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eprosartan mesylate. eprosartan and hydrochlorothiazide. Eprosartan in the treatment of essential hypertension, with special emphasis on systolic blood pressure and the secondary prevention of stroke. © 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: May 2005.

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2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

eprosartan mesylate

eprosartan and hydrochlorothiazide

Eprosartan in the treatment of essential hypertension, with special emphasis on systolic blood pressure and the secondary prevention of stroke

© 2005 Solvay Pharmaceuticals GmbH

® registered trademark

Date of preparation: May 2005


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Please see

Summary of Product Characteristics

before prescribing eprosartan

Other tradenames include Tevetens®, Tevetenz®, Teveten® HCT, Teveten® Comp, and Tevetens® Plus

References cited in this slide set are numbered to correspond with those in the companion eprosartan e-monograph


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Hypertension - is it well controlled?

“a large body of evidence suggests that, in overall terms, blood pressure is not well controlled, and in particular, that elevated systolic blood pressure is poorly controlled”13

“surveys continue to show substantial underdiagnosis, undertreatment and poor rates of blood pressure control”2

2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

HYPERTENSION

Why should hypertension be treated?

  • ischaemia

  • myocardial infarction

  • cardiac hypertrophy

  • congestive heart failure

  • stroke

  • TIA (transient ischaemic attack)

  • PRIND (prolonged, reversible, ischaemic, neurological deficit)

  • retinopathy

  • lesions

  • swelling of optic disc

  • blindness

  • nephrosclerosis

  • atrophy of nephrons

  • renal failure


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

A major risk factor for CVD

“The relationship between BP and risk of cardiovascular disease (CVD) events is continuous, consistent, and independent of other risk factors”14

“elevated systolic blood pressure is a particularly strong predictor for risk of stroke”13

14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 13. Swales JD. J Hypertens 1999;17(suppl2):S15-S19


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Mortality and morbidity

  • 12-14% of deaths from coronary heart disease are due to high blood pressure … 6% of these deaths could be avoided if the incidence of hypertension was reduced by 50%1

  • Approximately 20% of people die within the first few months after a stroke

  • Up to 35% of stroke victims will be dependent at 1 year2

1. Petersen S, Rayner M. Coronary heart disease statistics 2002 edition. British Heart Foundation Statistics Database Annual Compendium., 2. Williams B, et al. J Hum Hypertens 2004;18:139-185


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Grade 1 (mild)

Grade 2 (moderate)

Grade 3 (severe)

Classification of hypertension2,15

140-159 mmHg systolic

90-99 mmHg diastolic

160-179 mmHg systolic

100-109 mmHg diastolic

>180 mmHg systolic

>110 mmHg diastolic

The JNC-7 Report14 combines Grades 2 and 3

2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572., 15. ESH Guidelines Committee. J Hypertens 2003;21(6):1011-1053


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Isolated systolic hypertension (ISH)2,15

  • ISH means raised systolic BP with normal or low diastolic BP

  • Most older hypertensive patients have isolated systolic (or systolic predominant) hypertension

Grade 1 ISH = 140-159/<90 mmHg

Grade 2 ISH = >160/<90 mmHg

2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 15. ESH. J Hypertens 2003;21(6):1011-1053


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Importance of SYSTOLIC hypertension

  • Systolic blood pressure (SBP) is a powerful predictor of all-cause mortality, coronary artery disease, stroke and renal disease16

  • SBP is regarded as the major factor to control in patients over 50 years of age2,14

  • Optimal therapy for these patients should be to reduce SBP while minimising the reduction of DBP18

2. Williams B, et al. J Hum Hypertens 2004;18:139-185., 14. Chobanian AV, et al. JAMA 2003;289:2560-2572.,

16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 18. Kannel W. Drugs Aging 2003;20:277-286


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MRFIT study – importance of SBP4

MRFIT showed a strong correlation between risk of stroke and increased blood pressure, especially SBP

4. Stamler J, et al. Arch Intern Med 1993;153:598-615 (This diagram shows SBP and DBP at baseline and adjusted stroke mortality for men. Relative Risk was adjusted to take into account several factors including age, race, serum cholesterol, smoking and diabetic medication)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Benefits of reducing raised SBP

