Study finds valsartan to be safe and effective for paediatric hypertension? Reference: Hypertension 2008;52:201-202,222-228
Source: Hypertension
Date published: 01/09/2008 15:11
Summary
by: Nicola Pocock According to the results of a study published in the journal ‘Hypertension’, valsartan effectively lowers blood pressure in children aged 1 to 5 years with hypertension, without any apparent adverse effect on growth.
A total of 90 children aged 1-5 years (mean age 3.2 years) weighing at least 8kg with a seated systolic blood pressure (SBP) ≥ 95th percentile for age, gender, and height were included in the study. This consisted of four parts:
- One-week placebo run-in phase
- Phase 1: a two-week, double-blind, dose-response phase, during which participants were randomised to low, medium, or high valsartan dose groups; dosing in each group varied with patient weight
- Phase 2: patients were reassigned randomly to either continue their phase 1 valsartan dose or to switch to placebo for up to 14 additional days
- Phase 3: an optional 52-week, open-label treatment phase during which patients were treated with open-label valsartan (20mg – 80mg) to achieve a goal SBP of <95th percentile (hydrochlorothiazide could be added if this was not achieved using valsartan alone)
The primary endpoints were the change in mean seated SBP from baseline to the end of phase 1 and the change in mean seated SBP from the end of phase 1 to the end of phase 2. The main findings were as follows:
• In phase 1, valsartan lowered both SBP and diastolic blood pressure (DBP) in all dose groups (SBP: low dose: –8.4 mm Hg; medium dose: –8.3 mm Hg; high dose: –8.6 mm Hg; DBP: low dose: –5.5 mm Hg; medium dose: –6.4 mm Hg; high dose: –5.5 mm Hg)
• From the end of phase 1 to the end of phase 2, subjects who remained on valsartan exhibited a mean reduction in seated SBP of –1.5 mm Hg, whereas placebo recipients had a mean increase in SBP of 1.5 mm Hg (least-squares mean difference of –3.9 mmHg; P=0.02).
• During the open-label phase, 80 of 88 subjects (90.9%) remained on valsartan monotherapy (38 at 20 mg, 24 at 40 mg, and 18 at 80 mg), whereas 8 (9.1%) were treated with valsartan plus HCTZ (6 at 80/12.5 mg and 2 at other combinations). By the end of this phase, 77.3% of subjects had achieved a mean seated SBP <95th percentile.
• Adverse events were minor and occurred at similar frequencies in each of the 3 dose groups in phase 1 and at equal frequencies in the valsartan and placebo arms in phase 2. Serious adverse events and drug-related adverse events occurred infrequently during both the double-blind (2.2% and 5.6%, respectively) and open-label (14.8% and 6.8%, respectively) portions of the study. There were no demonstrable negative effects on growth and development.
The investigators conclude that “valsartan, a selective angiotensin type I receptor blocker, produced significant reduction in SBP compared with placebo with a low rate of discontinuations because of AEs. Further study is warranted to more clearly delineate the role of valsartan in the management of young children with hypertension.” The author of a related editorial suggests that the lack of a dose-response relation in this study as well as in other recent childhood antihypertensive studies may be due to the failure to use a broad enough dosing range.
Data Sheet
Paediatric Use
Antihypertensive effects of COZAAR have been established in hypertensive paediatric patients aged >1 month to 16 years. Use of COZAAR in these age groups is supported by evidence from adequate and well-controlled studies of COZAAR in paediatric and adult patients as well as by literature in paediatric patients.
The pharmacokinetics of losartan have been investigated in 50 hypertensive paediatric patients >1 month to <16 years of age following once daily oral administration of approximately 0.54 to 0.77 mg/kg of losartan (mean doses). The active metabolite is formed from losartan in all age groups. Pharmacokinetics of losartan and its active metabolite are generally similar across the studied age groups and consistent with pharmacokinetic historic data in adults.
In a clinical study involving 177 hypertensive paediatric patients 6 to 16 years of age, patients who weighed ≥20 kg to <50 kg received either 2.5, 25 or 50 mg of losartan daily and patients who weighed ≥50 kg received either 5, 50 or 100 mg of losartan daily. Losartan administration once daily lowered trough blood pressure in a dose-dependent manner. The dose response to losartan was observed across all subgroups (e.g., age, Tanner stage, gender, race). However, the lowest doses studied, 2.5 mg and 5 mg, corresponding to an average daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy. In this study, COZAAR was generally well tolerated.
For patients who can swallow tablets, the recommended dose is 25 mg once daily in patients ≥20 to <50 kg. The dose can be increased to a maximum of 50 mg once daily. In patients ≥50 kg, the starting dose is 50 mg once daily. The dose can be increased to a maximum of 100 mg once daily.
In paediatric patients who are intravascularly volume depleted, these conditions should be corrected prior to administration of COZAAR.
The adverse experience profile for paediatric patients appears to be similar to that seen in adult patients.
COZAAR is not recommended in paediatric patients with glomerular filtration rate <30 mL/min/1.73 m2, in paediatric patients with hepatic impairment, or in neonates as no data are available.
The 3 unsuccessful studies (trials of amlodipine, fosinopril, and irbesartan) used change in sitting systolic blood pressure as the primary outcome (Table 2).
Paediatric formulation of bosentan (Tracleer®) approved in EU Source: PharmaTimes
Date published: 07/07/2009 15:30
Summary
by: Nicola Pocock A paediatric dispersible formulation of bosentan (Tracleer®) has been approved in the EU for the treatment of pulmonary arterial hypertension (PAH) in children from two years of age.
Until now only the film-coated tablets have been available (62.5mg and 125mg); the dispersible 32mg tablet formulation allows a more flexible dosing regimen. According to the company press release, the key trials in the paediatric research program include:
• BREATHE-3 (Bosentan Randomized trial of Endothelin Antagonist THErapy for pulmonary hypertension): an open-label study that provided safety and efficacy data in children with PAH treated with Tracleer® with or without concomitant prostanoid therapy. It also provided important information on the dose required in the paediatric formulation.
• FUTURE-1 (Pediatric FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion): an open-label study that evaluated the safety and pharmacokinetics of a new dispersible tablet formulation of Tracleer®. This study provided important pharmacokinetic and dosing information using the new paediatric formulation of bosentan. In FUTURE-1, the observed exposure to Tracleer® was similar to that in children who participated in BREATHE-3.
• FUTURE-2: an open-label safety extension study is ongoing to assess long-term safety and outcome data.
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