Antihypertensive efficacy of amlodipine in children with chronic kidney diseases

(2001) 15, 387 391 2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Antihypertensive efficacy of amlodipine in children with chronic kidney diseases RO von Vigier, LMD Franscini, NDF Bianda, R Pfister, C Casaulta Aebischer and MG Bianchetti Division of Nephrology, University Children s Hospital, Inselspital, Bern, Switzerland In adults the calcium antagonist amlodipine given once a day has proved to be an attractive addition to the antihypertensive armamentarium. The present report describes our experience in 43 paediatric outpatients (26 boys and 17 girls, aged between 1.1 and 19, median 9.8 years) with chronic kidney diseases. The patients were given amlodipine for 16 weeks as part of their antihypertensive treatment. Before amlodipine arterial pressure was 150 (142 163)/90 (84 95) mm Hg (median and interquartile range). Six patients withdrew from amlodipine because of oedema, flushing or headache. In the remaining patients amlodipine 7.7 (6.9 9.4) mg/m 2 body surface area once a day significantly decreased arterial pressure by 17 (13 22)/10 (7 13) mm Hg. The efficacy of amlodipine was more pronounced in girls than in boys. No changes in heart rate, body weight and circulating haemoglobin, sodium, potassium and creatinine were noted. In none of the patients circulating potassium, sodium or creatinine changed by more than 0.5 mmol/l, 5 mmol/l respectively 20%. In 11 patients concomitantly treated with cyclosporine the dosage and the trough-level of this agent were stable throughout the trial. In conclusion the present experience in paediatric outpatients with chronic kidney diseases supports the view that amlodipine is an effective and rather well tolerated antihypertensive drug when given once a day. (2001) 15, 387 391 Keywords: amlodipine; calcium antagonist; childhood; kidney diseases Introduction In adults the calcium antagonist amlodipine has assumed an important role in therapeutics of arterial hypertension. 1 4 The success and widespread use of this dihydropyridine derivative is mainly related to its unique pharmacokinetic profile. 5 7 Amlodipine is a low-clearance, hepatically metabolised drug with high oral bioavailability. As would be expected from these data, amlodipine can be administered once a day with very limited interdose fluctuations in antihypertensive effect. In addition the pharmacokinetics indicates that the clearance of amolodipine is unchanged in kidney diseases. Finally the mentioned features suggest that amlodipine has a reduced propensity to cause side effects which result from rapid onset of vasodilatation such as flushing, headache and dizziness and may therefore enhance patient adherence to prescribed medications. 8 In paediatric patients antihypertensive drugs are not investigated prior to approval for marketing in adulthood and information is mostly obtained dur- Correspondence: MG Bianchetti, University Children s Hospital, Inselspital, CH-3010 Bern, Switzerland E-mail: mario.bianchetti insel.ch Received 3 December 2000; revised and accepted 13 February 2001 ing clinical use, with initial doses determined by extrapolation from adult doses. 9 11 The objective of the present report is to describe our prospective experience in children with chronic kidney diseases who were administered amlodipine for 16 weeks as part of their pharmacological treatment of arterial hypertension. The report includes 16 patients enrolled in a trial published in part earlier. 12 Patients and methods Forty-three Caucasian patients (26 male and 17 female subjects, aged between 1.1 and 19, median 9.8 years) on ambulatory follow-up at the Division of Nephrology, Department of Pediatrics, University of Bern, Switzerland, were prospectively evaluated between 1992 and 1999. The underlying conditions were glomerular diseases (n = 19), urinary tract malformations (n = 8), polycystic kidney disease (n = 3), renal artery stenosis (n = 3), interstitial nephritis (n = 1), renal hypoplasia (n = 1) and renal transplant (n = 8). Renal function was either normal (normal plasma creatinine for age and gender, n = 18), mildly reduced (plasma creatinine increased but less than 177 mol/l; n = 12) or moderately reduced (plasma creatinine ranging between 178 and 354 mol/l, n = 5). 13 Eight patients were on regular dialysis (haemodialysis, n = 3; home peritoneal dialysis, n =