  • Syst-Eur20

  • 4,695 elderly patients with ISH

  • treatment with the Ca-blocker nitrendipine gave a 42% risk reduction for total stroke

  • SHEP19

  • 4,736 elderly patients with ISH

  • antihypertensive treatment reduced stroke by 36%, CAD by 27%, and CHF by 49%

19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;350:757-764


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Syst-Eur (elderly patients with ISH)20

6

Fatal or non-fatal stroke

(events per 100 patients)

placebo

* p=0.003

5

4

3

*

active treatment

2

1

0

0

1

2

3

4

Time since randomisation (years)

20. Staessen JA, et al. Lancet 1997;350:757-764


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Arterial compliance and raised SBP

  • A major factor contributing to raised SBP is decreased arterial compliance, associated with altered aortic wave travel and reflection16,21

  • Reduced arterial compliance is generally caused by arterial stiffening

  • This is usually a consequence of aging or atherosclerosis, which may be why hypertension in older people is predominantly systolic

16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32., 21. London GM, Guerin A. J Hypertens 1999;17(Suppl 2):S3-S6


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

RAS and SNS both control of SBP16

RAS = renin-angiotensin system; SNS = sympathetic nervous system;

HTN = hypertension; CHF = congestive heart failure; ESRD = end-stage renal disease; CAD = coronary artery disease; LVH = left ventricular hypertrophy

16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

presynaptic AT1 receptor

sympathetic neurone

angiotensin II

postsynaptic AT1 receptor

(+)

norepinephrine

postsynaptic alpha-1 receptor

blood vessel

The neuro-effector junction16

Angiotensin II … postsynaptic and presynaptic effects

16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Renin-angiotensin system (RAS)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Primary intervention studies

  • Early trials found that treatment with diuretics or Ca-blockers reduced blood pressure and decreased morbidity and mortality19,20

  • It became a common conclusion that any drug which reduced blood pressure would reduce the risk of cardiovascular disease25

  • However, it has since been found that this is not the case for beta-blockers26-29 or the ACE inhibitor perindopril30

19. SHEP Cooperative Research Group. JAMA 1991;264:3255-3264., 20. Staessen JA, et al. Lancet 1997;360:757-764., 25. Messerli F. XXVI ESC, Munich, 2004., 26. MRC Working Party. BMJ 1985;291:97-104., 27. MRC Working Party. BMJ 1992;304:405-413., 28. The Dutch TIA trial study group. Stroke 1993;24:543-548., 29. Eriksson S, et al. Cerebrovasc Dis 1995;5:21-25., 30. PROGRESS Collaborative Group. Lancet 2001;358:1033-1041


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

AIIA intervention studies -1

LIFE31

Stroke rate was 5% with losartan and 7% with atenolol (RRR=25%)

SCOPE32

Candesartan significantly reduced the risk of non-fatal stroke in elderly patients by 27.8%

31. Dahlöf B, et al. Lancet 2002;359:995-1003., 32. Lithell H, et al. J Hypertens 2003;21:875-886


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

AIIA intervention studies -2

VALUE33

No significant differences between valsartan and amlodipine in CVD; valsartan significantly reduced the number of new cases of diabetes

CHARM34

Candesartan significantly reduced all-causes mortality and the number of patients developing new diabetes

33. Julius S, et al. Lancet 2004;363:2022-2031., 34. Kulbertus H. Rev Med Liege 2003;58(10):646-652


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

AIIA intervention studies -3

PRIME35

Irbesartan reduced the risk of progressing to more advanced stages of kidney disease in hypertensive patients with type-2 diabetes and kidney disease

It also significantly reduced the number of hospitalisations due to congestive heart failure

35. Program for irbesartan mortality and morbidity evaluations (PRIME). Data on file.


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

eprosartan mesylate

eprosartan and hydrochlorothiazide


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Eprosartan - unique dual action10,11,16

blockade of postsynaptic AT1 receptor inhibits action of angiotensin II

blockade of presynaptic AT1 receptor inhibits norepinephrine release into the synapse

