tolerability, safety and dosage of a fixed combination of sustained release nifedipine plus atenolol

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Short Communication Drugs 35 (Suppl. 4): 36-38 (1988) 0012-6667/88/0400-0036/$1.50/0 © ADIS Press Limited All rights reserved. Tolerability, Safety and Dosage of a Fixed Combination of Sustained Release Nifedipine Plus Atenolol D.I. Rees-Jones Totley, Sheffield Single-agent treatment of hypertension with either a j1-blocker or a calcium antagonist some- times fails to adequately control blood pressure (Daniels & Opie 1986). Therefore, it may be rea- sonable to attempt combination therapy, for ex- ample, using atenolol plus nifedipine. This paper describes an on-going study of this j1-blocker and calcium antagonist combination de- signed to evaluate blood pressure control, inci- dence of unwanted effects, and biochemistry and haematology. The appropriate dose frequency and dosage of the 2 constituents of the combination was also evaluated. 1. Study Design The study was a long term (1 year) multicentre design involving 17 general practitioner centres. The design was open, and included the option to increase dose based on blood pressure response. Males and females aged between 20 and 75 years were admitted to the study if they had a sitting diastolic blood pressure> 100mm Hg irrespective of prior treatment. The exclusion criteria were as follows: any usual contraindication to j1-blocker or calcium antagonist therapy, co-existing disease or medication likely to interfere with therapy, history of poor drug compliance, and sitting diastolic blood pressure > 120mm Hg. All patients who satisfied the early criteria were asked to discontinue their current antihypertensive medication and were transferred without a washout period to atenolol. No other antihypertensive drugs were taken during the study. 2. Study Protocol 2.1 Design The patients were started with atenolol 50mg once daily, taken in the morning, at entry (visit I). After 1 month (visit 2), they received a fixed dose combination capsule of sustained release nifedi- pine 20mg plus atenolol 50mg once daily in the morning, provided they still satisfied the entry blood pressure criteria. This regimen was contin- ued until 12 months if blood pressure control was satisfactory, which was defined as a sitting diastolic blood pressure < 90mm Hg. If, after I month (visit 3), this once-daily regimen did not provide satis- factory blood pressure control, the dose frequency was increased to twice daily. If satisfactory blood pressure was still not achieved after another month (visit 4), the dosage was further increased by add- ing sustained release nifedipine 20mg twice daily (to give a total dosage of nifedipine 40mg twice daily plus atenolol 50mg twice daily). Further clinic visits were made at 6 and 12 months after initial entry. Patients were instructed not to take medi- cation on the morning of their next clinic visit. The study design is summarised in figure 1. 2.2 Measurements Patients were assessed during 6 clinic visits dur- ing the year. At each visit sitting blood pressure and pulse rate were recorded by use of standard techniques (24 hours after the last dose for patients on the once-daily regimen, and 12 hours after the

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Page 1: Tolerability, Safety and Dosage of a Fixed Combination of Sustained Release Nifedipine Plus Atenolol

Short Communication

Drugs 35 (Suppl. 4): 36-38 (1988)

0012-6667/88/0400-0036/$1.50/0 © ADIS Press Limited All rights reserved.

Tolerability, Safety and Dosage of a Fixed Combination of Sustained Release Nifedipine Plus Atenolol

D.I. Rees-Jones Totley, Sheffield

Single-agent treatment of hypertension with either a j1-blocker or a calcium antagonist some­times fails to adequately control blood pressure (Daniels & Opie 1986). Therefore, it may be rea­sonable to attempt combination therapy, for ex­ample, using atenolol plus nifedipine.

This paper describes an on-going study of this j1-blocker and calcium antagonist combination de­signed to evaluate blood pressure control, inci­dence of unwanted effects, and biochemistry and haematology. The appropriate dose frequency and dosage of the 2 constituents of the combination was also evaluated.

1. Study Design

The study was a long term (1 year) multicentre design involving 17 general practitioner centres. The design was open, and included the option to increase dose based on blood pressure response. Males and females aged between 20 and 75 years were admitted to the study if they had a sitting diastolic blood pressure> 100mm Hg irrespective of prior treatment. The exclusion criteria were as follows: any usual contraindication to j1-blocker or calcium antagonist therapy, co-existing disease or medication likely to interfere with therapy, history of poor drug compliance, and sitting diastolic blood pressure > 120mm Hg. All patients who satisfied the early criteria were asked to discontinue their

current antihypertensive medication and were transferred without a washout period to atenolol. No other antihypertensive drugs were taken during the study.

2. Study Protocol 2.1 Design

The patients were started with atenolol 50mg once daily, taken in the morning, at entry (visit I). After 1 month (visit 2), they received a fixed dose combination capsule of sustained release nifedi­pine 20mg plus atenolol 50mg once daily in the morning, provided they still satisfied the entry blood pressure criteria. This regimen was contin­ued until 12 months if blood pressure control was satisfactory, which was defined as a sitting diastolic blood pressure < 90mm Hg. If, after I month (visit 3), this once-daily regimen did not provide satis­factory blood pressure control, the dose frequency was increased to twice daily. If satisfactory blood pressure was still not achieved after another month (visit 4), the dosage was further increased by add­ing sustained release nifedipine 20mg twice daily (to give a total dosage of nifedipine 40mg twice daily plus atenolol 50mg twice daily). Further clinic visits were made at 6 and 12 months after initial entry. Patients were instructed not to take medi­cation on the morning of their next clinic visit. The study design is summarised in figure 1.

