled.

General Advice

Patients should establish a routine pattern for taking aliskiren with regard to meals.

Storage/Stability

Store at 59° to 86°F. Protect from moisture.

Drug Interactions

ACE inhibitors (eg, captopril)

Routinely monitor electrolytes and renal function when these agents are coadministered, especially in diabetic patients.

Atorvastatin

Aliskiren C _max and AUC may be increased approximately 50%, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response of the patient and adjust the aliskiren dose as needed.

Cyclosporine

Aliskiren plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Coadministration of aliskiren and cyclosporine is not recommended.

Drugs that increase potassium levels, potassium-sparing diuretics (eg, spironolactone), potassium supplements, salt substitutes containing potassium

Increased serum potassium may occur. Use with caution. Monitor electrolytes.

Food

High-fat meals substantially reduce aliskiren absorption (eg, AUC and C _max 71% and 85%, respectively). Patients should establish a routine pattern for taking aliskiren with regard to meals.

Furosemide

Blood concentrations may be reduced by aliskiren, decreasing furosemide efficacy. Monitor the diuretic response. Adjust the furosemide dose as needed.

Irbesartan

Aliskiren C _max may be reduced up to 50%, decreasing the pharmacologic effect. Use with caution and monitor BP. Adjust the aliskiren dose as needed.

Ketoconazole

Aliskiren plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Monitor the clinical response of the patient and adjust the aliskiren dose as needed.

Thiazide diuretics (eg, hydrochlorothiazide)

Additive increases in serum uric acid levels may occur. Use with caution, especially in patients at risk for hyperuricemia.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Dermatologic

Rash (1%).

GI

Diarrhea (2%).

Lab Tests

Elevated BUN or serum creatinine (less than 7%); increased serum potassium (6%); increased creatine kinase (1%).

Respiratory

Increased cough (1%).

Precautions

Warnings

Use during the second and third trimesters can cause injury and death to the developing fetus. When pregnancy is detected, discontinue therapy as soon as possible.

Monitor

Routinely monitor electrolytes and renal function in diabetic patients on concomitant ACE inhibitor therapy. Consider periodic determinations of serum electrolytes in patients with severe renal impairment.

Pregnancy

Category C (first trimester); Category D (second and third trimesters).

Lactation

Undetermined.

Children

Safety and efficacy not established.

Renal Function

Patients with more than moderate renal impairment (creatinine 1.7 mg/dL for women and 2 mg/dL for men, and/or estimated CrCl less than 30 mL/min), history of dialysis, nephrotic syndrome, or renovascular hypertension were excluded from clinical studies of aliskiren.

Angioedema

Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported and may occur during treatment.

Hyperkalemia

Increases in serum potassium occurred infrequently (0.9%), but were more frequent (5.5%) among patients with diabetes on aliskiren and ACE inhibitor therapy.

Hypotension

Rarely, excessive fall in BP may occur.

In-utero exposure

Closely observe infants for hypotension, oliguria, and hyperkalemia.

Renal artery stenosis

No data available on the use in patients with unilateral or bilateral artery stenosis or stenosis of the artery to a solitary kidney.

Overdosage

Symptoms

Possible hypotension.

Patient Information

Inform women of childbearing potential of the risk associated with aliskiren exposure during the second and third trimesters of pregnancy. Advise these patients to report pregnancy to health care provider as soon as possible.
Advise patient to immediately report swelling of the face, extremities, eyes, lips, or tongue, or difficulty in swallowing or breathing to health care provider and not to take another dose until doing so.
Inform patients that light-headedness may occur, especially during the first days of therapy, and to report it to health care provider. Advise patient to discontinue aliskiren if syncope occurs until health care provider has been consulted.
Advise patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light-headedness and syncope.
Advise patients not to use potassium supplements or salt substitutes containing potassium without consulting health care provider.
Instruct patients to establish a routine pattern for taking aliskiren with regard to meals. High-fat meals substantially decrease absorption.