10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251., 11. Balt JC, et al. J Hypertens 2001;19(3):465-473., 16. Brooks DP, Ruffolo RR. J Hypertens 1999;17(Suppl 2):S27-S32


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Affinity for AT1 receptors

  • Inhibition of AT1 receptors by eprosartan is dose-dependent and ‘surmountable’ 37

  • Eprosartan can be displaced if angiotensin II output increases, eg. in response to a fall in blood volume

  • Most other AIIAs bind non-competitively to AT1 receptors and are not readily displaced by increased angiotensin II output38

37. Edwards RM, et al. J Pharmacol Exp Ther 1992;260:175-181., 38. Hollenberg NK. Pharmacotherapy 1999;19(4 Pt 2):71S-72S


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Dose-related inhibition of AT1 in man39

Percentage inhibition of the effects of angiotensin II by various doses of eprosartan in healthy volunteers

100 -

80 -

60 -

40 -

20 -

0 -

Inhibition of angiotensin II

(%)

86%

71%

56%

70mg

100mg

200mg

eprosartan dosage

39. Ilson B. Am J Hypertens 1998;11(4 Pt 2):108A (Abstract E051)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sympatho-inhibitory effects10

Acute effects on the pressor response to spinal cord stimulation in pithed rats of eprosartan, losartan, valsartan irbesartan (0.3mg/kg iv; n=4 for each AIIA)

40 -

20 -

0 -

- 20 -

- 40 -

Change in DBP vs controls (%)

eprosartan

losartan

valsartan

irbesartan

Sympathetic stimulation at 1Hz. Drugs were given intravenously 10 min before stimulation (acute effect)

p<0.05

10. Ohlstein EH, et al. Pharmacology 1997;55(5):244-251


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sympathetic inhibition in man40

  • Randomised, double-blind, crossover study

  • 16 healthy male volunteers received a single dose of eprosartan 600mg or placebo, followed by insulin-induced hypoglycaemia

  • The pulse pressure response to sympatho-adrenal activation was significantly reduced by eprosartan compared with placebo (p=0.02)

40. Christensen M, et al. Clin Sci 2005;108:113-119


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Overview of efficacy

  • Effect on SBP and pulse pressure

  • Studies versus active comparators

  • Studies versus placebo

  • Efficacy in older patients

  • Efficacy in black patients

  • Long-term efficacy

  • Efficacy in combination with other drugs

  • Secondary prevention of stroke (MOSES)

  • Effect on blood platelets / fibrinolytic function

  • Renoprotective effects


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sega – more effective than enalapril5

  • 118 patients with severe hypertension

  • Randomised, parallel group study

  • 8-week double-blind titration phase was followed by a 2-week maintenance phase

    • - eprosartan 400mg/day (up to 600 or 800mg)

    • - enalapril 10mg/day (up to 20 or 40mg)

    • - HCTZ 25mg/day added at week 6 in patients not achieving target BP

5. Sega R, et al. Blood Pressure 1999;8:114-121


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sega – more effective than enalapril5

Mean reduction from baseline of sitSBP and sitDBP, following treatment with eprosartan or enalapril in severe hypertension

sitting systolic BP

sitting diastolic BP

- 0 -

- 10 -

- 20 -

- 30 -

Reduction in blood pressure from baseline (mmHg)

-16.2

-20.1

-21.2

N.S.

-29.1

p=0.025

enalapril 10-40mg/day (n=46)

eprosartan 400-800mg/day (n=43)

5. Sega R, et al. Blood Pressure 1999;8:114-121


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Ruilope – effective control of SBP41

  • 12-week, double-blind, randomised trial in 334 patients aged >65 years with predominantly systolic hypertension

  • Eprosartan (600-800mg/day) and enalapril (5-20mg/day) reduced sitSBP to a similar extent

  • At week 3 there were significantly more responders with eprosartan than with enalapril for SBP (30% versus 20%, p=0.033)

41. Ruilope L, et al. Blood Pressure 2001;10:223-229


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Punzi – effective control of SBP42

