Product Spotlight: Tribenzor (olmesartan medoxomil, amlodipine, hydrochlorothiazide)

Tribenzor (olmesartan medoxomil [OM], amlodipine [AML], hydrochlorothiazide [HCTZ]) is a 3-in-1 combination product for the treatment of hypertension in patients who are not adequately controlled on any 2 of the following antihypertensive drug classes: angiotensin receptor blockers, calcium channel blockers, and diuretics at their maximally tolerated, labeled, or usual dose. Tribenzor combines the complementary actions of OM (which blocks angiotensin II receptors), AML (which inhibits the entrance of calcium into the blood vessel walls), and HCTZ (a diuretic that reduces water volume in the blood). It is not indicated for initial therapy.

Tribenzor is a taken orally once daily either with or without food. The tablets are formulated in the following strength combinations (OM/AML/HCTZ): 20/5/12.5 mg, 40/5/12.5 mg, 40/5/25 mg, 40/10/12.5 mg, and 40/10/25 mg. Dosage may be increased after 2 weeks to a maximum recommended dose of 40/10/25 mg, usually by increasing 1 component at a time. The full blood pressure (BP)-lowering effects are attained within 2 weeks after a change in dose. Hypertension, also known as high BP, is one of the most prevalent conditions in the United States, affecting nearly 1 in 3 adults. The disease has no specific symptoms but increases the risk of cardiovascular- and renal-related diseases, such as stroke, heart attack, and heart and kidney failure. Although the cause of 90% to 95% of high BP cases is unknown, high BP is easily detected and usually controllable. The US Food and Drug Administration (FDA) approved Tribenzor in July 2010. The safety and efficacy of OM, AML, HCTZ was established in a multicenter, randomized, double-blind, parallel-group study. This First Report–Managed Care Product Spotlight provides a summary of results from the pivotal study involving 2492 patients with hypertension.

PHASE 3 TRIAL

Below is a summary of a phase 3 trial that examined the effectiveness of OM, AML, and HCTZ in patients with hypertension. Results were presented at the 25th Annual Meeting of the American Society of Hypertension, May 1-4, 2010, in New York, New York, and the 20th Annual Meeting of the European Society of Hypertension, June 18-21, 2010, in Oslo, Norway.

Reference: Oparil S, Melino M, Lee J, Fernandez V, Heyrman R. Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: the TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Published online July 13, 2010 [Clin Ther. doi:10.1016/j.clinthera.2010.07.008].

Study Objective: The trial was designed to determine whether a triple combination of OM, AML, and HCTZ had a clinically significant benefit compared with a dual combination of the individual components in patients with moderate-to-severe hypertension.

Method: The trial was a multicenter, randomized, double-blind, parallel-group study conducted on an outpatient basis at 317 clinical sites in the United States and Puerto Rico. The first patient was enrolled in May 2008, and the last patient completed the study in February 2009. The authors compared patients aged ≥18 years who received 40 mg of OM, 10 mg of AML, and 25 mg of HCTZ with the following dual-combination treatment groups: 40 mg of OM and 10 mg of AML in fixed-dose combination, 40 mg of OM and 25 mg of HCTZ in fixed-dose combination, and 10 mg of AML and 25 mg of HCTZ. The study consisted of a 3-week washout period for patients receiving antihypertensive medications at screening and a 12-week double-blind treatment period. After the initial screening and washout period, eligible patients were grouped by age, race, and diabetes status. They were randomized to a treatment sequence that resulted in 4 groups that received treatment from weeks 4 to 12.

In the first 2 weeks of the double-blind treatment period, the researchers randomized all patients to receive 1 of the 3 dual-combination treatments or placebo. Patients assigned to a dual-combination treatment group continued the assigned treatment until week 4, while patients assigned to placebo were switched at week 2 to receive 1 of the dual-combination treatments until week 4. At week 4, patients either continued dual-combination treatment to week 12 or switched to the triple-combination treatment of 40 mg of OM, 10 mg of AML, and 25 mg of HCTZ to week 12. An interactive voice response system managed the distribution of patients among the 12 treatment sequences at randomization, providing the 4 final treatment groups.

During the 12-week double-blind period, the patients received 5 tablets per day. Each tablet looked different, corresponding to either the active or placebo image. This helped maintain blinding of investigators and patients to the 5 different dose images of active therapy. Patients were instructed to take all medication at the same time each day. The authors monitored patient adherence by assessing the tablet count from drug packages returned at each visit; patients who took <80% or >120% of the prescribed regimen were counseled on the importance of maintaining dosing adherence.