388 5). In the 43 patients sitting arterial pressure was persistently above the centile 95 for body length and gender. 14 Arterial hypertension was either mild (systolic value up to 19 mm Hg or diastolic value up to 9 mm Hg above centile 95; n = 14), moderate (systolic value 20 to 39 mm Hg or diastolic value 10 to 19 mm Hg above centile 95, n = 22) or severe (systolic value more than 39 mm Hg or diastolic value more than 19 mm Hg above centile 95, n = 7). 15 Sixteen of the 43 patients, subsequently reported to as pretreated, were on medication with a variety of antihypertensive agents: diuretics, n = 6; enalapril, n = 4; perindopril, n = 1; diuretics associated with enalapril, n = 5. The regularly scheduled antihypertensive regimen had not been changed for at least 4 weeks and was continued during treatment with amlodipine. The remaining 27 patients, subsequently reported to as unpretreated, were not on antihypertensive drugs. Arterial pressure, heart rate and body weight were measured and blood taken for the determination of haemoglobin, sodium, potassium, creatinine, aminotranferases and creatine kinase from each patient before entering the trial and 16 weeks after amlodipine (respectively immediately before withdrawing amlodipine). The whole blood cyclosporine trough-level was measured using a specific monoclonal fluorescent polarisation immunoassay in the patients treated with this agent. Patients were monitored by a written questionnaire before and during amlodipine for the presence of abdominal pain, constipation, cough, diarrhoea, dizziness, oedema, fatigue, headache, insomnia, nausea and rash. Amlodipine was started at a once a day dose of 2.5 (body weight ranging between 10 and 30 kg) or 5 mg (body weight 31 kg or more) on awakening. The dose was then increased (up to no more than 0.5 mg/kg body weight respectively 20 mg) if necessary: (a) failure to decrease systolic arterial pressure 5 mm Hg or more 3 to 4 weeks after amlodipine, or (b) systolic arterial pressure above the centile 95 for body length and gender 6 to 8 weeks after amlodipine. Sitting ( 10 min) arterial pressure (first and fifth sound) was measured after overnight by means of a mercury sphygmomanometer with a cuff covering approximately three quarters of the upper arm length from the acromion to the olecranon; each recorded value was the mean of at least three consecutive measurements. The arterial pressure response to amlodipine was evaluated 24 h postdose. Adherence to prescribed amlodipine was assessed by pill count and pharmacy records. The study protocol had been approved by the local ethical committee and by the participants. The results are given as median and interquartile range. Nonparametric analysis of variance for repeated measurements, the McNemar change test (with the Yates correction for continuity) and simple regressions with the coefficient of correlation r s were used for analysis. A P value below 0.05 was regarded as statistically significant. Results Before amlodipine arterial pressure was 150 (142 163)/90 (84 95) mm Hg and heart rate 77 (74 83) beats/min in the 43 patients enrolled in the trial. The written questionnaire disclosed adverse clinical events in 10 patients before (six male and four female subjects, aged between 5.0 and 17, median 11 years) and in 17 during (eight male and nine female subjects, aged between 3.2 and 17, median 8.4 years) amlodipine (P 0.05), as given in Table 1. The frequency of abdominal pain, constipation, cough, diarrhoea, dizziness, fatigue, insomnia, nausea and rash was similar before and with amlodipine, that of oedema and headache significantly increased on amlodipine. Consequently six patients (two boys and four girls, aged 3.2 to 17, median 11 years) withdrew from amlodipine because of oedema (n = 2), oedema and headache (n = 2). or headache (n = 2). The remaining adverse events were not relevent. Consequently no more than 37 patients (86%) brought the trial to completion. The laboratory safety values (aminotransferases and creatinine kinase) were similar before and during amlodipine. At the end of the 16-week treatment phase the use of amlodipine was associated with a significant (P 0.005) decrease in arterial pressure by 17 (13 22)/10 (7 13) mm Hg (Table 2). The antihypertensive efficacy of amlodipine was more pronounced (P 0.05) in girls (19 (15 213)/11 (8 13) mm Hg) than in boys (16 (12 20)/9 (6 12) mm Hg). The influence of amlodipine on arterial pressure was similar in the 23 unpretreated (16 (13 21)/10 (7 12) mm Hg) and in the 14 pretreated patients (18 (11 22)/9 (7 12) mm Hg) who brought the study to completion. At Table 1 Adverse clinical experiences and laboratory safety values before and with amlodipine in 43 paediatric patients with chronic kidney diseases (26 male and 17 female subjects, aged 1.1 to 19, median 9.8 years). Some adverse experiences concurrently occurred in the same patient Before With P value amlodipine amplodipine (n) (n) All events 10 17 0.05 Abdominal pain 1 1 NS Constipation 2 4 NS Cough 2 2 NS Diarrhoea 2 1 NS Dizziness 2 2 NS Oedema 0 4 0.05 Fatigue 3 3 NS Headache 0 4 0.05 Insomnia 2 2 NS Nausea 0 0 NS Rash 0 1 NS Pathologically increased Alanine aminotransferase 2 1 NS Aspartate aminotransferase 1 1 NS Creatine kinase 2 2 NS NS, not significant.