Mean change from baseline in sitSBP in ISH patients >60yrs of age: 9 weeks of monotherapy followed by 4 weeks in combination with HCTZ

week 3

week 6

week 9

week 13

- 0 -

- 5 -

- 10 -

- 15 -

- 20 -

- 25 -

Mean change in sitSBP from baseline (mmHg)

placebo

*

**

eprosartan

* p<0.0001 between treatments ** p<0.002 between treatments

42. Punzi HA, et al. J Human Hypertens 2004:1-7


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Teitelbaum – effective control of SBP43

  • Evaluated eprosartan (600mg/day alone or with HCTZ) in 195 patients aged 60-84yrs with ISH or combined systolic-diastolic hypertension

  • SBP was significantly reduced at study endpoint from baseline (p<0.0001)

  • Reduction in DBP was significantly greater in patients with combined systolic-diastolic hypertension than in those with ISH (12.2 versus 5.0 mmHg, respectively, p<0.0001)

43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Teitelbaum – pulse pressure reduction43

Mean pulse pressure during eprosartan treatment in patients with ISH or combined systolic-diastolic hypertension

* p<0.0001 ISH versus non-ISH

ISH

non-ISH

** p<0.05 ISH versus non-ISH

90 -

80 -

70 -

60 -

50 -

40 -

Mean pulse pressure (mmHg)

p<0.0001 versus baseline

*

**

week 2

week 4

week 6

week 10

baseline

follow-up (weeks)

43. Teitelbaum I, et al. Can J Cardiol 2004;20(Suppl C):11C-16C


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

de la Sierra – pulse pressure reduction46,47

  • 3,133 hypertensive patients in primary care

  • Eprosartan significantly reduced pulse pressure at 12 weeks (mean -13.5 mmHg from baseline, p<0.001)

  • In 895 patients with ISH, mean SBP and pulse pressure were reduced by 25.6 mmHg and 22.5 mmHg (both p<0.05 versus baseline)

  • DBP decreased by 3.1 mmHg in ISH patients (versus 16.7 mmHg for non-ISH patients)

46. de la Sierra A, et al. Can J Cardiol 2004;20(Suppl C):17C-22C., 47. de la Sierra A, et al. Blood Pressure 2004;13(Suppl 2):5-10


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Robles – pulse pressure reduction48

Reduction in mean pulse pressure, arterial pressure, SBP and DBP in a 16-week open-label study (n=566)

pulse

pressure

arterial

pressure

systolic

pressure

diastolic

pressure

- 0 -

- 10 -

- 20 -

- 30 -

Reduction in blood pressure from baseline (mmHg)

-13

-13

-17.4

-26

all changes p<0.0001 versus pretreatment baseline

48. Robles NR, et al. Int J Clin Pract 2005;59(4):478-484


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Elliott – study versus enalapril8

Responders to eprosartan (400-600mg/day) and enalapril

(5-20mg/day) at the end of 26 weeks of treatment in 528 patients with mild-to-moderate hypertension

% responders

p=0.018

100 -

80 -

60 -

40 -

20 -

0 -

81.7%

73.4%

70.3%

62.6%

eprosartan

monotherapy

eprosartan + HCTZ

enalapril monotherapy

enalapril + HCTZ

8. Elliott WJ, et al. J Hum Hypertens 1999;13:413-417


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Oparil – study versus enalapril9

Reduction in sitDBP from baseline to endpoint after 6 weeks of eprosartan (600mg/day), enalapril (20mg/day) or placebo in 136 patients with mild-to-moderate essential hypertension

eprosartan

600mg/day

enalapril

20mg/day

placebo

- 0 -

- 2 -

- 4 -

- 6 -

- 8 -

- 10 -

Reduction in sitDBP from baseline (mmHg)

- 4.4

- 7.9

- 8.7

p<0.002

p<0.035

9. Oparil S. Curr Ther Res 1999;60(1):1-14


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Puig – study versus losartan49

  • Compared 4 weeks of treatment with eprosartan (600mg/day) or losartan (50mg/day) in a randomised, double-blind study in 60 outpatients with mild-to-moderate hypertension

  • Mean sitting BP was reduced by 12.4/12.7 mmHg with eprosartan and by 9.6/10.9 mmHg with losartan (N.S.)

