ADIS DRUG PROFILE

Am J Cardiovasc Drugs 2010; 10 (6): 401-412 1175-3277/10/0006-0401/$49.95/0

2010 Adis Data Information BV. All rights reserved.

Telmisartan/Amlodipine
Single-Pill Combination in Hypertension
Marit D. Moen
Adis, a Wolters Kluwer Business, Auckland, New Zealand

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 401 1. Pharmacodynamic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 402 2. Pharmacokinetic Profile . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 403 3. Therapeutic Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 404 4. Tolerability. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 408 5. Dosage and Administration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410 6. Telmisartan/Amlodipine: Current Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 410

Abstract
Telmisartan/amlodipine is a single-pill combination of telmisartan, an angiotensin II receptor antagonist, and amlodipine, a dihydropyridine calcium channel antagonist, which is taken orally once daily for the treatment of hypertension. In the US and the EU, single-pill telmisartan/amlodipine can be used as a replacement for separate telmisartan and amlodipine tablets, and by patients not achieving BP goals with amlodipine monotherapy. In addition, the US indication includes patients not achieving BP goals with telmisartan (or another angiotensin II receptor antagonist or calcium channel antagonist other than amlodipine) alone, and as initial therapy in patients considered likely to require multiple drugs to achieve their BP goals. In an 8-week, randomized, double-blind, factorial-design, placebo-controlled, multicenter study in adult patients with hypertension (n = 1461), mean DBP was reduced from baseline to a significantly greater extent in recipients of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day than in those receiving equivalent dosages of telmisartan or amlodipine monotherapy. Single-pill telmisartan/amlodipine recipients had significantly greater reductions in BP than telmisartan or amlodipine monotherapy recipients in an 8-week, randomized, double-blind, multicenter study in adult patients with severe hypertension (n = 858), and in four 8-week, randomized, double-blind, multicenter trials in patients who had not responded to amlodipine (n = 1097, 947, and 531) or telmisartan (n = 314) monotherapy. Telmisartan/amlodipine was generally well tolerated in clinical trials, including two 36-week follow-up studies.
Features and properties of telmisartan/amlodipine (Twynsta)
Indication Hypertension Mechanism of action Combined effects of an angiotensin II receptor antagonist (telmisartan) and a dihydropyridine calcium channel antagonist (amlodipine) Dosage and administration Dose One tablet of telmisartan/amlodipine 40 mg/5 mg, 40 mg/10 mg, 80 mg/ 5 mg, or 80 mg/10 mg Oral Once daily

Route of administration Frequency of administration

Pharmacokinetic profile (of individual drugs) Time to peak plasma concentration Telmisartan: 0.51 h; amlodipine 612 h Telmisartan 24 h; amlodipine 3050 h

Mean terminal elimination half-life

Most common treatment-related adverse events Headache, peripheral edema

402

Moen

The risk of cardiovascular disease events, including heart failure, myocardial infarction, stroke, and kidney disease, increases with increasing BP.[1] Reduction of BP with antihypertensive treatment reduces the risk of cardiovascular and renal morbidity and mortality. For most patients with hypertension, treatment with two or more antihypertensive agents will be required to achieve the desired level of BP reduction (to <140/90 mmHg for most hypertensive patients).[1] The use of combinations of antihypertensive agents with complementary mechanisms of action can reduce BP significantly more than monotherapy.[2] An additional agent can be added when BP goals are not reached with a single antihypertensive treatment, or combination treatment may be used initially for patients who are considered likely to need treatment with more than one drug.[1] Historically, angiotensin II receptor antagonists have been combined with diuretics,[1] but more recently the angiotensin II receptor antagonist/calcium channel antagonist combination has been proven effective (reviewed by Bakris[3]) and several such combinations are available as singlepill combinations.[4-6] The use of a single-pill combination has been shown to improve patient compliance and treatment adherence,[7-9] which is a known problem with hypertension treatment,[10] and may also reduce healthcare costs.[9] Telmisartan, an angiotensin II receptor antagonist, and amlodipine, a calcium channel antagonist, have well established efficacy in the treatment of hypertension as monotherapy[11-15] or in combination with other antihypertensive agents.[4,5,16-19] A single-pill combination of telmisartan/amlodipine (Twynsta) is available in the US and the EU for once-daily administration in adult patients with hypertension.[20,21] This review provides a brief overview of the pharmacologic properties of telmisartan and amlodipine, and discusses the available clinical trial data for combination treatment with telmisartan/amlodipine. Medical literature on the use of telmisartan/amlodipine in hypertension was identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Searches were last updated 1 November 2010. 1. Pharmacodynamic Profile The pharmacodynamic effects of telmisartan and amlodipine that result in BP lowering are well established and have been reviewed elsewhere.[11-15] This section provides a brief overview of the mechanisms of action of telmisartan and amlodipine, with a focus on recent pharmacodynamic studies,
2010 Adis Data Information BV. All rights reserved.

most of which have investigated effects of telmisartan. Two studies[22,23] that investigated the telmisartan/amlodipine combination are discussed here (one is available as an abstract[23]); the BP-lowering effects of telmisartan/amlodipine in patients with hypertension are discussed in section 3.  Telmisartan and amlodipine have complementary mechanisms of action for lowering BP.[20] Telmisartan is an angiotensin II receptor antagonist that acts at the angiotensin II type 1 (AT1) receptor to block the effects of angiotensin II, namely vasoconstriction and aldosterone secretion. Amlodipine is a dihydropyridine calcium channel antagonist that inhibits the transmembrane influx of calcium into vascular smooth muscle and cardiac muscle cells. Its actions on vascular smooth muscle cells causes peripheral arterial vasodilation and reduces peripheral vascular resistance.[20]  Telmisartan also acts as a partial agonist at peroxisome proliferator-activated receptor-gamma (PPARg).[13] PPARg is a nuclear transcription factor that is involved in the regulation of glucose and lipid metabolism.[13] In vitro, telmisartan and irbesartan at 10 mmol/L enhanced PPARg-dependent 3T3-L1 adipocyte differentiation 3.1- and 3.3-fold (both p < 0.01 vs vehicle-treated cells).[24] Induction of adipogenic marker gene adipose protein 2 (aP2) expression was more pronounced with telmisartan (half maximal effective concentration [EC50] 0.13 mmol/L) than with irbesartan (EC50 3.5 mmol/L), or losartan (expression was only enhanced at a concentration of 100 mmol/L) and there were no significant changes in expression with eprosartan.[24] Activation of PPARg by telmisartan and irbesartan was independent of AT1 antagonistic activity.[24]  While amlodipine appears to have no adverse effects on insulin sensitivity or plasma lipid levels,[15] the actions of telmisartan on PPARg are thought to be at least partly responsible for possible favorable effects on glucose and lipid metabolism.[25] Although some of these effects are not yet well established, in some studies, telmisartan has been associated with improvements in insulin resistance and impaired glucose metabolism, and reductions in total cholesterol and low-density lipoprotein cholesterol levels.[25]  In patients with nonmodulating (n = 18) or modulating (n = 16) hypertension, insulin resistance, measured by the homeostasis model assessment index, was significantly (p < 0.05) improved after 3 months treatment with telmisartan versus either basal values or 3 months of ramipril treatment, despite similar reductions in BP in both treatment groups.[26] Furthermore, telmisartan recipients also had significant reductions in plasma triglyceride levels (p < 0.05 vs basal values or ramipril).[26] Plasma triglyceride levels were also significantly (p < 0.05) reduced from baseline in hypertensive hypercholesterolemic patients who received telmisartan and simvastatin for
Am J Cardiovasc Drugs 2010; 10 (6)

