Efficacy and safety of Minipress XL, a new once-a-day formulation of prazosin

Efficacy and Safety of Minipress XL, a New Once-a-Day Formulation of Prazosin WALTER SINGLEION, M.D., RORERT K. DIX, Ph.D., LISA MONSEN, M.D., DONNA MOISEY, Ph.D., MARCIA LEVENSTEIN, Sc.D., DENISE F. BOTTIGLIERI, Ph.D., LEWIS SILVER, Ph.D. NW York, New York

The efficacy and safety of prazosin GITS (gastrointestinal therapeutic system), a new extended- release once-a-day formulation, were assessed both as monotherapy in mild essential hypertension and in combination with a diuretic in moderate essential hypertension in two multicenter, double-blind, placebo-controlled trials. Prazosin GITS (Minipress XL) given once daily in doses of either 10 or 20 mg significantly reduced sitting and standing systolic and diastolic blood pressure compared with placebo in both mild and moderate essential hypertension. There were minimal, clinically insignificant changes in heart rate following prazosin-GITS treatment (2.5, 10, and 20 mg) compared with placebo treatment. Prazosin GITS was well tolerated; the most common adverse experiences reported were headache, dizziness, and fatigue. All adverse experiences in the moderate, hypertension group and the majority (91 percent) in the mild hypertension group were mild-to-moderate in severity. The results from these multicenter trials demonstrate the efficacy and safety of this new extended-release once-a- day formulation of prazosin in the treatment of patients with mild and moderate essential hypertension.

From Pfizer Inc.. New York New York Requests for reprints should be addressed to Dr. Robert K Dix. Clinical and Scientific Affairs, Pfizer Inc., 235 East 42nd Street, New York New York, 10016.

P razosin hydrochloride (Minipress XL) is a highly selective postjunctional alpha,-adrenoreceptor

antagonist approved in the United States and throughout the worlcl for the treatment of hypertension. Prazosin reduces total peripheral resistance, thus lowering bloocl pressure at rest ancl cluring exer- cise. The reduction in total peripheral resistance is not accompanied by a reflex tachycardia or a decrease in cardiac output [l]. In addition, prazosin has no adverse effects on plasma lipid levels, glucose metabo- lism in cliabetic patients, or plasma renin levels [ll.

The present marketed formulation of prazosin is a capsule that requires twice- or three-times-claily dosing. Prazosin GITS (gastrointestinal therapeutic system) is a new long-acting, once-a-day formulation designed as an osmotic pump (push-pull technology, Alzd). Through this innovative delivery system, prazosin is released at an approximately steady rate over a l&hour period. In addition to improving patient compliance, this formulation provides relatively smooth blood pressure control and attenuates the fluctuations in plasma concentrations that occur with more frequent daily dosing.

The major objectives of the two trials described here were to determine the efficacy and safety of prazosin GITS compared with placebo when used as monotherapy or in conjunction with a cliuretic in the treatment of patients with essential hypertension, and to determine if there were dose-related and/or plasma concentration-relatecl decreases in blood pressure following treatment.

PATIENTS AND METHODS Monotherapy

This multicenter study was a double-blind, placebo- controlled, parallel close-response trial consisting of four phases over a lo-week period (Table I). Phase I was a one-week washout period during which all anti- hypertensive medication was tapered off; Phase II was a two-week, -single-blind placebo phase. All patients were required to have discontinued diuretic therapy for a minimum of three weeks prior to entry into the placebo phase. Patients who demonstrated sitting diastolic blood pressure between 95 and 105 mm Hg for two consecutive weeks and had an average pill compliance between 80 ancl 120 percent during the placebo phase were then randomly assigned to one of four treatment groups: placebo, or prazosin GITS close groups (2.5, 10, or 20 mg) for entry into Phase III. Phase III consisted of a three-week, double-blind titration phase cluring which patients were titrated to their preassigned dose group. Phase IV was a four- week, double-blind efficacy phase with patients being maintained at their final titratecl dose level unless lim- ited by side effects. Blood pressure, heart rate, adverse experiences, and study drug compliance were

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TABLE I

General Study Design for Prazosin GITS Monotherapy Study

Washout Placebo Ruwln

Group Week 1 Week2 Week 3 Webk 4

Placebo Placebo Placebo Placebo

“; yingGlTS Placebo Placebo 2.5 mg 1Omg Placebo Placebo 2.5 mg 20 mg Placebo Placebo 2.5 mg

‘Efficacy phase for combinahon therapy protocol conslsted of Weeks 7 and 8.

