Aliskiren (Tekturna) is the first oral medication in a new class of antihypertensive drugs known as direct renin inhibitors. Aliskiren is manufactured by Novartis Pharmaceuticals and was approved by the Food and Drug Administration in March 2007. The antihypertensive effects of aliskiren have been demonstrated in six randomized, double-blind, placebo-controlled 8-week clinical trials in patients with mild-to-moderate hypertension, and the drug has been evaluated for safety in more than 6,460 patients.1 Published information from the clinical studies is limited but a number of outcome studies are planned. Results from the proposed outcome studies should help in determining the role of aliskiren in the treatment of hypertension.2

Aliskiren is currently indicated only for the treatment of hypertension. The drug can be used as monotherapy, but it has been evaluated and may be used in combination with other antihypertensive medications. Aliskiren has not been evaluated for use in patients with congestive heart failure or diabetic nephropathy.2

Mechanism of Action

The mechanism of action for many of the current antihypertensive medications targets specific sites in the renin-angiotensin-aldosterone system (RAAS). For example, angiotensin-converting enzyme (ACE) inhibitors prevent angiotensin I from being converted to angiotensin II. Angiotensin receptor blockers block the angiotensin II receptor. The ultimate effect of RAAS stimulation is an increase in blood pressure through renal sodium absorption, aldosterone secretion, and an increase in arterial tone. In addition, through suppression of the negative feedback loop, many antihypertensive drugs also increase plasma renin concentration.

Aliskiren's mechanism of action is different in that it inhibits renin directly, and therefore, limits the conversion of angiotensinogen to angiotensin I. Whether aliskiren is used as monotherapy or in combination therapy, the effect of increased renin levels is blocked, so the plasma renin activity, angiotensin I, and angiotensin II are all reduced.1

Drug Metabolism

Aliskiren reaches peak plasma levels in about 1 to 3 hours after oral administration. A steady-state blood level is achieved in 7 to 8 days.1 Drug absorption is significantly decreased when taken at the same time as a high-fat meal. The exact process for the metabolism of aliskiren is unknown, but based on in vitro studies, hepatic and specifically the CYP3A4 enzymes are responsible for drug metabolism. Elimination of the drug is through excretion by the kidneys into the urine.

Contraindications

No pregnant women were used as subjects during clinical studies. However, because of the drug's mechanism of action, aliskiren is listed as a pregnancy Category C during the first trimester and pregnancy Category D in the second and third trimesters.1 It is also unknown whether the drug is excreted in breast milk, and caution is advised when considering the use of aliskiren in lactating women.

Patients with mild-to-moderate renal impairment or hepatic insufficiency were included in clinical trials and no adjustment in dosing was required. Patients with greater than moderate renal dysfunction, receiving dialysis, or with nephrotic syndrome have not been evaluated using aliskiren.2

Aliskiren has not been studied in the pediatric population; therefore, no specific recommendations can be made regarding the use of this drug in patients younger than 18 years of age. In clinical trials, geriatric patients were included (19% older than 65 years and 3.4% older than 75 years) and the manufacturer indicates the drug does not need dose adjustments solely due to increased age.1 In addition, race was not considered a significant factor based on the inclusion of African-Americans, Caucasians, and Japanese in clinical trials.

Drug interactions with aliskiren are related mostly to the drugs that are metabolized by the liver's CYP450 3A4 enzymes. Coadministration of irbesartan (Avapro) produced a 50% reduction, and with atorvastatin (Lipitor) a 50% increase in aliskiren concentration.2 When administered with ketoconazole, plasma levels of aliskiren were increased by 80%.1 Aliskiren does not inhibit or induce the CYP450 system and coadministration does not appear to affect the pharmacokinetics of lovastatin, digoxin, valsartan (Diovan), amlodipine, metformin, celecoxib (Celebrex), atenolol, atorvastatin, ramipril (Altace), or hydrochlorothiazide.1 Concomitant use of aliskiren and furosemide produced a reduced blood concentration of furosemide, which may reduce its intended effect.

Adverse Reactions

Angioedema, also associated with ACE inhibitor use, was reported in 28 cases (two with respiratory symptoms). The overall rate of face, hands, or whole body edema was 0.4% in the aliskiren-treated group as compared to 0.5% in the placebo.1 Patients should be informed of this potential reaction and be advised to seek immediate treatment for any symptoms of swelling.

The most common adverse reaction reported by clinical trial patients was diarrhea, and it appeared to be dose-related. Women and patients older than 65 years of age or those taking the higher (300 mg) dose were more likely to experience diarrhea.1 Reports of dyspepsia, gastroesoph-ageal reflux, and abdominal pain were also reported with the 600 mg dose.

Other adverse reactions in which the treatment group reported a higher incidence than the placebo group included: cough (1.1% vs. 0.6%), rash (1% vs. 0.3%), elevated uric acid (0.4% vs. 0.1%), gout (0.2% vs. 0.1%), and renal stones (0.2% vs. 0%).1 Episodes of severe hypotension were not a reported adverse reaction. Rare instances of changes in laboratory values were noted during the clinical studies.

Dosage and Administration

The recommended starting dose of aliskiren is 150 mg once daily. If after a 2-week trial at this dose, the blood pressure is not adequately controlled, the once-daily dose may be increased to 300 mg. Dosages above 300 mg have not been shown to significantly further reduce the blood pressure but did result in increased rates of diarrhea. No dosage adjustment is recommended for geriatric patients, those with mild-to-moderate renal impairment, or mild-to-moderate hepatic insufficiency. Patients should be advised to establish a consistent, daily dosing schedule and to avoid taking aliskiren with high-fat meals, as this may reduce drug absorption. The medication may be taken with or without food.

Aliskiren is supplied as an unscored, light-pink 150 mg or light-red 300 mg tablet. These may be packaged in unit-dose blister packs or in bottles and should be stored in a dry container at room temperature. The cost is approximately $2 to $3 per day.

Aliskiren may be given as monotherapy for treating hypertension or in conjunction with other antihypertensive medications. To date, aliskiren has been coadministered with the diuretic hydrochlorothiazide, valsartan, ramipril, and amlodipine. It has not been studied with maximal doses of ACE inhibitors.1

Special Instructions

Patients should be specifically advised to take the drug at the same time each day and not to take it with a high-fat meal. If a dose is missed, patients should take the drug as soon as possible. If it is close to the time of taking the next dose, the missed dose should be skipped. Providers are advised to carefully monitor their patients that are prescribed new drugs such as aliskiren, as new or more prominent adverse reactions may appear when dispensed to larger and more diverse populations. As with any new medication, patients should be given adequate information regarding their medication. Novartis has a patient information handout that is available at http://www.Tekturna.com.

Based on the limited published studies, aliskiren appears to be an effective and well-tolerated new medication for treating hypertension. Planned, future outcomes studies will help evaluate how this drug will fit in the overall guidelines for the treatment of hypertension.

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