Telmisartan/Amlodipine: Adis Drug Profile

403

4 weeks (n = 16), but not when the same patients were crossed over to treatment with bisoprolol and simvastatin.[27]  Another study in patients with hypertension (n = 15) suggested that telmisartan can improve endothelial function.[28] Plasma levels of asymmetric dimethylarginine, an endothelial nitric oxide synthase inhibitor that has been associated with endothelial dysfunction and atherosclerosis, were significantly lower than baseline levels after patients received telmisartan 40 mg/day for 6 months (0.42 vs 0.48 nmol/mL at baseline; p = 0.01).[28]  Telmisartan may have protective effects on renal function,[25] although this has not been consistently demonstrated.[29] In hypertensive patients with diabetic nephropathy (n = 860), the urinary albumin : creatinine ratio was significantly (both p < 0.0001) reduced from baseline after 52 weeks of treatment with telmisartan (29.8% reduction) or losartan (21.4% reduction); however, the extent of the reduction was significantly greater for telmisartan recipients (p = 0.03 vs losartan), despite similar reductions in BP.[30]  In diabetic patients with microalbuminuria (n = 210) who received combination treatment with telmisartan 40 mg/day plus amlodipine 2.5 mg/day, uptitration of telmisartan (to 80, 120, and 160 mg/day) while maintaining a constant amlodipine dosage resulted in significantly (p < 0.05) greater reductions in the urinary albumin excretion rate (by 47.5%, 65.3%, and 77%) than with uptitration of amlodipine (to 5, 7.5, and 10 mg/day with reductions of 34%, 37%, and 33%), despite similar reductions in BP levels.[22] Microalbuminuria was reduced significantly (p = 0.041) more after 52 weeks with telmisartan/amlodipine (by 54.9%) than with losartan/amlodipine (by 38.5%) in patients with well controlled type 2 diabetes mellitus and microalbuminuria (n = 240 randomized patients) who responded to treatment (dosages were uptitrated for nonresponders, and nonresponders at 20 weeks were discontinued).[23] 2. Pharmacokinetic Profile This section provides a brief overview of the pharmacokinetics of telmisartan and amlodipine as individual agents (reviewed in detail elsewhere[13,15]). Two studies in healthy volunteers (n = 12[31] and 38 [available as an abstract/poster[32]]) that investigated the pharmacokinetics of the individual agents and of telmisartan and amlodipine used in combination are also discussed. Additional data have been obtained from the manufacturers prescribing information.[20]
Telmisartan

oral administration.[13,20] Bioavailability of telmisartan is dose dependent (42% with telmisartan 40 mg and 58% with 160 mg) and is also affected by food, although this is not considered clinically relevant.[20] Non-linear pharmacokinetics are observed over the dose range 20160 mg. Following once-daily administration, steady-state telmisartan plasma concentrations are reached in 57 days,[13] with an accumulation index of 1.52.0.[20]  In healthy volunteers who received telmisartan 80 mg/day for 9 days, the geometric mean Cmax on day 9 (i.e. at steady state) was 272 ng/mL; Cmax was reached at a mean 0.69 hours after the last dose.[32] The mean area under the plasma concentration-time curve (AUC) at steady state was 1020 ng h/mL.[32]  Plasma protein binding is high (>99.5%), and telmisartan is bound mainly to albumin and a1-acid glycoprotein.[20] The drug has a high volume of distribution (500 L).  Telmisartan is eliminated via biliary-fecal excretion, primarily as unchanged drug (>97% of a radiolabelled dose).[20] The only telmisartan metabolite identified in human plasma or urine is an inactive acylglucuronide metabolite. The mean terminal elimination half-life (tg) of telmisartan is approximately 24 hours.[20]

Amlodipine

 The absorption of oral amlodipine is slower than that of telmisartan, Cmax occurs 612 hours after amlodipine administration, and steady-state plasma concentrations are generally reached after 78 days of multiple doses.[20] The estimated bioavailability of amlodipine is 6490%.[20]  Following a single dose of oral amlodipine 10 mg to healthy volunteers, a geometric mean Cmax of 5.4 ng/mL was reached a median 7.0 hours after administration.[31] After 9 days of amlodipine 10 mg/day, a mean Cmax of 17.7 ng/mL was reached a median 6.0 hours after drug administration, and the Cmax accumulation ratio was 3.3.[31]  Amlodipine is highly plasma protein bound (93% in hypertensive patients), and has a large volume of distribution (21 L/kg).[20]  Extensive metabolism of amlodipine (approximately 90% of the dose) to inactive metabolites occurs in the liver.[15,20] Amlodipine is eliminated mainly as parent drug (10%) or metabolites (60%) in the urine and has a long tg (3050 hours).[20] In healthy volunteers who received amlodipine 10 mg/day for 9 days, the geometric mean tg of amlodipine was 55.9 hours.[31]
Telmisartan/Amlodipine

 Telmisartan is absorbed rapidly, and peak plasma concentrations (Cmax) are reached approximately 0.51 hours after
2010 Adis Data Information BV. All rights reserved.

 The pharmacokinetics of amlodipine were not affected by coadministration of telmisartan in healthy volunteers.[31] The Cmax and AUC ratios for amlodipine plus telmisartan at steady
Am J Cardiovasc Drugs 2010; 10 (6)

404

Moen

state versus amlodipine monotherapy were 1.06 (90% CI 0.97, 1.14) for Cmax, and 1.06 (90% CI 0.98, 1.16) for AUC; both 90% CIs fell within the prespecified limits for bioequivalence (90% CI 0.8, 1.25). The ratio for clearance was 1.09 (90% CI 0.79, 1.50), which did not met bioequivalence criteria. This was thought to be because of high variability in amlodipine renal excretion, and was not considered clinically relevant.[31]  In another study in healthy volunteers, amlodipine coadministration did not affect telmisartan pharmacokinetics.[32] The ratio of AUC at steady state for telmisartan plus amlodipine versus telmisartan monotherapy (0.976 [90% CI 0.895, 1.065]) met the standard bioequivalence criteria. Although the ratio for Cmax at steady state (0.890 [90% CI 0.763, 1.037]) did not meet standard bioequivalence criteria, the 90% CI fell within the range of 0.751.33, which was a pre-defined widened acceptance range for drugs with a highly variable Cmax.[32]

3. Therapeutic Efficacy The efficacy of telmisartan or amlodipine as monotherapy in the treatment of hypertension has been well established in clinical trials (reviewed elsewhere[11-15]). This section focuses on randomized, double-blind, multicenter trials comparing telmisartan plus amlodipine combination therapy with the component monotherapies and/or placebo in adult patients with hypertension. The maximum recommended dosages of telmisartan and amlodipine when administered alone are 80[33] and 10[34] mg/day. It should be noted that, as individual agents, telmisartan reduces the risk of cardiovascular events,[33,35] and amlodipine is effective in the treatment of angina and in reducing the risk of hospitalization due to angina and the risk of a coronary revascularization procedure in patients with coronary artery disease.[34] However, cardiovascular endpoints other than BP reduction have not been assessed in trials of telmisartan plus amlodipine combination therapy.
Randomized Factorial Study

focuses on the telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day dosages (the dosages available as single-pill telmisartan/amlodipine). Exclusion criteria included prespecified renal or hepatic disorders, congestive heart failure, relevant cardiac arrhythmias, severe obstructive coronary artery disease, or unstable diabetes. Patients were also excluded if they had a known sensitivity to the study treatments or prior angioedema related to use of an ACE inhibitor or angiotensin II receptor antagonist. Other medications known to affect BP were prohibited during the study. The mean age of patients was 53.1 years and 50.4% were male. Mean baseline BP was 153.2/101.7 mmHg and the mean baseline pulse rate was 74.4 beats/min. Patients were Caucasian (79.4%), Black (16.2%), or Asian (4.4%), and the mean body mass index was 31.3 kg/m2. Most patients had been hypertensive for more than 5 years (55.2%) and had used one (36.3%) or at least two (42.6%) antihypertensive agents previously. The primary endpoint of the study was the change in in-clinic seated trough DBP (measured 2030 hours after last dose) from baseline to the end of the study. Least-square mean values were adjusted for dosage, country/region, and baseline BP. Efficacy was analyzed in the modified intent-to-treat population (all patients who received at least one dose of study medication and had at least one trough BP measurement at baseline and at the target dosage; n = 1423). The study was also designed to determine the optimal dosages of telmisartan plus amlodipine.
Main Outcomes