Titration

Week 5

Placebo

2.5 mg 5.0 mg 5.0 mg

Week 6 Week 7

Placebo Placebo

2.5 mg 2.5 mg 10mg 10 mg 10 mg 20 mg

Efficacy*

Week 6 Week9

Placebo Placebo

2.5 mg 2.5 mg IOmg 10mg 20 mg 20mg

Week 10

Placebo

2.5 mg 10mg 20 mg

lata are expressed as mean + SD. ii ‘he analysis compared whites wrth nonwhites.

TABLE II

Demographic Characteristics of Monotherapy Patients

Prazosin GITS

Placebo Variable (ix, (n=48) p Value*

Age (yean)t 54.4 2 11.3 54.1 ? 12.2 57.1 2 10.5 55.0 2 10.6 0.781

Durabon of hypertension (yean)t 8.6 2 7.3 8.6 5 8.0 7.8 + 6.4 10.4 2 9.7 0.284

Body weight (pounds)t 192.1 2 30.3 186.2 r 30.4 190.9 t 36.9 185.4 ? 32.8 0.939

Height (mches)t 68.4 + 4.0 67.9 2 4.1 68.1 + 3.8 67.2 + 4.3 0.265

Race White Black Other

40 IO 2

42 5

0.280$

Sex Female Male ::

) values reffect the test of any drfferences between treatment erouos.

0.761

monitored weekly. In addition, steady-state prazosin g;zfe @sma levels were evaluated weekly during

Combination Therapy This multicenter study was a double-blind, placebo-

controlled, parallel dose-response trial lasting eight weeks and consisting of four phases.

All phases of the study followed a protocol similar to the monotherapy study except that Phase IV lasted two weeks and patients were required to receive maintenance diuretic therapy for a minimum of four weeks prior to beginning of Phase I and throughout the study. Blood pressure, heart rate, adverse experiences, and drug compliance were monitored weekly. In addition, prazosin GITS steady-state plasma levels were evaluated during Phase IV.

Blood Pressure and Plasma Level Analyses Blood pressure readings and prazosin plasma con-

centrations were obtained at specified times (zero, six, and 12 hours after receiving daily drug dose) one day prior to the end of Weeks 7 to 10 (monotherapy) and Weeks 7 and 8 (combination therapy) for all prazosin GITS and placebo-treated groups. In addition, for all treatment groups 24-hour blood pressure readings and drug plasma concentrations were obtained at the end of Weeks 7 to 10 (monotherapy), and at the end of

Weeks 7 and 8 (combination therapy). Correlations between actual drug dose and drug plasma concentration, drug dose and blood pressure measurements, and drug plasma concentration and blood pressure measurements were examined over the 24-hour clos- ing interval.

Efficacy and Safety Therapeutic efficacy in both studies was assessed

by calculating the differences between baseline blood pressure and heart rate values ancl values obtained at the last treatment visit (end-point analysis), and com- paring them between the treatment groups. In addition, the difference between blood pressure measurements obtained at baseline and mean blood pressure measurements obtained weekly was calculated for the prazosin GITS and placebo groups. Measurements were obtained 24 hours postdose from Weeks 4 to 10 in monotherapy or Weeks 4 to 8 in combination therapy. Finally, the proportion of patients who had a response to treatment with a diastolic blood pressure below 90 mm Hg at the final visit was analyzed.

The safety of prazosin GITS was evaluated on the basis of the incidence and severity of reported adverse experiences and clinical laboratory data. Physical examinations, laboratory evaluations, chest radio- graphic examinations, electrocardiographic examinations, and urinalyses were performed at the end of

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TABLE III

Distribution of Mean Values for Blood Pressure and Heart Rate in Monotherapy Patients

Prazosin GITS

(FE) (tE%) Placebo (n=48) p Value*

Sittingt Systolic BP 15$.; 4 $1 150.0 f 13.2 155.6 + 16.1 0.361 Diastolic BP

1615 I 100.6 c 3.0 loo.1 + 3.0

15l; i ;pie 0.088

Heart rate a.8 76.0 + 9.1 75.7 2 a.8 77.6 I

a.0 0.743

Standingt Systolic BP Diastolic BP Heart rate

150.6 + 13.6 149.5 + 14.1 154.6 + 16.5 150.8 + 17.1 0.349 100.5 + 5.8 101.8 + 5.4 101.8 2 5.0 101.3 f 5.9 0.424 80.1 + 9.0 77.5 2 a.8 78.6 2 a.7 al.2 r a.4 0.248

