Pharmacology Update

Olmesartan, Amlodipine, Hydrochlorothiazide Tablets (Tribenzor™)

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

A new three-drug antihypertensive pill, combining an angiotensin II receptor antagonist (olmesartan [OLM]), a calcium channel blocker (amlodipine [AML]), and a thiazide diuretic (hydrochlorothiazide [HCTZ]), has been approved by the FDA. The new combination is marketed by Daiichi Sankyo as Tribenzor™.

Indications

OLM/AML/HCTZ is indicated for the treatment of hypertension in patients who are not adequately controlled on any two drugs in the combination. It is not indicated for initial therapy.1

Dosage

The tablet is taken once daily. It may be taken without regard to meals. The initial dose will depend on the current dosage of antihypertensives. The dose may be increased every 2 weeks up to a maximum dose of 40/10/25 mg.

OLM/AML/HCTZ is available as 20/5/12.5 mg, 40/5/12.5 mg, 40/5/25 mg, 40/10/12.5 mg, and 40/10/25 mg.

Potential Advantages

The combination provides a convenient tablet that includes three drugs with different mechanisms of action. It reduces pill burden and copays, and may improve medication adherence. Adherence is known to decline as the number of drugs in a regimen increases.2

Potential Disadvantages

A branded combination is typically more expensive than combining 3 drugs that are available as generics.

Comments

The efficacy of OLM/AML/HCTZ was studied in 2492 hypertensive subjects with a mean baseline blood pressure of 169/101 mmHg.1 Subjects were randomized to receive one of three dual combinations (OLM/AML, OLM/HCTZ, or AML/HCTZ) for 2-4 weeks, then continue on the dual combinations or to the triple combination. After 8 weeks, the triple combination produced greater BP reduction than the dual combinations. Additional systolic BP reduction ranged from 7.6 to 8.4 mmHg and 4.5 to 5.4 mmHg for diastolic BP. Benefit appears to be similar for those < 65 years of older, black and non-black subjects, and diabetic and non-diabetic subjects.1,3 Dizziness was more common with OML/AML/HCTZ (5.8%-8.9%) compared to 1.4%-3.6% for dual combinations. The discontinuation rate was slightly higher for OML/AML/HCTZ (4%) compared to 1%-2% for the various dual combinations.

Clinical Implications

Many patients are not able to achieve adequate BP control with monotherapy. Therefore, combination therapy involving different mechanisms of action is a practical necessity.4 The actions of an ARB and a diuretic or an ARB and a CCB are fully additive, while that of a CCB and a diuretic are partially additive. The first two combinations are considered preferred regimens by the American Society of Hypertension while the third is acceptable.4 Recent concerns have been raised regarding the safety of angiotensin II receptor antagonists in general, and olmesartan in particular. A meta-analysis of clinical trials published before November 2009 suggests a modest increase in cancer risk (1.08; 95% confidence interval, 1.01-1.15; P = 0.016) compared to controls.5 The FDA is evaluating whether olmesartan was associated with an increased risk of cardiovascular death (25/2514 vs 6/2499 for placebo) in patients with type 2 diabetes.6 Both of these may be chance findings or due to confounding factors, and warrant further investigation. At this time, the benefit of the ARBs appears to outweigh their risk. OLM/AML/HCTZ provides a convenient single-pill combination for patients inadequately controlled on dual regimens.

References

1. Tribenzor Prescribing Information. Parsipanny, NJ: Daiichi Sankyo; July 2010.

2. Fung V, et al. Hypertension treatment in a medicare population: Adherence and systolic blood pressure control. Clin Ther 2007;29:972-984.

3. Oparil S, et al. Long-term efficacy of a combination of amlodipine and olmesartan medoxomil+/-hydrochlorothiazide in patients with hypertension stratified by age, race and diabetes status. J Hum Hypertens 2010;Mar 4; Epub ahead of print.

4. Gradman A, et al. Combination therapy in hypertension. J Am Soc Hypertens 2010;4:90-98.

5. Sipahi I, et al. Angiotensin-receptor blockade and risk of cancer: Meta-analysis of randomised controlled trials. Lancet Oncol 2010;11:627-636.

6. FDA Drug Safety Communication: Ongoing safety review of Benicar and cardiovascular events. Available at: www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm215222.htm. Accessed Aug. 7, 2010.