The efficacy of the telmisartan plus amlodipine combination was evaluated in a large (n = 1461), 8-week, randomized, double-blind, 4 4 factorial-design, placebo-controlled, multicenter study in adult patients with hypertension.[36] Eligible patients were aged 18 years and had stage 1 or 2 hypertension, defined as DBP 95 mmHg and 119 mmHg. The study had 16 treatment groups; patients received telmisartan 20, 40, or 80 mg, or telmisartan placebo, and amlodipine 2.5, 5, or 10 mg, or amlodipine placebo once daily for 8 weeks, following a 21- to 28-day, single-blind, placebo run-in period. Discussion here
2010 Adis Data Information BV. All rights reserved.

 The telmisartan plus amlodipine combination resulted in greater reductions in DBP than telmisartan or amlodipine monotherapy after 8 weeks treatment in adult patients with hypertension (primary endpoint; figure 1). In-clinic seated trough DBP was significantly (p < 0.0001) lowered from baseline for telmisartan plus amlodipine recipients (irrespective of dosage) at the end of the 8-week study, and there was no telmisartan-by-amlodipine interaction. Recipients of telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg once daily had significantly (p < 0.05) greater reductions in DBP than recipients of the corresponding monotherapy dosages (figure 1). Numerically, the greatest decrease in BP from baseline occurred in recipients of telmisartan 80 mg/day plus amlodipine 10 mg/day (mean reduction -26.4/-20.1 mmHg [SBP/DBP]).  In-clinic seated trough SBP values were also significantly reduced from baseline after 8 weeks in telmisartan plus amlodipine recipients (secondary endpoint; figure 1). All combinations of telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg once daily resulted in significant (p < 0.05) reductions in SBP versus corresponding monotherapy dosages.
Am J Cardiovasc Drugs 2010; 10 (6)

Telmisartan/Amlodipine: Adis Drug Profile

405

DBP SBP TEL 40 n= 0 Change in BP from baseline (mmHg) 129 TEL 80 132 AML 5 137 AML 10 124 TEL 40 + AML 5 141 TEL 80 + AML 5 143 TEL 40 + AML 10 123 TEL 80 + AML 10 136

* * * * * * * *

Fig. 1. Efficacy of telmisartan (TEL) plus amlodipine (AML) in adult patients with hypertension.[36,37] Least-squares mean changes in DBP and SBP from baseline to the end of the study, adjusted for dosage, country/region and baseline BP (data from abstract/poster[37]). In this randomized, double-blind, factorial-design, multicenter study, patients with hypertension received oral TEL 20, 40, or 80 mg, or placebo (PL), plus AML 2.5, 5, or 10 mg, or PL once daily for 8 weeks (n = 1423). Only clinically relevant dosages are shown. * p < 0.05 vs corresponding TEL monotherapy dosage; - p < 0.05 vs corresponding AML monotherapy dosage.

 A DBP response (DBP <90 mmHg or DBP decrease 10 mmHg) and/or an SBP response (SBP <140 mmHg or SBP decrease 15 mmHg) was achieved by 8192% of patients who received once-daily telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg and by 6486% of recipients of the corresponding monotherapy dosages. Over half (5977%) of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day recipients achieved BP control (DBP <90 mmHg and SBP <140 mmHg) after 8 weeks, and 7285% achieved DBP control (DBP <90 mmHg). In the corresponding monotherapy dosage groups, 4263% of patients achieved BP control and 5373% achieved DBP control.
Subanalyses in Special Patient Populations

 In the subgroup of patients with moderate or severe hypertension (DBP 100 mmHg; n = 1050 evaluable for efficacy analysis), reductions in in-clinic seated trough DBP and SBP were significantly (p < 0.05) greater for telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg once-daily recipients than for equivalent monotherapy dosage recipients.[38] The greatest numerical reduction in BP from baseline occurred in the telmisartan 80 mg plus amlodipine 10 mg once-daily group (-26.5/-21.0 mmHg).  Response and BP control rates were generally high in patients with moderate or severe hypertension who received telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg once daily.[38] DBP and SBP response rates were 8293% and 8091%, respectively, and BP and DBP control rates were 5477% and 6985%. In the corresponding monotherapy dosage groups, DBP and SBP response rates were 6383% and 6277%, and BP and DBP control
2010 Adis Data Information BV. All rights reserved.

rates were 3352% and 4365%. The highest rates of response and BP control occurred in the telmisartan 80 mg plus amlodipine 10 mg once-daily group.  Post hoc subanalyses of various patient subgroups (available as abstracts) suggested that the telmisartan plus amlodipine combination effectively reduced BP and improved BP control regardless of age (<65 or 65 years),[39] ethnicity (Black, Asian, or Caucasian),[40] geographic location (North America or Latin America),[41] diabetes (yes or no),[42] obesity (yes or no),[43] previous antihypertensive treatment (yes or no),[44] and baseline SBP (<160 or 160 mmHg).[45]  Patients with a baseline SBP 160 mmHg appeared to have greater reductions in SBP (-26.6 to -34.7 mmHg) with telmisartan 40 or 80 mg plus amlodipine 5 or 10 mg per day than those with a baseline SBP <160 mmHg (-18.2 to -21.5 mmHg) [no statistical analysis reported].[45] BP reductions appeared greatest in the subgroup of Asian patients (-43.2/-28.0 mmHg), then in the Caucasian subgroup (-26.2/-20.0 mmHg), and lowest in the subgroup of Black patients (-21.5/-16.4 mmHg) who received telmisartan 80 mg/day plus amlodipine 10 mg/day (n = 136) [no statistical analysis].[40]
Ambulatory BP Monitoring Substudy

Approximately half of the patients in the factorial-design study (n = 562) took part in an ambulatory BP monitoring (ABPM) substudy.[46] ABPM measurements were taken every 20 minutes over 24 hours at baseline and after 8 weeks taking study medication. The primary endpoint was the change from baseline in mean 24-hour DBP after 8 weeks.
Am J Cardiovasc Drugs 2010; 10 (6)

406

Moen

DBP SBP TEL 40 n= 0 Change in 24-hour ambulatory BP from baseline (mmHg) 50 TEL 80 43 AML 5 52 AML 10 58 TEL 40 + AML 5 57 TEL 80 + AML 5 56 TEL 40 + AML 10 57 TEL 80 + AML 10 52

** * * * ** ** ** **

Fig. 2. Efficacy of telmisartan (TEL) plus amlodipine (AML) in adult patients with hypertension in an ambulatory blood pressure monitoring (ABPM) substudy.[46] Mean changes in DBP and SBP from baseline to the 8-week assessment. Patients with hypertension received oral TEL 20, 40, or 80 mg, or placebo (PL), plus AML 2.5, 5, or 10 mg, or PL once daily for 8 weeks (n = 1423) in a randomized, double-blind, factorial-design, multicenter study;[36] 562 patients took part in the ABPM substudy. Only clinically relevant dosages are shown. * p < 0.001, ** p < 0.0001 vs corresponding TEL monotherapy dosage; - p < 0.0001 vs corresponding AML monotherapy dosage.