BP = blood pressure. l p values reflect the test of any differences between treatment groups. iValues are mean I! SD in mm Hg (for blood pressure) or beats/minute (for heart rate]

Phases I, II, and IV. The laboratory tests included a complete blood count with differential platelet count and a SMA-18 or -20. Clinical laboratory values were reviewed by a physician, and abnormal laboratory values were characterized according to possible cause and clinical significance.

Statistical Methods Baseline comparability of treatment groups for pa-

tient characteristics was established using analysis of variance or chi-square tests. Blood pressure changes from baseline until the final visit were evaluated by analysis of covariance, taking into account the effects of baseline, treatment, and study site. In addition, the blood pressure changes from baseline to each treatment visit and to the mean of all visits during the efficacy phase were evaluated in the same way; The rela- tionships between the prazosin plasma levels and actual prazosin-GITS dose and blood pressure response were evaluated using linear correlations. Pairwise comparisons between dose levels of prazosin GITS and placebo were made by t tests. Treatment differences in the proportions of responders were also evaluated using categorical linear models. All p values of 0.05 or less were considered statistically significant.

RESULTS Monotherapy

A total of 205 patients (49 patients receiving prazosin GITS 2.5 mg, 56 receiving prazosin GITS 10 mg, 52 receiving prazosin GITS 20 mg, and 48 receiving placebo) from nine different study sites were included in the efficacy analysis. The demographic characteristics of all efficacy-evaluated patients are presented in Table II. There were no statistically or clinically significant differences between prazosin GITS (2.5, 10, and 20 mg) and placebo treatment groups per-taming to age, sex, race, duration of hypertension, weight, or height. Blood pressure and heart rate measurements from all treatment groups were compared at baseline (Table III). No significant differences in baseline blood pressure and heart rate measurements were found in patients in either the sitting or standing position between the prazosin GITS and placebo groups.

When baseline blood pressure and heart rate measurements were compared with values obtained during the last treatment visit (end-point analysis), the

data indicated that increasing the dose of prazosin GITS (2.5, 16, and 20 mg) generally resulted in greater reductions in systolic and diastolic blood pressure (Table IV). In this regard, both the lo- and 20-mg doses of prazosin GITS statistically significantly decreased sitting systolic and diastolic blood pressure compared with placebo (10 mg, -11.5/-10.7 mm Hg; 20 mg, -14.0/-10.9 mm Hg; placebo -2.31 -3.9 mm Hg). Similar statistically significant reductions were seen in standing blood pressure. A statistically significant increase in standing heart rate occurred in patients treated with prazosin GITS 20 mg, but the increase is not clinically meaningful.

A weekly analysis of mean sitting and standing systolic and diastolic blood pressure measurements indicated that the overall mean reductions in blood pressure were greater at almost all weekly visits during the double-blind treatment period for all prazosin- GITS groups compared with placebo (Figures 1 and 2). Significant reductions in both sitting and standing diastolic blood pressure were observed by Week 6 in both the lo- and 20-mg treatment groups, whereas significant reductions in systolic blood pressure were evident by Week 7. These reductions in blood pressure were maintained throughout the study.

Therapeutic efficacy was further evaluated by de-

TABLE IV

Mean Blood Pressure and Heart Rate Changes from Baseline in Monotherapy Pati&s*

Prarosin GITS

25 mg lding 20 mg Placebo

Sitting systolic BP Diastolic BP Heart rate

-5.9 -2.3 -6,3 -3.9 t1.7 -0.4

1

Standing Systolic BP Diastolic BP Heart rate

BP = blood pressure,

-

-5.5 -13.5t -5.4 +2.4 -0.3

*Values are mean changes in mm Hg (for blood prwure) or beats/minute (for heart rate), from the end.point analysis. tSlgniftcantly different from placebo mean changes at the 0.01 level. ~lgniflcantly different from placebo mean changes at the 0.05 level.