  • At study endpoint there were 73% eprosartan responders and 53% losartan responders (N.S.)

49. Puig JC, et al. J Hypertens 1999;17:1033-1039


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Hedner – study versus placebo50

Reduction in sitDBP from baseline to endpoint after 13 weeks treatment with eprosartan 400-800mg bd or od compared with placebo in 243 patients with mild-to-moderate hypertension

eprosartan

400-800mg

once-daily

eprosartan

400-800mg

twice-daily

placebo

  • 0 -

  • 2 -

  • 4 -

  • 6 -

  • 8 –

  • - 10 -

Reduction in sitDBP from baseline (mmHg)

- 4

- 9

- 9

p<0.0001

p<0.001

50. Hedner T, et al. J Hypertens 1999;17(1):129-136


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Hedner – study versus placebo50

Overall response rate after 13 weeks treatment with eprosartan 400-800mg bd or od compared with placebo in 243 patients with mild-to-moderate hypertension

* p=0.05

46.8%*

Response rate (%)

50 -

40 -

30 -

20 -

10 -

0 -

35.1%

eprosartan

once-daily

placebo

50. Hedner T, et al. J Hypertens 1999;17(1):129-136


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Gradman – study versus placebo51

Change in mean sitSBP and sitDBP from baseline after

8 weeks of treatment with eprosartan (600mg/day) or placebo

in 243 patients with mild-to-moderate hypertension

SYSTOLIC BP

DIASTOLIC BP

eprosartan

placebo

eprosartan

placebo

  • 2 -

  • 0 -

  • 2 -

  • 4 -

  • 6 -

  • 8 -

  • - 10 -

Change in sitBP from baseline (mmHg)

0.8

- 1.9

- 6.0

- 7.5

p<0.0001

p<0.0001

51. Gradman AH, et al. Clin Ther 1999;21:442-453


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Argenziano – study in older patients52

Percentage of elderly and younger responders after 26 weeks of treatment with eprosartan (400-600mg/day) and enalapril (5-20mg/day) in patients with mild-to-moderate hypertension

% responders

100 -

80 -

60 -

40 -

20 -

0 -

87.3%

80.0%

77.4%

72.1%

eprosartan

< 65 yrs

eprosartan > 65 yrs

enalapril

< 65 yrs

enalapril > 65 yrs

52. Argenziano L, Trimarco B. Curr Med Res Opin 1999;15(1):9-14


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Levine – study in black patients53

Response in black patients after 26 weeks of treatment with eprosartan (400-600mg/day) or enalapril (5-20mg/day) with or without HCTZ in patients with mild-to-moderate hypertension

% responders

p<0.018

p<0.05

100 -

80 -

60 -

40 -

20 -

0 -

66.7%

52%

42.1%

26%

eprosartan

monotherapy

eprosartan + HCTZ

enalapril monotherapy

enalapril + HCTZ

53. Levine B. Curr Med Res Opin 1999;15:25-32


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Levine – long-term study54

Mean sitSBP and sitDBP in a 24-month study in patients

with mild-to-moderate hypertension who received eprosartan (400-800mg/day) with or without HCTZ (12.5-25mg/day)

mean sitDBP

mean sitSBP

160 -

120 -

80 -

40 -

0 -

Mean BP (mmHg)

145.9

139.5

136

136.7

94.9

88.7

86.4

86.9

baseline

(n=591)

titration

endpoint

(n=577)

12 months

(n=571)

24 months

(n=300)

54. Levine B. Curr Med Res Opin 2001;17(1):8-17


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sachse – combination with HCTZ55

Mean change in sitDBP from baseline after 8 weeks treatment with eprosartan 600mg/day with or without HCTZ 12.5mg/day

eprosartan

(n=156)

eprosartan + HCTZ

(n=149)

Mean change in sitDBP from

baseline (mmHg)