 The combinations of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day provided consistent mean BP (over 24 hours) reductions (n = 222 for relevant dosages). The mean reductions in 24-hour DBP (primary endpoint) and SBP from baseline were significantly (p < 0.001) greater for recipients of combinations of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day than for recipients of the corresponding telmisartan or amlodipine monotherapy dosages after 8 weeks (figure 2).  BP control (24-hour mean SBP/DBP <130/<80 mmHg) was achieved by 5483% of telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day recipients compared with 3044% of telmisartan 40 or 80 mg/day recipients, 3839% of amlodipine 5 or 10 mg/day recipients, and 19% of placebo recipients (p < 0.01 for telmisartan 40 or 80 mg/day plus amlodipine 10 mg/day vs corresponding monotherapy dosages).  There were consistent reductions in 24-hour ambulatory BP from baseline to the end of the study for telmisartan plus amlodipine combination recipients versus monotherapy in various patient subgroups. Patients with stage 2 hypertension who received telmisartan 40 or 80 mg/day plus amlodipine 5 or 10 mg/day had significantly (p < 0.01) greater reductions in 24-hour BP from baseline versus recipients of the corresponding monotherapy dosages. After 8 weeks, recipients of telmisartan/amlodipine 80 mg/10 mg per day had mean BP reductions of -22.7/-15.3 mmHg (p < 0.0001 vs telmisartan or amlodipine monotherapy).  In subgroup analyses (some available as abstracts[47-49]), reductions in 24-hour BP for telmisartan plus amlodipine recipients versus monotherapy appeared consistent (no statistical analysis) regardless of age (<65 or 65 years),[46] baseline SBP (<160 or 160 mmHg),[47] diabetic or obesity status,[48]
2010 Adis Data Information BV. All rights reserved.

ethnicity (Black or non-Black),[46] or geographic location (Latin America or North America).[49]

Severe Hypertension Study

The efficacy of single-pill telmisartan/amlodipine in adult patients with severe hypertension was assessed in a randomized, double-blind, multicenter, 8-week study (TEAMSTA severe HTN [TElmisartan 80 mg plus AMlodipine 10 mg fixed-dose combination tablet STudy versus Amlodipine 10 mg over encapsulated tablets or telmisartan 80 mg tablets as first line therapy in patients with severe HyperTeNsion] study [n = 858]; available as an abstract and poster).[50] Severe hypertension was defined as mean seated cuff SBP 180 mmHg and mean seated cuff DBP 95 mmHg. Patients were eligible if they could stop their current antihypertensive treatment without unacceptable risks. Patients with mean SBP 200 mmHg and/or mean DBP >120 mmHg were excluded from the study. Patients received single-pill telmisartan/amlodipine 80 mg/ 10 mg per day or telmisartan 80 mg/day or amlodipine 10 mg/day monotherapy for at least 6 weeks after a 2-week uptitration of amlodipine dosages. The primary endpoint was the change from baseline to the end of the 8-week study in mean seated trough cuff SBP. The mean age of patients was approximately 58 years and mean baseline trough SBP and DBP values were 185.2 185.6 mmHg and 103.2103.5 mmHg.  Telmisartan/amlodipine combination therapy resulted in significantly greater reductions in mean SBP than telmisartan or amlodipine monotherapy in adult patients with severe hypertension. After 8 weeks, mean reductions in SBP from baseline to
Am J Cardiovasc Drugs 2010; 10 (6)

Telmisartan/Amlodipine: Adis Drug Profile

407

the end of the study (primary endpoint) were -47.5 mmHg for telmisartan/amlodipine 80 mg/10 mg per day recipients versus -36.9 mmHg for telmisartan 80 mg/day recipients (p = 0.0001 vs combination treatment) and -43.2 mmHg for amlodipine 10 mg/day recipients (p = 0.0002).  The reduction in mean SBP from baseline was also significantly (p < 0.01) greater for telmisartan/amlodipine combination recipients than monotherapy recipients at study assessments at 1, 2, 4, and 6 weeks (key secondary endpoint). After 1 week, patients in the telmisartan/amlodipine 80 mg/10 mg group had a significantly greater improvement in SBP (-31.9 mmHg) than those in the telmisartan 80 mg/day (-25.4 mmHg; p < 0.0001) or amlodipine 10 mg/day (-28.6 mmHg; p = 0.0077) groups.  Reductions in DBP from baseline were also significantly greater for single-pill telmisartan/amlodipine recipients than for telmisartan or amlodipine monotherapy recipients at the end of the study (-18.7 vs -13.8 and -16.3 mmHg; both p < 0.001) and at assessments at weeks 1, 2, 4, and 6.  Approximately 50% of telmisartan/amlodipine recipients met the BP goal of <140/<90 mmHg compared with 24.1% of telmisartan recipients and 35.6% of amlodipine recipients. SBP response (SBP <140 mmHg or 10 mmHg reduction) and DBP response (DBP <90 mmHg or 10 mmHg reduction) rates were 99.7% and 91.4% for telmisartan/amlodipine, 91.5% and 69.3% for telmisartan monotherapy, and 98.5% and 83.9% for amlodipine monotherapy recipients.
Studies in Patients Not Adequately Responsive to Telmisartan or Amlodipine Monotherapy

hypertension) study[51,52] and a secondary endpoint in the TEAMSTA-10 (TElmisartan plus AMlodipine STudy in Amlodipine 10 mg non-responders in hypertension) study.[54,55] Data from the TEAMSTA-5 and -10 studies are available as abstracts and posters[51,54] (with additional data obtained from the manufacturers clinical trial results database).[52,55] Data from the other two studies, which were conducted in Japan, have been obtained from the manufacturers clinical trial results database.[53,56]
Main Outcomes

Four 8-week, randomized, double-blind, multicenter trials evaluated the efficacy of single-pill telmisartan/amlodipine at clinically relevant dosages (see table I) in adult patients with uncontrolled hypertension after 6 weeks of monotherapy with amlodipine 5 mg/day (n = 1097[51,52] and 531[53]) or 10 mg/day (n = 947)[54,55] or telmisartan 40 mg/day (n = 314)[56] [numbers of randomized patients]. Uncontrolled hypertension at baseline (at the end of the 6-week run-in period) was defined as DBP 90 mmHg,[51,54] or DBP 90 mmHg and 114 mmHg, and SBP 200 mmHg.[53,56] Patients were randomized to treatment with single-pill telmisartan/amlodipine or telmisartan or amlodipine monotherapy; patient numbers and treatment regimens are described in table I. The primary endpoint in all studies was the change in seated trough DBP from baseline to the end of the study. The incidence of edema adverse events (see section 4) was another primary endpoint in the TEAMSTA-5 (TElmisartan plus AMlodipine STudy in Amlodipine 5 mg non-responders in
2010 Adis Data Information BV. All rights reserved.