Table 2 Clinical and laboratory values before and with amlodipine in 37 paediatric patients with chronic kidney diseases (24 male and 13 female subjects, aged 1.1 to 19, median 9.0 years) who brought the study to completion. The results are as given as median and interquartile range 389 Before amlodipine With amlodipine P value Arterial pressure, absolute value systolic (mm Hg) 150 (140 164) 136 (126 146) 0.005 diastolic (mm Hg) 91 (84 95) 81 (78 85) 0.005 Arterial pressure, above centile 95 a systolic (mm Hg) 32 (19 46) 16 (10 24) 0.005 diastolic (mm Hg) 12 (8 15) 2 ( 2 7) 0.005 Heart rate (beats/min) 79 (74 83) 81 (73 88) NS Body weight (kg) 33 (24 50) 37 (24 50) NS Blood haemoglobin (g/l) 124 (111 136) 125 (114 135) NS Plasma creatinine ( mol/l) 75 (58 83) 75 (65 85) NS Plasma sodium (mmol/l) 138 (135 140) 136 (135 140) NS Plasma potassium (mmol/l) 4.2 (3.9 4.5) 4.2 (3.9 4.5) NS a For gender, age and height. NS, not significant. that time both systolic and diastolic arterial pressure were below centile 95 in 12 of the 37 patients who completed the study. The initial amlodipine dosage of 0.13 (0.10 0.15) mg/kg once a day had been subsequently increased up to 0.26 (0.20 0.33) mg/kg once a day (corresponding to 7.7 (6.9 9.4) mg/m 2 body surface area). No significant changes in heart rate, body weight and circulating haemoglobin, sodium, potassium and creatinine were noted. In none of the patients plasma potassium, sodium or creatinine levels changed by more than 0.5 mmol/l, 5 mmol/l respectively 20%. The antihypertensive effect of amlodipine (17 (12 22)/10 (7 13) vs 18 (13 21)/9 (7 11) mm Hg) and its dose (0.27 (0.15 0.32) vs 0.25 (0.21 0.34) mg/kg body weight once a day) were similar in 15 patients with normal and in 22 with reduced renal function who brought the study to completion. Linear regression analysis disclosed a significant inverse relationship between patient age and final amlodipine dose, expressed in mg/kg body weight daily (Figure 1). No significant correlation was demonstrated between patient age and amlodipine dose, expressed in mg/m 2 body surface area daily (Figure 2). Further regression analysis failed to demonstrate a significant relationship between amlodipine dose, expressed either as mg/kg body weight daily or as mg/m 2 body surface area daily, and change in arterial pressure. Finally no significant correlation was noted between patient age and the influence of amlodipine on arterial pressure. In the patients treated with cyclosporine the dosage and the trough-level of this agent were stable throughout the trial, as shown in Table 3. Discussion The L-type voltage gated calcium channels are responsible for vascular smooth muscle contractility and myocardial contractility. 16 Acting on the mentioned channels the dihydropyridines are potent vasodilators with little or no effect upon cardiac Figure 1 Relationship between patient age and dose of amlodipine in mg/kg body weight daily in 37 paediatric patients with chronic kidney diseases (24 male and 13 female subjects, aged 1.1 to 19, median 9.0 years). contractility. 16,17 Based upon half-life and effect on myocardial contractility these agents are divided into three categories: 16,17 the short-acting (such as standard nifedipine), the longer-acting formulations with little cardiac depressant activity (such as slow release nifedipine, felodipine, isradipine and nicardipine) and the long-acting agents with no cardiac depressant activity (such as amlodipine). The present experience indicates that amlodipine given once a day in a dose of approximately 7 to 10 mg/m 2 body surface area is an effective treatment for the long term management of mild to severe arterial hypertension in children with chronic kidney diseases. Females show a geater response to this dihydropyridine than males. 1 3 In this study younger patients required significantly higher doses per kilogram of body weight than older children, as previously noted by others. 18 No significant relationship was demonstrated, how-