The authors measured BP at all study visits during the double-blind treatment period, including on day 1 and weeks 2, 4, 6, 8, 10, and 12. During each visit, they obtained 3 BP measurements at 1-minute intervals and recorded the mean of the 3 measurements as the BP value for that visit. They defined baseline BP as the mean of measurements from the randomization visit and the visit immediately preceding randomization. Patients were discontinued from the study if a mean seated systolic blood pressure (SeSBP) ≥220 mm Hg was recorded before randomization or if a mean SeSBP <90 mm Hg or mean seated diastolic blood pressure (SeDBP) >120 mm Hg was recorded during the double-blind treatment period.

Population: To be eligible for randomization, patients had to be ≥18 years with a mean seated blood pressure (SeBP) ≥140/100 or ≥160/90 mm Hg (off treatment). They could be newly diagnosed with hypertension, be receiving no current antihypertensive therapy (no antihypertensive medication for at least 3 weeks), or be undergoing a washout of current antihypertensive therapy. The following groups were excluded: patients with a recent history or presence of cerebrovascular disease, coronary artery disease, New York Heart Association class III or IV congestive heart failure, secondary hypertension, symptomatic resting bradycardia, heart block greater than first-degree atrioventricular block, chronic atrial fibrillation or flutter, severe renal insufficiency (creatinine clearance <30 mL/min), or uncontrolled diabetes (glycosylated hemoglobin >9%). Patients with a mean SeDBP <90 mm Hg or a mean SeSBP <140 mm Hg were also excluded. In addition, patients with laboratory values or systemic disease considered clinically significant by the investigator, or patients taking any concomitant medication that could interfere with the BP-lowering objectives of the study were ineligible.

Patients could be included in the study if they had type 1 or type 2 diabetes controlled with insulin, diet, or oral hypoglycemic agents at doses that had been stable for at least 30 days or if they had chronic kidney disease (screening creatinine clearance ≥30 and ≤60 mL/min). Before undergoing any study procedures, patients provided written informed consent at screening. They received medications free of charge and were compensated for their time, travel expenses, and other out-of-pocket expenses, as approved by the institutional review board. They did not receive any other compensation.

Primary end point: • Change in SeDBP from baseline to week 12 (SeDBP reduction ≥2 mm Hg was considered a clinically significant benefit)

Secondary end points: • Change in SeSBP at week 12
• Percentage of patients achieving BP targets of <140/90 mm Hg, <120/80 mm Hg, SeSBP <140 mm Hg, and SeDBP <90 mm Hg at week 12
• Tolerability of the treatments evaluated based on adverse events, clinical laboratory evaluations (chemistry, hematology, and urinalysis), physical examinations, and 12-lead electrocardiograms

Results

The authors concluded that the adult patients with moderate-to-severe hypertension who received a triple-combination treatment of 40 mg of OM, 10 mg of AML, and 25 mg of HCTZ were associated with significant BP reductions in SeDBP and SeSBP compared with patients who received dual combinations of the individual components. The reductions in BP translated into a greater percentage of patients achieving the BP goal. The triple-combination treatment was also associated with a higher percentage of patients reaching the BP goal and BP treatment targets compared with the dual-combination treatments. Of 6724 patients screened, 2492 were randomized and 2116 completed the study. Among those who were screened, 4232 patients (62.9%) were not randomized and did not enter the double-blind treatment period.

The primary reason for discontinuation before randomization was failure to satisfy all inclusion/exclusion criteria (3066 [45.6%]). The randomized patients were 52.9% male, 66.8% white, and 30.4% black. They had a mean weight of 96.0 kg (standard deviation [SD] 22.9 kg) and a mean age of 55.1 years (SD 10.9 years); 18.9% were ≥65 years. Researchers found diabetes present in 15.5% of the population, chronic cardiovascular disease in 9.1%, and chronic kidney disease in 4.1%. The mean duration of hypertension was 9.9 years, and mean SeBP was 168.5/100.9 mm Hg at baseline. Within 3 weeks of screening, 33.5% of patients had not received antihypertensive medication. The patients had a mean body mass index (BMI) of 33.1 kg/m2, and 62.4% of patients had a BMI ≥30 kg/m2. There were no statistically significant differences among treatment groups in terms of baseline demographic characteristics. In addition, there was similar adherence to study medication across treatment groups, ranging from 98.0% to 98.5%. The authors found that the triple-combination treatment at week 12 was associated with significantly greater least squares mean reductions in SeBP compared with the dual combinations (SeDBP: −21.8 vs −15.1 to −18.0 mm Hg, respectively [P<.001]; SeSBP: −37.1 vs −27.5 to −30.0 mm Hg [P<.001]).