 In adult patients with hypertension not adequately controlled with amlodipine or telmisartan monotherapy, mean reductions from baseline in seated trough DBP values (primary endpoint) were significantly greater for single-pill telmisartan/amlodipine recipients than for those who received amlodipine or telmisartan monotherapy in all four studies (table I).[51-56]  Where reported, combination treatment recipients showed statistically significant improvements in the percentage of patients achieving BP control and the percentage of BP responders (secondary endpoints) compared with recipients of amlodipine or telmisartan monotherapy (table I).[51-56] Mean reductions in SBP values were significantly greater in telmisartan/amlodipine recipients than in monotherapy recipients.  The percentages of patients achieving DBP control were also significantly greater for single-pill telmisartan/amlodipine recipients than for amlodipine or telmisartan monotherapy recipients in all studies (table I; two studies stated there was a significant difference but p-values were not reported[53,56]).  Of note, in patients who had not responded adequately to amlodipine 10 mg/day monotherapy in TEAMSTA-10,[54,55] there were significant improvements for telmisartan/amlodipine 40 mg/ 10 mg or 80 mg/10 mg per day versus amlodipine 10 mg/day for all endpoints (table I).  In the TEAMSTA-5 and -10 studies, at the end of the 8-week treatment period, 4147% of patients in the telmisartan/amlodipine groups and 4652% in the amlodipine monotherapy groups had stage 1 hypertension, and 4352% of patients in the combination therapy groups and 2640% of patients in the monotherapy groups had optimal, normal, or high normal BP.[52,55]
Open-Label Follow-Up Studies

The TEAMSTA-5 and -10 studies had long-term follow-up extensions, which continued treatment (open-label) for an additional 36 weeks after the end of the initial studies (also reported as abstracts and posters).[57,58] The primary efficacy endpoint for both follow-up studies was the percentage of patients achieving DBP control, and long-term safety was also assessed (see section 4).
Am J Cardiovasc Drugs 2010; 10 (6)

408

Moen

Table I. Efficacy of once-daily, single-pill telmisartan (TEL)/amlodipine (AML) in adult patients (pts) with hypertension not adequately controlled with TEL or AML monotherapy. Results of four randomized, double-blind, active-controlled, multicenter, 8-week studies (data obtained from abstracts[51,54] and/or the manufacturers clinical trial results database[52,53,55,56]) Study [study acronym] Regimen (mg/day) No. of evaluable pts Mean change from baseline to end of study (mmHg) [baseline] DBPc In pts not adequately responsive to AML 5 mg/day monotherapy Neldam et al.[51,52] [TEAMSTA-5] TEL/AML 40/5 TEL/AML 80/5 AML 5 AML 10 Ogiharad[53] TEL/AML 40/5 AML 5 270 271 255 261 263 257 -9.4**--- [96.9] -10.6**- [96.5] -5.7 [96.4] -8.0 [96.5] -9.56** -4.45 -13.6**--- [149.7] -15.0**- [148.7] -6.2 [150.5] -11.1 [149.0] -13.04** -5.77 56.7* 63.8* 42.0 56.7 68.1e 47.1 60.0* 65.7* 39.2 54.4 NR NR 65.6 69.0 45.5 62.5 NR NR 69.3 73.8 46.3 63.6 NR NR SBP Percentage of pts achieving controla (%) DBP SBP Percentage of pts achieving responseb (%) DBP SBP

In pts not adequately responsive to AML 10 mg/day monotherapy Neldam et al.[54,55] [TEAMSTA-10] TEL/AML 40/10 TEL/AML 80/10 AML 10 Ogiharad[56] 306 310 305 -9.2--- [95.5] -9.3
---

-11.1--- [148.1] -11.3

---

63.766.5 51.1 78.4e 46.8

--

58.860.3 50.2
-

66.068.7 53.4
--

64.765.854.1

[95.6]

[147.4]

-6.5 [95.6] -13.49 -5.47

-7.4 [146.8] -17.86 -6.51

In pts not adequately responsive to TEL 40 mg/day monotherapy TEL/AML 40/5 TEL 40 153 158 NR NR NR NR NR NR

a DBP control defined as DBP <90 mmHg and SBP control defined as SBP <140 mmHg. b DBP response defined as DBP control or DBP reduction of 10 mmHg from baseline, and SBP response defined as SBP control or SBP reduction of 15[51,54] or 20[53,56] mmHg from baseline. c Seated trough values. Primary endpoint in all studies. d Principal investigator (as stated in clinical trial results database). e Significant difference vs comparator; p-values not reported. NR = not reported. * p < 0.001, ** p < 0.0001 vs AML 5 mg/day; - p < 0.05, -- p < 0.001, --- p < 0.0001 vs AML 10 mg/day; p < 0.0001 vs TEL 40 mg/day.

Patients received telmisartan/amlodipine 40 mg/5 mg in the TEAMSTA-5 follow-up study (n = 976),[57] and telmisartan/ amlodipine 40 mg/10 mg or 80 mg/10 mg in the TEAMSTA-10 follow-up study (n = 838)[58] for 4 weeks, then the telmisartan dosage was uptitrated (to a maximum 80 mg) or additional antihypertensive drugs were added as required.  Long-term treatment with telmisartan/amlodipine (plus additional antihypertensive therapy in some patients) resulted in additional clinically meaningful (no statistical analysis) achievement of DBP goals over 36 weeks in the TEAMSTA-5 and -10 follow-up studies. At the end of the studies, 79.5% of patients in the TEAMSTA-5 follow-up study (who received telmisartan/amlodipine 40 mg/5 mg or 80 mg/5 mg per day with or without additional antihypertensive therapy), and 89.2% of patients in the TEAMSTA-10 follow-up study (who received telmisartan/amlodipine 40 mg/10 mg or 80 mg/10 mg per day with or without additional antihypertensive therapy) achieved the DBP goal of <90 mmHg.  In the TEAMSTA-5 and -10 follow-up studies, 63% and 77% of patients overall achieved the BP goal of <140/90 mmHg, and
2010 Adis Data Information BV. All rights reserved.

the mean reductions in SBP and DBP from the end of the 8-week studies to the end of the follow-up studies were -5.0/-4.4 mmHg and -5.7/-4.9 mmHg, resulting in mean BP values of 132.9/83.7 mmHg and 132.5/82.8 mmHg at the end of the studies. 4. Tolerability This section provides a brief summary of the tolerability profiles of telmisartan and amlodipine as individual agents, and reports adverse event data from the clinical trials discussed in section 3 (see section 3 for study details).  Adverse events associated with telmisartan are generally mild and transient in nature.[20] In placebo-controlled trials, the adverse events that occurred in 3% of telmisartan recipients, with a higher incidence than in placebo recipients, were upper respiratory tract infection (7% of telmisartan recipients [n = 1455] vs 6% of placebo recipients [n = 380]), back pain (3% vs 1%), sinusitis (3% vs 2%), and diarrhea (3% vs 2%).[20]
Am J Cardiovasc Drugs 2010; 10 (6)

Telmisartan/Amlodipine: Adis Drug Profile

409

 Amlodipine has been associated with generally mild or moderate adverse events, with some events being related to dose.[20] The most common dose-related adverse events in controlled clinical trials of amlodipine were edema (3.0% and 10.8% of amlodipine 5 [n = 296] or 10 mg [n = 268] recipients vs 0.6% of placebo recipients [n = 520]), dizziness (3.4% and 3.4% vs 1.5%), flushing (1.4% and 2.6% vs 0%), and palpitations (1.4% and 4.5% vs 0.6%).[20] For other adverse events that were not clearly dose related, the most common events (occurring in >2% of amlodipine recipients) in placebo-controlled trials of amlodipine were headache (7.3% of amlodipine recipients [n = 1730] vs 7.8% of placebo recipients [n = 1250]), fatigue (4.5% vs 2.8%), and nausea (2.9% vs 1.9%).[20]  Combination therapy with telmisartan plus amlodipine was generally well tolerated in clinical trials in adult patients with hypertension,[36] including trials in patients who had not responded adequately to amlodipine or telmisartan monotherapy.[51-56] Adverse events overall occurred at similar rates across treatment groups within each study.  Discontinuation because of adverse events was uncommon in the factorial-design study (2.2% of telmisartan plus amlodipine recipients and 4.3% of placebo recipients),[20] and in the studies in patients who had not responded adequately to amlodipine or telmisartan monotherapy (2.9% across treatment groups, apart from 7.6% of amlodipine 10 mg/day monotherapy recipients in the TEAMSTA-5 study [5.4% discontinued due to peripheral edema][51,52]).[53-56]  In the factorial-design study, eight patients overall (0.5%) experienced serious adverse events; one patient (in the telmisartan 80 mg/day plus amlodipine 2.5 mg/day group) experienced chest pain that was thought to be related to study drug treatment.[36] In the trials in patients who had not responded adequately to amlodipine or telmisartan monotherapy, most adverse events were mild or moderate in severity, and there were no drug-related serious adverse events.[51-56]  Peripheral edema and headache were the most common adverse events overall in the factorial-design study and in the study in patients with severe hypertension. In the factorialdesign study, headache occurred in 4.7% of patients who received telmisartan plus amlodipine, 5.9% of telmisartan monotherapy recipients, 6.0% of amlodipine monotherapy recipients, and 10.9% of placebo recipients. The incidence of peripheral edema appeared to be dose related (figure 3), and the addition of telmisartan appeared to reduce the incidence of edema compared with amlodipine monotherapy.[36]  In patients with severe hypertension, peripheral edema was reported by 13.1%, 3.7%, and 15.0% of telmisartan/amlodipine 80 mg/10 mg per day, telmisartan 80 mg/day, and amlodipine
2010 Adis Data Information BV. All rights reserved.