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BP difference (mm W

-8

-12

-16

I Placebo

mrm 2.5 mg

m 10mg Study week

0 mm 20mg

-2

-4

-6 BP difference -8 (mm W

-10

-12

Study week

3P liff erence mm W

-8

-12

-16

I Placebo

mm 2.5 mg 4 5 6 7

m 10mg Study week

0 mm 20mg

-2

-4

BP difference (mm W

-6

-8

-10

4 5 6 7 8 9 10 Study week

Rgure 1. Monotherapy: the differences between baseline and treatment for sitting (top) systolic and (bottom] diastolic blood pressure (BP) in the prazosin gastrointestinal therapeutic system (2.5, 10, and 20 mp) and placebo groups. Values were obtained at baseline (Week 0) and during the double-blind treatment phase (Weeks 4 to 10).

Figure 2. Monotherapy: the differences between baseline and treatment for standing [top) systolic and (bottom] diastolic blood pressure (BP) in the prazosin gastrointestinal therapeutic system (2.5,10, and 20 mg) and placebo groups. Values were obtained at baseline (Week 0) and during the double-blind treatment phase (Weeks 4 to 10).


SYMPOSIUM ON SELECTIVE ALPHA-ADRENERGIC RECEPTOR INHlBlTlON /SINGLETON ET AL

termining the proportion of patients who had a favora- ble response with a reduction in diastolic blood pressure to less than 90 mm Hg following treatment with prazosin GITS or placebo. The proportion of patients in the prazosin GITS (2.5, 10, and 20 mg) and placebo treatment groups who demonstrated this response at the final treatment visit is presented in Table V. The prazosin GITS lo- and 20-mg treatment groups con- tained a significantly greater proportion of responders in both the sitting (10 mg, 48 percent; 20 mg, 46 percent) and standing (20 mg, 54 percent) positions compared with placebo-treated patients (sitting 25 percent, standing 19 percent).

Prazosin plasma levels were obtained at several time points over a single-dose interval. Relatively constant (minimal peak-to-trough fluctuations) plasma levels were observed with each dose level of prazosin GITS (2.5, 10, and 20 mg) over the 24-hour dosing interval (Table VI). In addition, prazosin plasma levels increased with increasing prazosin GITS doses for.all hourly measurements obtained during Weeks 7 to 10. For example, 2.5 mg prazosin GITS yielded a mean plasma level of approximately 3 rig/ml, lo-mg dose yielded approximately 16 rig/ml, and the 20-mg dose yielded approximately 30 rig/ml. Finally, a weak correlation between sitting and standing blood pressure reductions and prazosin plasma levels was observed.

Blood pressure measurements were obtained at zero, six, 12, and 24 hours after dosing during Weeks 7 to 10 of therapy to determine consistency of blood pressure response throughout the dosing interval. The results indicate that prazosin GITS given once a day provides 24-hour control of blood pressure with minimal fluctuations over the dosing interval (Figure 3).

A total of 220 patients randomly assigned to receive study medication were included in the safety analysis (166 prazosin GITS-treated patients and 54 placebo- treated patients). Adverse experiences were reported according to the randomly assigned dose group. There was no significant difference in the number of patients reporting adverse experiences across prazosin GITS treatment groups or placebo-treated patients (p < 0.570). Thirteen patients (nine prazosin GITS- treated [5.4 percent] and four placebo-treated patients [7.4 percent]) withdrew from the study because of adverse experiences. No deaths occurred in any group.

Overall, the most commonly reported adverse experiences in the prazosin GITS group were headache (17.5 percent), dizziness (13.3 percent), and fatigue (7.2 percent), whereas headache (27.8 percent), rhini- tis (9.3 percent), and dizziness (7.4 percent) were com-

Treatment Sitting Position Standing Position

Group n Percent pValue* n Percent p Value

Prazosin GITS

E; 19/49 27156 ii 0.113 0.014 20156 15149 i:, 0.182 0.071 20 mg 24152 46 0.019 28152 54 0.001

Placebo 12l48 25 9148 19

TABLE V

Proportion of Monotherapy Patients with Diastolic Blood Pressure Less Than 90 mm Hg at the Final Treatment Visit

I

me p value for the comparison with placebo is from the lo&tic regression including stte and treatment.

mon in the placebo group. Greater than 90 percent of adverse’experiences reported in each of the randomly assigned treatment groups were mild-to-moderate in severity. In addition, only 1 percent of the laboratory abnormalities in the prazosin GITS treatment groups and 0.7 percent in the placebo groups were believed to be related to the study drug.

