Pharmacology Update

Aliskiren and Hydrochlorothiazide Tablets (Tektura®HCT)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The combination of the first direct renin inhibitor and hydrochlorothiazide was approved by the FDA this year for the treatment of hypertension. This combination is not indicated for initial therapy but as add-on therapy for those inadequately controlled on either agent alone or as a substitute for titrated components.1 The combination is marketed by Novartis Pharmaceutical Corporation as Tektura HCT.

Indications

Aliskiren/HCTZ is indicated for the treatment of hypertension. It is recommended for use as add-on therapy under the following situations:1

1. Blood pressure is not adequately controlled with either agent alone.

2. The patient is experiencing adverse events with either component and the combination permits dosing at a lower dose of that component and still achieve blood pressure control.

3. The combination is substituted for the titrated components for convenience pill burden.

Dosage

The recommended dose of aliskiren/HCTZ is 150 mg/12.5 mg once daily up to 300 mg/25 mg. If blood pressure is not adequately controlled after 2 to 4 weeks of therapy, the dose may be titrated to the maximum dose (300 mg/25 mg). The drug should be taken in a consistent routine manner with regards to meals. High fat meals decrease the absorption of aliskiren. No dosage adjustment is required for hepatic impairment or the elderly. The combination is not recommended for patients with severe renal impairment.1

Aliskiren/HCTZ is available as 150 mg/12.5 mg, 150 mg/25 mg, 300 mg/12.5 mg, and 300 mg/25 mg tablets.

Potential Advantages

The combination provides agents with two different mechanisms of action and is more effective than monotherapy with either component alone.1,2 In addition aliskiren opposes the hypokalemic effect and elevation of plasma renin activity of hydrochlorothiazide.2,3,4

Potential Disadvantages

Adverse events that occurred at a higher frequency than placebo include dizziness (2.3% vs 1.0%) influenza (2.3% vs 1.6%), diarrhea (1.6% vs 0.5%), cough (1.3% vs 0.5%), vertigo (1.2% vs 0.5%), and arthralgia (1.0% vs 0.5%).1 Aliskiren is metabolized by CYP3A4. Ketoconazole and atorvastatin decrease the level while irbesartan increases the level of aliskiren.1 Aliskiren carries the same pregnancy warning as ACEIs and ARBs.

Comments

The renin-angiotensin aldosterone system (RAAS) is an important target for antihypertensive and heart failure therapy. Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists are effective and well tolerated agents currently in widespread use. ACEIs and ARBs act on different parts of the RAAS pathway. As a result, compensatory feedback is activated. ACEIs increase plasma renin activity and angiotensin I while ARBs increase these as well as angiotensin II. In contrast aliskiren does not increase angiotensin I or II but does increase renin levels.

Aliskiren is a direct inhibitor of renin which is the enzyme responsible for the production of angiotensin II. In clinical trials, over 2700 subjects were exposed to aliskiren/HCTZ.1 The combination provides more effective blood pressure reduction than either drug alone.1,2 The placebo-adjusted systolic/diastolic blood pressure decrease ranged from 10-14/5-7 mm Hg for the combination (150 mg-300 mg/12.5 mg-25 mg) compared to 5-8/2-3 mm Hg for aliskiren and 6-7/2-3 mm Hg for hydrochlorothiazide.1 The combination is well tolerated with less than 5% of subjects discontinuing as result of adverse events.2

Clinical Implications

Clinical experience with aliskiren is still limited. ACEIs and ARBs are still preferred due to their vast clinical experience. The combination of aliskiren/HCTZ is an effective alternative for patients inadequately controlled on other blood pressure regimens.

References

1. Tekturna HCT Product Information. Novartis Pharmaceutical Corporations. January 2008

2. Villamil A, et al. J Hypertens. 2007;(1):27-26.

3. Motwani JG. J Renin Angiotensin Aldosterone Syst 2002;3:72-43an

4. O'Brien E, et al. Hypertens. 2007;49(2):276-84.