TEL 40

TEL 80

AML 5

AML 10

TEL 40 + AML 5

**

TEL 80 + AML 5

**

TEL 40 + AML 10

TEL 80 + AML 10

PL 0

5 10 15 20

Incidence (% of patients)

Fig. 3. Incidence of treatment-emergent peripheral edema in patients with hypertension receiving telmisartan (TEL) plus amlodipine (AML) or TEL or AML monotherapy.[20,36] In this randomized, double-blind, factorial-design study, adult patients with hypertension received oral TEL 20, 40, or 80 mg, or placebo (PL), plus AML 2.5, 5, or 10 mg, or PL once daily for 8 weeks (n = 1461). Only clinically relevant dosages are shown. Number of patients in treatment groups were 129146 apart from the PL group (n = 46).[59] y = occurred in 0% of patients. * p < 0.05, ** p < 0.0001 vs AML 10 mg/day (statistical analysis only reported for TEL/AML combinations versus AML 10 mg/day).[36]

10 mg/day recipients, respectively, and the corresponding incidences of headache were 3.8%, 8.3%, and 5.5%.[50]  Drug-related adverse events occurred in 12.9% of telmisartan plus amlodipine recipients, 6.5% of telmisartan monotherapy recipients, 12.2% of amlodipine monotherapy recipients, and 13.0% of placebo recipients in the factorial-design study; headache (3.4%) and peripheral edema (2.1%) were also the most common drug-related adverse events overall.[36] In the study in patients with severe hypertension, the incidences of drug-related adverse events were 12.6% (telmisartan/amlodipine 80 mg/10 mg per day), 6.9% (telmisartan 80 mg/day), and 16.4% (amlodipine 10 mg/day).[50]  Peripheral edema was the most common adverse event in the TEAMSTA-5 and -10 studies that assessed this adverse event as a primary[51,52] or secondary[54,55] endpoint, and in the openlabel TEAMSTA-5[57] and -10[58] follow-up studies. Peripheral edema was not reported in the other two studies in patients who had not responded to telmisartan or amlodipine monotherapy.[53,56]  In TEAMSTA-5,[52] treatment-related peripheral edema occurred in 3.2% and 2.9% of telmisartan/amlodipine 40 mg/5 mg
Am J Cardiovasc Drugs 2010; 10 (6)

410

Moen

or 80 mg/5 mg per day recipients versus 7.1% and 22.5% of amlodipine 5 or 10 mg/day recipients. The pooled incidence of peripheral edema in telmisartan/amlodipine recipients was significantly lower than that in amlodipine 10 mg/day recipients in this study (p < 0.001).[51] The incidence of drug-related peripheral edema in the TEAMSTA-10 study was 5.4% and 6.9% in telmisartan/amlodipine 40 mg/10 mg or 80 mg/10 mg per day recipients versus 6.3% in the amlodipine 10 mg/day group.[55] These apparently similar incidences (no statistical analysis) may be explained by the study design, which selected for patients who could tolerate amlodipine 10 mg/day.  The incidence of treatment-related peripheral edema was generally low (3.9%) in telmisartan/amlodipine recipients in the open-label TEAMSTA-5[57] and -10[58] follow-up studies. When corrected for patient years, the incidence of treatment-related peripheral edema appeared similar between treatment groups within each study (5.7 and 5.3 patients per 100 patient-years for telmisartan/amlodipine 40 mg/5 mg or 80 mg/5 mg per day recipients in the TEAMSTA-5 follow-up study, and 7.9 and 7.1 patients per 100 patient-years for telmisartan/amlodipine 40 mg/10 mg or 80 mg/10 mg per day recipients in the TEAMSTA-10 follow-up study). It should be noted that all patients who took part in these follow-up studies had tolerated treatment and completed the 8-week TEAMSTA-5 or -10 studies.  Other reported adverse events in the four trials in patients who had not responded adequately to amlodipine or telmisartan monotherapy were headache and dizziness (incidences for treatment groups not reported; incidence 2% overall),[51,52] hypercholesterolemia, arthralgia, diabetes, and hypertriglyceridemia (incidence 1% to <2.5% in any treatment group),[54,55] and nasopharyngitis (9.313.0% across treatment groups in two studies).[53,56] 5. Dosage and Administration Single-pill telmisartan/amlodipine is indicated for use in adult patients with hypertension in the US[20] and the EU,[21] and can be used as a replacement for separate telmisartan and amlodipine tablets. In the EU, telmisartan/amlodipine is also indicated for patients whose BP is not adequately controlled with amlodipine. In the US, telmisartan/amlodipine can be used by patients not achieving BP goals with amlodipine or telmisartan (or another calcium channel antagonist or angiotensin II receptor antagonist) alone, and may also be used as initial therapy if it is considered likely that the patient will require multiple drugs to achieve their BP goals, and after an assessment of potential risks and benefits for the patient. One telmisartan/amlodipine tablet should be taken once daily, with or without food.[20,21] The tablets are available in
2010 Adis Data Information BV. All rights reserved.

four single-pill combinations: telmisartan/amlodipine 40 mg/5 mg, 40 mg/10 mg, 80 mg/5 mg, and 80 mg/10 mg. As initial therapy, the recommended starting dosage is telmisartan/amlodipine 40 mg/5 mg once daily, or telmisartan/amlodipine 80 mg/5 mg once daily in patients requiring larger BP reductions.[20] Patients already taking telmisartan and amlodipine as separate tablets can transfer to telmisartan/amlodipine tablets at the same component doses if they are achieving satisfactory BP levels,[20,21] or change to telmisartan/amlodipine at a higher dosage if BP levels are not satisfactory.[20] Single-pill telmisartan/amlodipine dosages must be individualized.[20,21] The maximum recommended dosage is telmisartan/amlodipine 80 mg/10 mg once daily. The US manufacturers prescribing information contains a boxed warning to avoid use of telmisartan/amlodipine in pregnancy, because the drugs may cause injury or death to the fetus.[20] Local prescribing information should be consulted for other warnings and precautions, specific dosage and titration recommendations in special patient populations and drug interactions. 6. Telmisartan/Amlodipine: Current Status Single-pill telmisartan/amlodipine is approved in the US, the EU, and Japan for the treatment of hypertension.[60] Treatment with telmisartan/amlodipine resulted in significantly greater reductions in BP than telmisartan or amlodipine monotherapy in six randomized, double-blind, multicenter, 8-week trials in patients with hypertension, including some patients who had not responded to amlodipine or telmisartan monotherapy and some with severe hypertension. Most of the patients who received telmisartan/amlodipine achieved BP control during the studies. The telmisartan/amlodipine combination was effective in all patient populations in an ABPM substudy and across all subgroups in post hoc analyses of a large factorial-design study. Telmisartan/amlodipine was generally well tolerated in the 8-week studies and in two 36-week followup studies; in several studies the incidence of peripheral edema was lower with telmisartan/amlodipine combination therapy than with amlodipine 10 mg/day monotherapy. Acknowledgments and Disclosures
The manuscript was reviewed by: C. Borghi, Department of Cardiology, University of Bologna, Bologna, Italy; R. Guthrie, Department of Emergency Medicine, Ohio State University, Columbus, Ohio, USA. The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Am J Cardiovasc Drugs 2010; 10 (6)