  • 0 -

  • 2 -

  • - 4 -

  • - 6 -

  • 8 -

  • - 10 -

  • - 12 -

- 7.9

- 10.7

p=0.001

55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Sachse – combination with HCTZ55

Percent responders after 8 weeks treatment with eprosartan 600mg/day with or without HCTZ 12.5mg/day

p=0.004

% responders

100 -

80 -

60 -

40 -

20 -

0 -

73.2%

57.1%

eprosartan

eprosartan + HCTZ

55. Sachse A, et al. J Hum Hypertens 2002;16: 169-176


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Secondary stroke prevention (MOSES)6

  • Eprosartan (n=710) versus nitrendipine (n=695) (the calcium channel blocker shown to reduce strokes in Syst-Eur)

  • The study included hypertensive patients with proven ischaemia, TIA/PRIND or intracerebral haemorrhage during the previous 24 months

MOrbidy and mortality after Stroke - Eprosartan compared with nitrendipine for Secondary prevention

6. Schrader J, et al. Stroke 2005;36: (In Press). Additional information: ESC, Munich, 2004/data on file


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Secondary stroke prevention (MOSES)

  • Combined primary endpoint: total mortality plus the total cardiovascular and cerebrovascular events, including all recurrent events

  • Secondary endpoints: The single components of the combined primary endpoint, and an assessment of functional status and cognitive function

  • Mean follow-up: 2.5 years

  • Mean dosages: 623mg eprosartan 16mg nitrendipine


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MOSES - blood pressure changes

Effect of eprosartan and nitrendipine on blood pressure in hypertensive patients with previous stroke/TIA/PRIND

eprosartan

nitrendipine

Blood pressure

(mmHg)

160 -

140 -

120 -

100 -

80 -

60 -

SBP

DBP

0

3

6

3

6

12

18

24

36

48

weeks

months

76% of patients on eprosartan had their BP normalised.

This was higher than in LIFE (46%) or VALUE (64%)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MOSES - primary endpoint

Reduction in total mortality, cardiovascular and cerebrovascular events during treatment with eprosartan or nitrendipine in hypertensive patients with previous stroke/TIA/PRIND

21% risk reduction with eprosartan (p=0.014)

Number of events

nitrendipine

300 -

250 -

200 -

150 -

100 -

50 -

0 -

eprosartan

0

250

500

750

1000

1250

1500

1750

days


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MOSES - stroke recurrence

Reduction in stroke recurrence during treatment with eprosartan or nitrendipine in hypertensive patients with previous stroke/TIA/PRIND

25% risk reduction with eprosartan (p=0.02)

nitrendipine

Number of events

150 -

100 -

50 -

0 -

eprosartan

0

250

500

750

1000

1250

1500

1750

days


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MOSES - other efficacy data

  • Eprosartan showed a trend towards a reduced risk of fatal/non-fatal cardiac events (p=0.06)

  • There was a statistically significant difference in favour of eprosartan for first occurrence of cardiovascular events (p=0.03)

  • No difference between groups in overall mortality

  • No difference between groups in functional status and cognitive function


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

MOSES - conclusion

  • Both agents produced similar reductions in blood pressure

  • Therefore the reduced incidence of cerebrovascular and cardiovascular events in patients receiving eprosartan indicates that it offers additional protection above that offered by blood pressure reductions


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Effect on platelets/fibrinolysis

  • Hypertension is often associated with undesirable changes in platelet function59

  • Abnormalities of the coagulation/fibrinolytic system may predispose to a procoagulant state, which increases the risk of cardiovascular disease60

  • The renin-angiotensin system appears to play an important role in regulating fibrinolytic balance and haemostatic function60

59. Labios M, et al. Am J Hypertens 2004;17(9):757-763., 60. Makris TK, et al. Drugs Exptl Clin Res 2004;30(3):125-132


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Makris - effect on platelets/fibrinolysis60

Percentage change in haemodynamic and haemostatic factors after six months of eprosartan 600mg/day or losartan 100mg/day compared with baseline in 86 hypertensive patients. Differences between the drugs were statistically significant.