2.2 Measurements

Patients were assessed during 6 clinic visits dur­ing the year. At each visit sitting blood pressure and pulse rate were recorded by use of standard techniques (24 hours after the last dose for patients on the once-daily regimen, and 12 hours after the

Page 2: Tolerability, Safety and Dosage of a Fixed Combination of Sustained Release Nifedipine Plus Atenolol

Tolerability, Safety and Dosage

Twice-daily +

nifedipine 2

Twice-daily

Once-daily

Omg SR b.d.

Step 1

Entry

Atenolol Atenolol 50mg +

50mg Nifedlplne 20mg SR

Step 2

Atenolol 50mg +

Nifedlpine 20mg SR

Atenolol 50mg +

Nifedlplne 20mg SR

Atenolol 50mg Atenolol 50mg : Atenolol 50mg I

+ + I + Nifedipine 20mg SR Nifedipine 20mg SR : Nifedipine 20mg SR

+ + + Nifedipine 20mg SR Nifedipine 20mg SR Nifedipine 20mg SR

Atenolol 50mg Atenolol 50mg I Atenolol 50mg I + + I +

Nifedipine 20mg SR Nifedipine 20mg SR I Nifedlplne 20mg SR ..1

Atenolol 50mg Atenolol 50mg I Atenolol 50mg + + I +

Nifedipine 20mg SR Nlfedlplne 20mg SR : Nifedlplne 20mg SR

Visit 1

Visit 2

Visit 3

Visit 4

Visit 5 (a)

Visit 5 (b)

(dispensing only)

Visit 6

o month 1 month 2 months 4 months

Fig_ 1. Outline design of study protocol.

last dose for those on the twice-daily regimen). The incidence of volunteered side effects were also re­corded. Haematological and biochemical tests were monitored at entry, at 4 months and at 12 months. Haematology included red cell count, white cell count and platelet count, and biochemistry in­cluded Na+, K+, urea, creatinine, AST, bilirubin, urate and glucose.

3. Results 3.1 Patients

6 months

180

170

9 months 12 months

F 160 148mmHg

~ 150 _____ ::-:_=an_=_1_5_3_~~n~=~8",2 -; 140 Systolic blood pressure

" ::l 130

[ 120

gttOi~ :0 100 .~ 90 87mmHg t: ---

Mean fall in b.p. = 18/15 mmHg

iii 80 Diastolic blood pressure

70 601~~~~ ____ ~ ________ ~

Entry I 3 6 12 Run-in

Time on treatment (months)

Fig. 2. Effects of all treatments on blood pressure.

3.2 Blood Pressure Change

37

By 21 March 1986, 307 patients had been sel­ected for the study; 20 of these had withdrawn and to were still on run-in, leaving a total of 277 who received the combination of atenolol and nifedi­pine. The patients' ages ranged from 24 to 75 years and the duration of their hypertension from 0 to 24 years. Overall, the total exposure to the com­bination regimen has been 139 patient-years and the full I-year course has been completed by 86 patients.

The mean systolic and diastolic blood pressure is shown in figure 2. No differentiation was made

Page 3: Tolerability, Safety and Dosage of a Fixed Combination of Sustained Release Nifedipine Plus Atenolol

Tolerability, Safety and Dosage

between patients on different antihypertensive reg­imens. Each step in treatment showed a progres­sive reduction in blood pressure.

3.3 Dose Frequency and Dosage

Preliminary analysis showed that 69% of patients achieved satisfactory blood pressure with sustained release nifedipine plus atenolol once daily, 21% re­quired the twice-daily regimen, and 10% required additional nifedipine. These percentages were sim­ilar when calculated for those patients who had completed the study.

3.4 Unwanted Effects

Of the 277 patients on combined therapy, 33 (1\.9%) withdrew: I did not attend, I was normo­tensive, 6 had previously unknown co-existing dis­ease, and 25 withdrew because of unwanted effects. The 25 patients who withdrew reported a total of 63 unwanted effects. These included 6 reports of oedema, 6 of flushes and hot sweats, 6 of head­aches, 6 of tiredness and 4 of dizziness - i.e, side effects usually associated with {3-blocker or calcium antagonist therapy, The volunteered side effects re­ported by the 277 patients who continued in the study are shown in table I. During the atenolol run­in the most common complaints were headaches and tiredness. After the first month on combina­tion therapy the number of headaches and the re­ports of tiredness had decreased, though headaches were still the most commonly reported side effect. Flushes and hot sweats, which had not occurred during the run-in, were presumably due to the va­sodilatory effect of nifedipine. The incidence of oedema also increased with combination therapy.

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Table I. Incidence of side effects (no. of patients)

Atenolol Combined therapy run-in

first total month

Dizziness 9 11 18 Headaches 19 14 22 Flushes and hot 0 10 21 sweats Oedema ankles/ 3 8 24 feet Tiredness 21 6 21

No clinically relevant biochemical or haematolog­ical changes were found during the period of the study.

4. Conclusions

Almost 70% of patients achieved adequate blood pressure on a fixed dose combination of sustained release nifedipine 20mg plus atenolol 50mg once daily. A further 21 % required this dosage twice daily. 90% of patients therefore achieved an ac­ceptable blood pressure with the once- or twice­daily regimen. The mean decrease in sitting blood pressure was 18/ 15mm Hg compared with the mean value at the end of the run-in period. The com­bination regimen appeared to be well tolerated and no unexpected unwanted effects were observed.

Reference

Daniels A, Opie LH. Atenolol plus nifedipine for mild to mod­erate systemic hypertension after fixed doses of either agent alone. American Journal of Cardiology 57: 965-970, 1986

Author's address: Dr D.I. Rees·Jones. 180 Baslow Road. Sheffield S17 4DS (United Kingdom).