Meanwhile, a significantly higher proportion of patients receiving triple-combination treatment reached BP targets compared with the dual combinations at week 12 (P<.001). The proportions of patients reaching the BP target of <140/90 mm Hg at week 12 was 69.9% in the triple-combination treatment group and 52.9%, 53.4%, and 41.1% in the treatment groups receiving 40 mg of OM and 10 mg of AML in fixed-dose combination, 40 mg of OM and 25 mg of HCTZ in fixed-dose combination, and 10 mg of AML 10 and 25 mg of HCTZ, respectively (P<.001, triple combination vs each dual combination). The incidence of treatment-emergent adverse events (TEAEs) was 58.4% for triple-combination treatment and 51.7% to 58.9% for the dual combinations. Most TEAEs were mild or moderate in severity.

The most common TEAEs in the triple-combination treatment group were dizziness (9.9%), peripheral edema (7.7%), and headache (6.4%). There were 52 patients (2.3%) who discontinued the study due to TEAEs—6 (1.0%) in the OM 40-mg/AML 10-mg group, 12 (2.1%) in the OM 40-mg/HCTZ 25-mg group, 11 (2.0%) in the AML 10-mg/HCTZ 25-mg group, and 23 (4.0%) in the OM 40-mg + AML 10-mg/HCTZ 25-mg group. In addition, 32 patients (1.4%)—4 (0.7%), 5 (0.9%), 5 (0.9%), and 18 (3.1%) in the respective treatment groups—discontinued the study due to TEAEs. In this study, the researchers changed from a dual-combination treatment to triple-combination treatment at week 4, and approximately 90% to 95% of the maximum effect on SeDBP and SeSBP reduction occurred within the subsequent 2 weeks, with only slight additional BP reductions from week 6 to week 12. The majority of patients treated with triple-combination treatment reached the BP treatment goal by week 6 (357/555 [64.3%]), similar to the number reaching the goal (395/614 [64.3%]) by week 12.

Safety Notes

Tribenzor is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs. Symptomatic hypotension may occur after initial treatment of Tribenzor in patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients. Thus, the treatment should start under close medical supervision. Patients with severe obstructive coronary artery disease may develop increased frequency, duration, or severity of angina or acute myocardial infarction when starting calcium channel blocker therapy or when increasing the dosage. Pregnant women should not use Tribenzor because drugs that act directly on the renin-angiotensin system can cause injury or possibly death to the developing fetus.

Patients with severely impaired renal function (creatinine clearance ≤30 mL/min) should also avoid using Tribenzor. In addition, if progressive renal impairment becomes evident, patients should consider withholding or discontinuing Tribenzor. Studies of angiotensin-converting enzyme inhibitors in patients with unilateral or bilateral renal artery stenosis have shown increases in serum creatinine or blood urea nitrogen. There has been no long-term use of OM in patients with unilateral or bilateral renal artery stenosis, but similar effects would be expected with Tribenzor because of the OM component.

Patients with severely impaired hepatic function should not use Tribenzor. Minor alterations of fluid and electrolyte balance due to HCTZ may precipitate hepatic coma. The HCTZ component of Tribenzor should also cause clinicians to observe patients for clinical signs of fluid or electrolyte imbalance. Patients with or without a history of allergy or bronchial asthma may also experience hypersensitivity reactions to HCTZ. Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus. Acute hypotension has rarely been reported after oral administration, although patients with severe aortic stenosis may be at particular risk. Dizziness (5.8%-8.9%) was the most frequently reported adverse reaction, while the other most frequent adverse reactions occurring in ≥2% of patients treated with Tribenzor were peripheral edema (7.7%), headache (6.4%), fatigue (4.2%), nasopharyngitis (3.5%), muscle spasms (3.1%), nausea (3.0%), upper respiratory tract infection (2.8%), diarrhea (2.6%), urinary tract infection (2.4%), and joint swelling (2.1%).

Tribenzor Facts
• Tribenzor was approved by the FDA on July 26, 2010
• Tribenzor is marketed and manufactured by Daiichi Sankyo

Additional Resource

Prescribing Information for Tribenzor: https://www.tribenzor.com/