Telmisartan/Amlodipine: Adis Drug Profile

411

References
1. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA 2003 May 21; 289 (19): 2560-72 2. Neutel JM. Prescribing patterns in hypertension: the emerging role of fixeddose combinations for attaining BP goals in hypertensive patients. Curr Med Res Opin 2008 Aug; 24 (8): 2389-401 3. Bakris GL. Combined therapy with a calcium channel blocker and an angiotensin II type 1 receptor blocker. J Clin Hypertens (Greenwich) 2008 Jan; 10 (1 Suppl. 1): 27-32 4. Plosker GL, Robinson DM. Amlodipine/valsartan: fixed-dose combination in hypertension. Drugs 2008; 68 (3): 373-81 5. Sanford M, Keam SJ. Olmesartan medoxomil/amlodipine. Drugs 2009; 69 (6): 717-29 6. Chrysant SG. Using fixed-dose combination therapies to achieve blood pressure goals. Clin Drug Investig 2008; 28 (11): 713-34 7. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010 Feb; 55 (2): 399-407 8. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007 Aug; 120 (8): 713-9 9. Dickson M, Plauschinat CA. Compliance with antihypertensive therapy in the elderly: a comparison of fixed-dose combination amlodipine/benazepril versus component-based free-combination therapy. Am J Cardiovasc Drugs 2008; 8 (1): 45-50 10. Erdine S. Compliance with the treatment of hypertension: the potential of combination therapy. J Clin Hypertens (Greenwich) 2010 Jan; 12 (1): 40-6 11. McClellan KJ, Markham A. Telmisartan. Drugs 1998 Dec; 56 (6): 1039-44 12. Sharpe M, Jarvis B, Goa KL. Telmisartan: a review of its use in hypertension. Drugs 2001; 61 (10): 1501-29 13. Battershill AJ, Scott LJ. Telmisartan: a review of its use in the management of hypertension [published erratum appears in Drugs 2006; 66 (15): 1987]. Drugs 2006 Oct; 66 (1): 51-83 14. Murdoch D, Heel RC. Amlodipine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease. Drugs 1991; 41 (3): 478-505 15. Haria M, Wagstaff AJ. Amlodipine: a reappraisal of its pharmacological properties and therapeutic use in cardiovascular disease. Drugs 1995; 50 (3): 560-86 16. Plosker GL, White WB. Telmisartan/hydrochlorothiazide: a review of its use as fixed-dose combinations in essential hypertension. Drugs 2008; 68 (13): 1877-99 17. Frampton JE, Scott LJ. Amlodipine/valsartan single-pill combination: a review of its use in the management of hypertension. Am J Cardiovasc Drugs 2009; 9 (5): 309-30 18. McKeage K, Siddiqui MAA. Amlodipine/atorvastatin fixed-dose combination: a review of its use in the prevention of cardiovascular disease and in the treatment of hypertension and dyslipidemia. Am J Cardiovasc Drugs 2008; 8 (1): 51-67 19. Fenton C, Keating GM, Scott LJ. Telmisartan/hydrochlorothiazide: in the treatment of essential hypertension. Drugs 2003; 63 (19): 2013-26 20. Twynsta (telmisartan/amlodipine) tablets: US prescribing information. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals Inc., 2009 Oct 21. Twynsta (telmisartan/amlodipine) 40 mg/5 mg, 80 mg/5 mg, 40 mg/10 mg and 80 mg/10 mg tablets: EU summary of product characteristics. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH, 2010 22. Fogari R, Derosa G, Zoppi A, et al. Effect of telmisartan-amlodipine combination at different doses on urinary albumin excretion in hypertensive diabetic patients with microalbuminuria. Am J Hypertens 2007 Apr; 20 (4): 417-22 23. Fogari R, Preti P, Lazzari P, et al. Antiproteinuric effect of telmisartan/ amlodipine versus losartan/amlodipine combination in microalbuminuric hypertensive patients with type 2 diabetes [abstract no. P4.120]. J Hypertens 2009; 27 Suppl. 3: S71
2010 Adis Data Information BV. All rights reserved.

24. Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator-activated receptor-g activity. Circulation 2004 May 4; 109 (17): 2054-7 25. Inoue T, Node K. Telmisartan as a metabolic sartan for targeting vascular failure. Expert Opin Pharmacother 2008 Jun; 9 (8): 1397-406 26. Sanchez RA, Masnatta LD, Pesiney C, et al. Telmisartan improves insulin resistance in high renin nonmodulating salt-sensitive hypertensives. J Hypertens 2008 Dec; 26 (12): 2393-8 27. Veronesi M, Cicero AFG, Prandin MG, et al. Effects of telmisartan and bisoprolol on blood pressure, peripheral haemodynamic and lipid profile in statin-treated hypertensive hypercholesterolaemic patients. High Blood Press Cardiovasc Prev 2009; 16 (1): 7-12 28. Ono Y, Nakaya Y, Bando S, et al. Telmisartan decreases plasma levels of asymmetrical dimethyl-L-arginine and improves lipid and glucose metabolism and vascular function. Int Heart J 2009 Jan; 50 (1): 73-83 29. Mann JF, Schmieder RE, Dyal L, et al. Effect of telmisartan on renal outcomes: a randomized trial. Ann Intern Med 2009 Jul 7; 151 (1): 1-10, W1-2 30. Bakris G, Burgess E, Weir M, et al. Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy. Kidney Int 2008 Aug; 74 (3): 364-9 31. Stangier J, Su C-APF. Pharmacokinetics of repeated oral doses of amlodipine and amlodipine plus telmisartan in healthy volunteers. J Clin Pharmacol 2000 Dec; 40 (12 Pt 1): 1347-54 32. Tanswell P, Kunz U, Harada A, et al. Pharmacokinetics of telmisartan after repeated oral dosing are not altered by concomitant administration of amlodipine [abstract no. P27.338]. J Hypertens 2009; 27 Suppl. 3: S282-283. Plus poster presented at the 19th European Meeting on Hypertension; 2009 Jun 13-16; Milan 33. Micardis (telmisartan) tablets: US prescribing information. Ridgefield (CT): Boehringer Ingelheim Pharmaceuticals, Inc., 2009 Oct 34. Norvasc (amlodipine besylate) tablets for oral administration: US prescribing information. New York: Pfizer Labs, 2010 Jan 35. Micardis (telmisartan) 20/40/80 mg tablets: EU summary of product characteristics. Ingelheim am Rhein, Germany: Boehringer Ingelheim International GmbH, 2010 36. Littlejohn III TW, Majul CR, Olvera R, et al. Results of treatment with telmisartan-amlodipine in hypertensive patients. J Clin Hypertens (Greenwich) 2009 Apr; 11 (4): 207-13 37. Littlejohn T, Majul C, Oigman W, et al. Superior antihypertensive efficacy of the combination of telmisartan and amlodipine versus respective monotherapies in patients with hypertension: results of a factorial design study [abstract no. PS32/WED/39]. J Hypertens 2008; 26 Suppl. 1: S460. Plus poster presented at the 18th European Meeting on Hypertension; 2008 Jun 14-19; Berlin 38. Littlejohn III TW, Majul CR, Olvera R, et al. Telmisartan plus amlodipine in patients with moderate or severe hypertension: results from a subgroup analysis of a randomized, placebo-controlled, parallel-group, 4 4 factorial study. Postgrad Med 2009 Mar; 121 (2): 5-14 39. Littlejohn III T, Dahlof B, Chrysant SG, et al. Combination of telmisartan with amlodipine provides an effective treatment option for elderly patients: subanalysis from a factorial design study [abstract no. P26.310]. J Hypertens 2009; 27 Suppl. 3: S274 40. Littlejohn T, Graff A, Punzi H, et al. Efficacy of telmisartan in combination with amlodipine in hypertensive patients according to race: sub-analysis from a factorial design study [abstract no. P-50]. J Clin Hypertens 2009; 11 Suppl. A (4): A37 41. Littlejohn T, Graff A, Majul CR, et al. Efficacy of telmisartan in combination with amlodipine in hypertensive patients from Latin and North America: subanalysis from a factorial design study [abstract no. P-48]. J Clin Hypertens 2009; 11 Suppl. A (4): A36 42. Littlejohn III T, Ruilope LM, Raskin P, et al. Telmisartan in combination with amlodipine provides a highly effective and well tolerated treatment option for hypertensive patients with diabetes: sub-analysis from a factorial design study [abstract no. P26.313]. J Hypertens 2009; 27 Suppl. 3: S275
Am J Cardiovasc Drugs 2010; 10 (6)