20 -

0 -

- 20 -

- 40 -

% difference from baseline

10.3

6.3

PAI-1

TM

fibrinogen

tPA

-2.3

-5.5

-9.5

-16.9

-17.6

eprosartan (n=45)

-31.0

losartan (n=41)

PAI-: plasminogen activator inhibitor-1 TM: thrombomodulin

tPA: tissue plasminogen activator inhibitor antigen

60. Makris TK, et al. Drugs Exptl Clin Res 2004;30(3):125-132


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Labios - effect on platelet function59

  • Assessed platelet function in 30 patients with mild-to-moderate hypertension before and after 8 weeks of treatment with eprosartan 600mg/day

  • There was a significant reduction in platelet microparticles after blood shear exposure (p<0.01) and after exposure to calcium-ion ionophore activation (p<0.05)

  • Eprosartan reduced the trend for platelets to be more readily activated in hypertensive patients

59. Labios M, et al. Am J Hypertens 2004;17(9):757-763


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Neumann – renoprotective effects61

Mean muscle sympathetic nerve activity (MSNA) in nine hypertensive patients with chronic renal failure given 6 weeks of treatment with eprosartan alone or in combination with the centrally-acting sympatholytic agent moxonidine

p<0.05

p<0.05

40 -

20 -

0-

Mean MSNA (burst per min)

healthy controls

baseline

eprosartan

eprosartan+

moxonidine

61. Neumann J, et al. J Am Soc Nephrol 2004;15:2902-2907


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Frank – renoprotective effects63

  • Double-blind, placebo-controlled study of eprosartan (600mg/day for 7 days) in 10 normotensive and 14 borderline hypertensive patients

  • In patients receiving eprosartan, disturbing cardiopulmonary baroreceptors by lower body negative pressure did not alter GFR

  • GFR was significantly decreased in patients receiving placebo (p<0.05)

63. Frank H, et al. Kidney Int 2003;63:617-623


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Treatment-emergent adverse events

  • Cumulative exposure to eprosartan worldwide is currently over 300 million patient days

  • Well tolerated in controlled studies - most adverse events were mild or transient, irrespective of dose7

  • Frequency of adverse events is not affected by age, gender or race

  • Incidence of impotence, oedema, flushing, fatigue and dizziness is similar to placebo7

7. Gavras I, Gavras H. Pharmacotherapy 1999;19(4 Pt 2):102S-107S


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Adverse events from SmPC


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Adverse events in older patients66

Most common therapy-related adverse events (>5%) by age in patients receiving eprosartan; data from 15 studies (n=2,334)

% patients with adverse event

<65yrs (n=1653)

20 -

15 -

10 -

5 -

0 -

>65yrs (n=681)

head-

ache

URTI

myalgia

pharyn-

gitis

cough

rhinitis

dizziness

66. Harland D, et al. Am J Hypertens 1998; 11:78A (Abstract D039)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Low incidence of “ACEi” cough8

Incidence of dry persistent cough (not due to URTI) during

12 weeks of treatment with eprosartan or enalapril. The low incidence of cough has been confirmed in other studies,9 including in the elderly41,52 and in black patients53

10 -

8 -

6 -

4 -

2 -

0 -

% patients

p=0.018

5.4%

1.5%

eprosartan

(n=259)

enalapril

(n=261)

8. Elliott WJ, et al. J Hum Hypertens 1999;13:413-417., 9. Oparil S. Curr Ther Res 1999;60(1):1-14., 41. Ruilope L, et al. Blood Pressure 2001;10:223-229., 52. Argenziano L, Trimarco B. Curr Med Res Opin 1999;15(1):9-14.,

53. Levine B. Curr Med Res Opin 1999;15:25-32


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No effect on uric acid excretion49

Change from baseline in the ratio of uric acid to creatinine

in the urine after 4 weeks of treatment with eprosartan (600mg/day) or losartan (50mg/day) in 60 outpatients with mild-to-moderate hypertension in a double-blind study