390 Figure 2 Relationship between patient age and dose of amlodipine in mg/m 2 body surface area daily in 37 paediatric patients with chronic kidney diseases (24 male and 13 female subjects, aged 1.1 to 19, median 9.0 years). Table 3 Dosage and blood concentration of cyclosporine levels in 11 pediatric patients (six boys and five girls, aged between 2.9 and 17, median 11 years) with chronic kidney diseases before and during treatment with amlodipine. Results are given as median and interquartile range Before With P value amlodipine amlodipine Cyclosporine dosage 4.9 (4.2 6.0) 5.0 (4.3 5.9) NS (mg/kg) a Cyclosporinemia 115 (88 153) 121 (99 161) NS ( g/l) a Given in two daily doses. NS, not significant. ever, between amlodipine dose and patient age when the dosage was expressed as mg/m 2 body surface area. This observation confirms the traditional assumption that dosage schedules based on body surface area are a more reliable guide for the calculations of dosages than those based on body weight. 11,19 The side effects noted in our paediatric patients given amlodipine are similar to those reported in adults and children treated with amlodipine or other dihydropyridines. 1 4,18,20 23 These vasodilators lead in 10 to 20% of patients to one or more of the following: headache, dizziness or lightheadedness, flushing, and peripheral oedema. The peripheral oedema is related to redistribution of fluid from the vascular space into the interstitium, possibly induced by vasodilatation which allows more of the arterial pressure to be transmitted to the capillary circulation. 8 Females appear more susceptible to this adverse effect of dihydropyridines than males. 8 Furthermore, concomitant medication with converting enzyme inhibitors might counter the tendency towards peripheral oedema induced by calcium antagonists. 8 Our patients who developed peripheral oedema and headache on amlodipine discontinued the agent, as previously reported by others. Instead, amlodipine dose reduction was recently suggested. 18 Finally in patients given calcium antagonists acute vasodilatation can enhance sympathetic activity resulting in an increase in heart rate. This change is primarily observed with the short acting, but not with the long-acting dihydropyridine amlodipine. 1 4,16,17 The catabolism of cyclosporine is modified by the concomitant use of the calcium antagonists verapamil and diltiazem, which significantly increase cyclosporine levels. Cyclosporine levels during amlodipine treatment have been so far evaluated in at least eight studies, as recently reviewed. 24 Our observations support the literature and suggest that the effect of amlodipine on the cyclosporine biotransformation is not as great as that seen with verapramil or diltiazem. Amlodipine offers some practical advantages over other dihydropyridine derivatives, which are relevant for treating arterial hypertension in children with chronic kidney diseases. Unlike nifedipine, amlodipine is formulated as a non-sustained release tablet, that can be divided (or dissolved in a liquid preparation) without destroying the integrity of the dosage form. 25 In addition the practice to give drugs once a day provides a convenient dosing schedule that helps to improve adherence to prescribed medications. Finally dose adjustment is superfluous in renal impairment. 1 4,16,17 Paediatric use of amlodipine has previously been reported, 12,18,20 23 but previous reports have been limited by small patient numbers 12,20 23 and rather heterogenous patient populations, that included both in- and outpatients 18,20 or both renal and non renal hypertension. 12,18,20,21 In conclusion the results of the present experience in paediatric outpatients with chronic kidney diseases support the view that amlodipine is an effective and rather well tolerated antihypertensive drug when given once a day in a dosage of 7 to 10 mg/m 2 body surface area and suggest that it has obvious advantages over other dihydropyridines. 26 References 1 Tyler HM. Amlodipine: an effective once-daily antihypertensive agent. J Hum Hypertens 1991; 5 (Suppl 1): 61 66. 2 Kaplan NM. Amlodipine in the treatment of hypertension. Postgrad Med J 1991; 67 (Suppl 5): S15 S19. 3 Clavijo GA, de Clavijo IV, Weart CW. Amlodipine: a new calcium antagonist. Am J Hosp Pharm 1994; 51: 59 68. 4 Staessen JA et al. Efficacy of antihypertensive drugs given once a day: the calcium antagonists revisited. J Hypertens Suppl 1994; 12: S107 S115. 5 Reid JL, Meredith PA, Donnelly R, Elliott HL. Pharmacokinetics of calcium antagonists. J Cardiovasc Pharmacol 1988; 12 (Suppl 7): S22 S26. 6 Abernethy DR. The pharmacokinetic profile of amlodipine. Am Heart J 1989; 118: 1100 1103.

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