412

Moen

43. Littlejohn III T, Ruilope LM, Chrysant SG, et al. Efficacy of telmisartan in combination with amlodipine in obese hypertensive patients: sub-analysis from a factorial design study [abstract no. P26.305]. J Hypertens 2009; 27 Suppl. 3: S272 44. Littlejohn III T, Dahlof B, Punzi H, et al. Telmisartan in combination with amlodipine is effective in both treatment-naive and previously treated hypertensive patients: sub-analysis from a factorial design study [abstract no. P26.321]. J Hypertens 2009; 27 Suppl. 3: S277 45. Littlejohn III T, Dahlof B, Chrysant SG, et al. Telmisartan and amlodipine in combination provide an effective treatment option for patients with elevated systolic BP: sub-analysis from a factorial design study [abstract no. P26.312]. J Hypertens 2009; 27 Suppl. 3: S274-5 46. White WB, Littlejohn TW, Majul CR, et al. Effects of telmisartan and amlodipine in combination on ambulatory blood pressure in stages 1-2 hypertension. Blood Press Monit 2010 Aug; 15 (4): 205-12 47. Littlejohn III T, Mancia G, Christensen S, et al. Telmisartan and amlodipine in combination are effective at lowering 24-hour BP in elderly hypertensive patients and those with elevated SBP: findings of an ABPM sub-study [abstract no. P26.308]. J Hypertens 2009; 27 Suppl. 3: S273 48. Littlejohn III T, Mancia G, Guthrie R, et al. Telmisartan and amlodipine in combination are effective at lowering 24-hour BP in diabetic and obese hypersensitive patients: findings of an ABPM sub-study [abstract no. P26.307]. J Hypertens 2009; 27 Suppl. 3: S273 49. Littlejohn III T, Mancia G, Guthrie R, et al. Telmisartan and amlodipine in combination are effective at lowering 24-hour BP in Black and Latin American hypertensive patients: findings of an ABPM sub-study [abstract no. P26.322]. J Hypertens 2009; 27 Suppl. 3: S278 50. Neutel J, Mancia G, Black H, et al. Single-pill combination of telmisartan 80 mg/amlodipine 10 mg provides superior blood pressure reductions in patients with severe hypertension: TEAMSTA severe HTN study [abstract no. HT.1.04]. J Hypertens 2010 Jun; 28 e-Suppl. A: e46. Plus poster presented at the 25th Annual Scientific Meeting of the American Society of Hypertension; 2010 May 1-4 51. Neldam S, Lang M, TEAMSTA-5 Study Investigators. Fixed-dose combination therapy with telmisartan and amlodipine 5 mg in non-responders to amlodipine 5 mg provides superior blood pressure reductions to, and is better tolerated than, amlodipine 10 mg [abstract no. P26.309]. J Hypertens 2009; 27 Suppl. 3: S273-274. Plus poster presented at the 19th European Meeting on Hypertension; 2009 Jun 12-16; Milan 52. Boehringer Ingelheim International GmbH. Telmisartan plus amlodipine study in amlodipine 5 mg non-responders in hypertension: TEAMSTA-5 (clinical trial results database; trial no. 1235.5) [online]. Available from URL: http://trials.boehringer-ingelheim.com/com/Home/TrialResults/index.jsp [Accessed 2010 Apr 19]

53. Boehringer Ingelheim International GmbH. A randomised, double-blind trial to compare telmisartan 40 mg plus amlodipine 5 mg fixed-dose combination to amlodipine 5 mg monotherapy in patients not controlled with amlodipine 5 mg monotherapy (clinical trial results database; trial no. 1235.13) [online]. Available from URL: http://trials.boehringer-ingelheim.com/com/Home/ TrialResults/index.jsp [Accessed 2010 Apr 19] 54. Neldam S, Edwards C, TEAMSTA-10 Study Investigators. Switch to a fixeddose combination therapy with telmisartan and amlodipine provides significant blood pressure reduction and control in patients not adequately controlled with amlodipine 10 mg [abstract no. P26.319]. J Hypertens 2009; 27 Suppl. 3: S277. Plus poster presented at the 19th European Meeting on Hypertension; 2009 Jun 12-16; Milan 55. Boehringer Ingelheim International GmbH. Telmisartan plus amlodipine study in amlodipine 10 mg non-responders in hypertension: TEAMSTA-10 (clinical trial results database; trial no. 1235.6) [online]. Available from URL: http://trials.boehringer-ingelheim.com/com/Home/TrialResults/index.jsp [Accessed 2010 Apr 19] 56. Boehringer Ingelheim International GmbH. A randomised, double-blind trial to compare telmisartan 40 mg plus amlodipine 5 mg fixed-dose combination to telmisartan 40 mg monotherapy in patients not controlled with telmisartan 40 mg monotherapy (clinical trial results database; trial no. 1235.14) [online]. Available from URL: http://trials.boehringer-ingelheim.com/com/Home/ TrialResults/index.jsp [Accessed 2010 Apr 19] 57. Neldam S, Lang M, Jones R. Long-term efficacy and safety profile of single-pill combinations of telmisartan/amlodipine in patients not controlled on amlodipine 5 mg: open-label follow-up of TEAMSTA-5 [abstract plus poster]. 20th European Meeting on Hypertension; 2010 Jun 18-21; Oslo 58. Neldam S, Edwards C, Jones R. Long-term efficacy and safety profile of singlepill combinations of telmisartan/amlodipine in patients not controlled on amlodipine 10 mg: open-label follow-up of TEAMSTA-10 [abstract plus poster]. 20th European Meeting on Hypertension; 2010 Jun 18-21; Oslo 59. Boehringer Ingelheim Pharmaceuticals. Telmisartan (Micardis) and amlodipine (Norvasc) factorial design study for the treatment of hypertension [ClinicalTrials.gov identifier NCT00281580]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://www.clinicaltrials.gov [Accessed 2010 May 20] 60. Boehringer Ingelheim. European Medicines Agency approves Twynsta (telmisartan plus amlodipine) a new single pill combination that delivers powerful and consistent blood pressure reductions throughout 24 hours [media release]. 2010 Oct 12

Correspondence: Marit D. Moen, Adis, a Wolters Kluwer Business, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, North Shore 0754, Auckland, New Zealand. E-mail: demail@adis.co.nz

2010 Adis Data Information BV. All rights reserved.

Am J Cardiovasc Drugs 2010; 10 (6)