Combination Therapy (prazosin GITS plus diuretic) A total.of 193 patients (50 patients receiving prazo-

sin GITS 2.5 mg, 48 receiving prazosin GITS 10 mg, 47 receiving prazosin GITS 20 mg, and 48 receiving placebo). from eight different study sites were included in the efficacy analysis. This study followed the same protocol as the monotherapy study except that Phase IV lasted two weeks and patients were required to receive a diuretic for a minimum of four weeks before beginning the placebo phase of the study and maintain diuretic therapy (same type and dose) throughout the study. The demographic characteristics of all efficacy-evaluated patients are presented in Table VII. There were no statistically or clinically significant differences between prazosin GITS (2.5, 10, and 20 mg) and placebo treatment groups with respect to age, sex, race, weight, height, or duration of hypertension. Blood pressure and heart rate measurements from all treatment groups were compared at baseline (Table VIII). No significant differences in sitting and standing blood pressure and heart rate measurements were found between prazosin GITS and placebo groups.

End-point analysis of blood pressure and heart rate values indicated that greater reductions in sitting and standing blood pressure were generally observed with increasing doses of prazosin GITS compared with placebo (Table IX). Systolic and diastolic blood pressures were significantly reduced from baseline in the sitting

TABLE VI

Summary of Prazosin Plasma Levels from Monotherapy Patients*

Averaged over Weeks 7-10 n 2.5 mg

O,hours 6 hours :i ;; f t.7”

3:4 I20 12 hours :; 24 + 1:4 hours 2.8

Values are mean 2 SD in nglml for prazosin plasma levels,

Prezosin GITS Plkebo

n 10 mg n 20smg n Level

60 15.6 ? 8.6 26.3 t 12.9

ii

0.0 + 0.0 16.0

+ 19

ii 28.5 ? 13.9

ii

16.8 f 7.1 ii

32.1 k 14.3 39 Ml

Ei 16.7 f 8.5 29.7 f 10.6 40 0:o 5 0:o

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5-l

0

BP -5 difference (mm W

-10

-15

Placebo

2.5 mg

10 mg 20 mg

I 0

I I I I 6 12 18 24

Time oostdose Ih)

Figure 3. Twenty-four.hour slttmg dlastohc blood pressure (BP) for monotherapy patients .

( (change from basehne In mm Hg).

TABLE VII

Demographic Characteristics of Moderately Hypertensive Patients

Prazosin GITS

Placebo Variable (n=48) p Value*

Age (years)t 52.4 z 12.0 51.2 + 12.2 55.0 ? 10.3 54.2 2 14.4 0.389

Durahon of hypertenston (yean)t 7.8 + 6.0 7.9 2 6.0 9.7 I 8.7 8.9 i 6.5 0.367

Body weight (pounds)t 180.9 ? 34.2 187.3 + 32.8 184.9 z 31.2 185.4 t 37.5 0.760

Heght (Inches)t 67.8 2 3.9 68.5 = 4.2 68.6 2 3.8 69.0 + 3.8 0.250

Race

White 44 41 40 Black

40 0.932t 5

Other I Ii ; !

Sex Female Male

0.849

values rellecl the test of any dtfferences between treatment groups. Nata are expressed as mean + SD. he analysis compared whites with nonwhltes.

TABLE VIII

Distribution of Mean Values for Blood Pressure and Heart Rate at Baseline in Moderately Hypertensive Patients*

Prazosin GITS

Placebo (n=4B) p Valuet

siilng Systolic BP Dlastoltc BP Heart rate

Standlna

141.2 ? 12.5 145.6 + 11.7 149.0 I 14.4 98.2 145.0 ? 14.9 0.085 T 2.5 98.9 t 2.8 98.8

2 2.4 98.7 2 2.8 77.6 2 7.1 0.696 n.5 t 7.0

77.4 2 7.4 772 2 7.3 0.919

Systoilc BP Dlastollc BP Heart rate

BP = blood oressure.

138.5 : 12.2 143.3 f 12.8 145.3 t 14.2 98.1 143.3 2 4.6 13.8 t 99.2

0.199 2 4.7 2 100.1 4.9 99.0 f 80.3 8.2 4.5 2

80.5 0.348 t

7.2 79.8 i 8.3 80.7 I 1.5 0.595

‘Values are mean + SD In mm Hg (for blood pressure] or beatslmlnute (for heart rate). tp values reflect the test of any differences between treatment groups.