0.2 -

0.1 -

0 -

- 0.1 -

- 0.2 -

Change in ratio from baseline

0.11

- 0.04

losartan

eprosartan

p<0.01

49. Puig JC, et al. J Hypertens 1999;17:1033-1039


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Well tolerated when used with HCTZ70

  • Meta-analysis of 17 studies (n=1,899 )

  • Eprosartan/HCTZ combinations were well tolerated in all grades of hypertension

  • In the controlled studies, headache, dizziness, myalgia and upper respiratory tract infections were the most frequently reported adverse events

  • Dizziness may be attributable more to HCTZ

70. Böhm M, Sachse A. Drug Safety 2002;25(8):599-511


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Chemically distinct from other AIIAs

Eprosartan is a non-biphenyl, non-tetrazole AIIA (all other AIIAs are biphenyl tetrazoles)

eprosartan

losartan, candesartan, irbesartan, valsartan, telmisartan, olmesartan


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Plasma profile72

Plasma concentration following administration of single doses of eprosartan 100-800mg to healthy volunteers (n=23)

Plasma concentration (ng/ml)

800mg

400mg

200mg

100mg

10,000 -

1,000 -

100 -

0 -

0

4

8

12

16

20

24

time after administration (hours)

72. Chapelsky MC, et al. J Clin Pharmacol 1998;38:34-39


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Other pharmacokinetic data

  • 98% protein bound, unaffected by age, gender, hepatic dysfunction or mild-to-moderate renal impairment

  • Low volume of distribution (approximately 13L)

  • Negligible metabolism - no active metabolites

  • Does not affect hepatic P450 enzymes, thereby avoiding many potential drug interactions

  • Mostly (90%) excreted in the faeces


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Low potential for drug interactions

  • Does not inhibit cytochrome P450 enzymes (CYP1A, CYP2A6, CYP2C9/8, CYP2C19, CYP2D6, CYP2E and CYP3A) in vitro at clinically relevant concentrations

  • No effect on the pharmacokinetics of digoxin, warfarin, glibenclamide, ranitidine, fluconazole or ketoconazole

  • Has been used concomitantly with thiazides, calcium channel blockers and hypolipidaemic agents (eg. statins) without evidence of clinically significant adverse interactions


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Special patient groups

  • No differences in safety or efficacy have been observed in the elderly - dose adjustment is not usually required

  • AUC and Cmax are 30-50% higher in moderate-severe renal impairment - the daily dose should not exceed 600mg for these patients

  • AUC (but not Cmax) is increased in hepatic impairment, but no dose adjustment is required

In some countries, licensed dosage recommendations may vary from the above – please consult national SmPC


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Dosage and administration

  • Recommended starting and maintenance dose is 600mg once-daily, to be taken in the morning

  • Maximum blood pressure reduction normally takes 2-3 weeks

  • Doses up to 1200mg/day for 8 weeks have been shown in clinical trials to be effective with no apparent dose relationship in the incidence of adverse experiences reported


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Eprosartan – benefits to patients (1)

  • The systolic component of blood pressure is a better predictor of cerebrovascular and cardiovascular risk than the diastolic component

  • Most hypertensive people over 50 years of age have predominantly systolic hypertension

  • Eprosartan gives a statistically significantly greater reduction of systolic blood pressure than enalapril


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Eprosartan – benefits to patients (2)

  • Recurrent stroke is a major cause of death and disability. MOSES showed that eprosartan is significantly more effective than a calcium channel blocker in reducing secondary stroke in hypertensive patients

  • Cough is a frequent problem with ACE inhibitors. Eprosartan is associated with a lower incidence of dry, persistent cough than enalapril (comparable incidence to placebo)


2005 solvay pharmaceuticals gmbh registered trademark date of preparation may 2005

Eprosartan – benefits to patients (3)

  • Eprosartan is effective in Afro-Caribbeans, who may be less responsive to some other treatments such as ACE inhibitors

  • Eprosartan gives effective 24-hour control of hypertension from a single 600mg once-daily starting and maintenance dose for most patients. It can be combined with other antihypertensive agents such as HCTZ if required

  • For patients taking concomitant medications, eprosartan will not interfere with their metabolism by cytochrome P450 enzymes


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