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position in the prazosin GITS lo- and 20-mg groups compared with placebo (10 mg, - 10.6 mm Hg [systolic only]; 20 mg, -12.1/-10.3 mm Hg; placebo, -4.61 -7.2 mm Hg). Similar reductions in blood pressure were observed in the standing position. Weekly reductions in blood pressure were of similar magnitude. There were no significant changes in heart rate following prazosin GITS treatment compared with placebo treatment.

The response to treatment was further evaluated by determining the proportion of patients who had a response (defined as a sitting diastolic blood pressure less than 90 mm Hg following therapy) to treatment with prazosin GITS or placebo (Table X). A larger proportion of patients in all the prazosin GITS groups had a sitting and standing diastolic blood pressure less than 90 mm Hg at the final visit during the efficacy phase compared with placebo, and these differences were statistically significant in the 2.5-mg group (sitting, 58 percent versus 38 percent for placebo) and the 20-mg group (sitting, 62 percent versus 38 percent for placebo; and standing, 60 percent versus 33 percent for placebo).

Prazosin plasma levels were obtained at several time points over a single dose interval. Relatively constant (minimal peak-to-trough fluctuations) prazosin plasma levels were observed with increasing closes of prazosin GITS (2.5, 10, and 20 mg) over the 24-hour dosing interval (Table XI). In addition, prazosin plasma levels increased with increasing prazosin GITS doses (2.5, 10, and 20 mg) when averaged over Weeks 7 and 8. For example, 2.5-, lo-, and 20-mg prazosin GITS yielded approximate plasma concentrations of 3, 13, and 25 rig/ml, respectively. Pairwise comparisons between groups demonstrated that the prazosin plasma levels were significantly increased compared with placebo, except for the zero-hour average com- paring the 2.5-mg and placebo groups. Blood pressure changes from baseline were also correlated with the prazosin plasma levels combined over the three close groups. Finally, a significant but small correlation between the reductions in sitting and standing systolic and standing diastolic blood pressure and plasma levels was present.

A total of 203 patients ranclomly assigned to receive study medications were included in the safety analysis (153 prazosin GITS- and 50 placebo-treated patients). Adverse experiences were reported as in the monotherapy study. There were no significant differences in the number of patients reporting adverse experiences across prazosin GITS treatment groups or placebo (p = 0.114). One patient randomly assigned to

TABLE IX

Mean Blood Pressure and Heart Rate Changes from Baseline in Moderately Hypertensive Patients*

Sitting

25 mg

Prazosin GITS

10 mg 20 mg Placebo

1

Systolic BP -5.0 -10.6t -4.6 Diastolic BP -9.0 -9.4 -1.2 Heart rate -4.6t -0.2 -0.6 -1.1

Standing Systolrc BP Diastolic BP Heart rate

BP = blood pressure.

-2.0 -1.3 -3.9

-9.3t -7.9 to.3

-3.8 -4.8

to.7 -0.8

*Values are mean changes tn mm Hg (for blood pressure) or beats/minute (for heart rate) from the end point analysis. kgmflcantly different from placebo mean changes at the 0.05 level. SSigniftcantly different from placebo mean changes at the 0.01 level.

TABLE X

Proportion of Moderately Hypertensive Patients with Diastolic Blood Pressure Less Than 90 mm Hg at the Final Treatment Visit

Treatment Group

Sitting Position Standing Position

n Percent pValue* n Percent p Value*

Prazosin GfTS 2.5 mg 10 mg 20 mg

Placebo

29150 23148 29147 18148

0.039 25/50 0.286 21/48 0.016 28147 - 16148

0.089 0.252 0.010 -

I.

‘The p value for the comparison with placebo is from the logistic regression including site and treatment.

the 2.5-mg prazosin GITS group withdrew from the study due to an adverse experience. No deaths occurred in any group.

The most commonly reported adverse experiences in the prazosin GITS plus diuretic group were headache (4.6 percent), dizziness (3.9 percent), and fatigue (3.3 percent). The most common adverse experiences in the placebo-plus-diuretic group were headache (4 percent), nausea (4 percent), and insomnia (4 percent). All adverse experiences were mild-to-moderate in severity. In addition, only 1.3 percent of the laboratory abnormalities in the prazosin GITS treatment groups, and 1.5 percent in the placebo treatment group were believed to be related to study drug.

TABLE Xl

Summary of Prazosin Plasma Levels from Moderately Hypertensive Patients*

Averaged over Weeks 7-8

Prazosin GITS Placebo

n 2.5 mg n 10 mg n 20 mg n Level

0 hours 48 2.4 + 1.9 12.7 ? 8.1 + 6 hours 23.1 12.3 i;

0.0 2 3.2 + 3.3 zi 12.7 f 7.1

:; 0.0 12 hours 25.3 t 10.9

z 0.0 2 3.2 3.1 0.0 ?

13.5 ?:

7.4 24 hours 26.2 + 11.4 49 46 + 2.1 ? 3.9 ;; 0.0 0.0 12.2

_+ 6.8

z 23.5 2 10.5 48 0.0 + 0.0

Values are mean 2 SD ~n naiml for orazosin olasma IPVPI<

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COMMENTS The results from these two multicenter studies

demonstrate the efficacy and safety of prazosin GITS, a new extended-release once-a-day formulation, in the treatment of patients with mild and moderate hypertension. In both studies, once-a-day administration of lo- or 20-mg doses of prazosin GITS was significantly more effective than placebo in lowering both systolic and diastolic blood pressure. Blood pressure reduction was also maintained with minimal fluctuations over the 24-hour dosing interval. The GITS formulation of prazosin is designed to deliver prazosin at a zero-order (constant) rate over a four- to X-hour period. Conse- quently, plasma levels of prazosin rise more slowly and are maintained at a relatively constant level over 24 hours. This is in contrast with the current capsule formulation of Minipress, with which peak plasma levels are achieved one to three hours postdose, resulting in significant peak-to-trough fluctuations with twice- a-day or three times-a-day dosing. Hence, the slower release rate and longer time to peak of prazosin GITS theoretically provide a situation in which alpha-aclren- ergic-receptor blockade might proceed more graclu- ally, allowing the circulatory system to better accom- modate to the imposed hemodynamic alteration. This sustained release would also result in a more consistent 24-hour control of blood pressure. As a result, blood pressure control would be smoother and the in- tensity of posturally related hypotensive episodes may be decreased with the GITS formulation.

Indeed, the occurrence of posturally related hypotensive effects appeared to be minimized with the GITS formulation of prazosin. No hypotension or syncope was reported with an initial dose of 2.5 mg prazosin GITS in over 300 patients in long-term, multiple- dose clinical trials. Dizziness was the only posturally related side effect, reported by 1.7 percent of prazosin

GITS-treated patients within the first 24 hours of receiving the initial 2.5-mg dose. Furthermore, the overall incidence of syncope was less than 1 percent (one patient) with long-term therapy. In acldition, treatment with prazosin GITS did not result in any clinically significant increases in heart rate.

As discussed earlier, another advantage of this new formulation would be to minimize the changes in plasma levels observed over a 24-hour dosing interval. In this regard, plasma levels achievecl with each close were in fact consistent over the 24-hour dosing interval. A statistically significant correlation between drug plasma levels and dose was observed. Correla- tions between plasma levels and blood pressure reductions were not as strong. Thus, this new formulation achieves relatively constant plasma concentrations with minimal peak-to-trough fluctuations, leading to relatively consistent blood pressure control. In addition, prazosin GITS treatment was well-tolerated and the majority of adverse experiences were milcl-to- moderate in severity.

ACKNOWLEDGMENT Pfizer Pharmaceuticals thanks the following decli-

cated investigators who participated in these clinical trials: John Simmons, M.D., Joan Friedland, M.D., Jerry Ryan, M.D., Paul Kaihlanen, M.D., Thomas Woehler, M.D., Paul Klotman, M.D., Jordan Holtz- man, M.D., Cliff Ratliff, Jr., M.D., Merrill Anderson, M.D., Kola Danisa, M.D., Randall Gore, M.D., Har- old Schnaper, M.D., W. Tyson Bennett, M.D., John Fillingim, M.D., Douglas Owens, M.D., Joseph Intile, M.D., James Tarro, M.D.

REFERENCE 1. Dzau VJ: Evolution of the clinlcal management of hypertension: emergmg role of spe cific vasodilators as lnltlal therapy. Am J Med 1987; 82 (suppl 1A): 36-43.


Efficacy and safety of Minipress XL, a new once-a-day formulation of prazosin

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