© 2005 Solvay Pharmaceuticals GmbH ® registered trademark Date of preparation: December 2005Material Code: 201 0241

MOXONIDINE

A review of moxonidine in essential hypertension, with emphasis on metabolic syndrome and other conditions associated with sympathetic overactivity

®

®

Please seeSummary of Product Characteristics

before prescribing moxonidine

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

Details of formulations and dosage recommendations may vary between countries

Trade names include: Physiotens®, Cynt®, Fisiotens®, Moxon®, Norcynt® and Normatens®

Metabolic syndrome

1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

• Elevated blood pressure is often associated with obesity, insulin resistance and dyslipidaemia

• Clustering of these symptoms has given rise to the concept of the ‘metabolic syndrome’ (with high risk of diabetes and CVD)

They may all reflect varying degrees of sympathetic overactivity1

Sympathetic overactivity

Sympathetic overactivity may be a central feature linking hypertension with other components of the metabolic syndrome

2. Mancia G et al. J Hum Hypertens 1997;11(suppl 1):S3-S8., 3. Goldstein DS. Hypertension 1981;3:48-52., 4. Julius S, Valentini M. Blood Press 1998;7(suppl 3):5-13

• In animal models, sympathetic overactivity can initiate and maintain elevated blood pressure2

• In humans, plasma norepinephrine levels in hypertensive patients are significantly higher than in normotensive controls (p<0.05)3

• Sympathetic activation is seen in early phases of hypertension and may precede blood pressure elevation in some patients4

Link with hypertension

1. Rahn KH et al. J Hypertens 1999;17(suppl 3):S11-S14

• Sympathetic activity can be high in young subjects with borderline hypertension

• This suggests that increased sympathetic activity is the cause, rather than the consequence, of blood pressure elevation1

Link with hypertension

5. Scherrer U et al. Circulation 1994;89:2634-2640., 6. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158

• Raised BMI is associated with an increased rate of sympathetic nerve discharge in skeletal muscle5

• There is a correlation between BMI, body fat distribution and urinary norepinephrine excretion6

Link with obesity

7. Jamerson KA et al. Hypertension 1993;21:618-623., 8. Huggett RJ et al. Circulation 2003;108:3097-3101.,9. Valensi P et al. ESC 2004 (www.solvaycardio.com)

• Sympathetic activation is a major component of insulin resistance in clinical experiments7 and in humans with type 2 diabetes8

• Cardiac autonomic dysfunction occurs in:

- 30-50% of patients with diabetes

- 40% of obese patients without diabetes9

Link with insulin resistance and diabetes

10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19., 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65., 12. Lanfranchi A et al. Blood Press 1998;7(suppl 3):40-45

• Sympathetic overactivity is also implicated in:

- renal disease10

- left ventricular hypertrophy11

- congestive heart failure12

Link with other risk factors

Incidence of metabolic syndrome13

13. Isomaa B et al. Diabetes Care 2001;24:683-689

In a study of 4,483 subjects aged 35-70 years, metabolic syndrome was present in:

• 10-15% with normal fasting blood glucose

• 42-64% with impaired glucose tolerance/ impaired fasting glucose

• 78-84% with type 2 diabetes

Metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria

Risk of CHD, stroke and CV mortality was higher in people with metabolic syndrome (p<0.001)

Origin of cardiovascular symptoms9

9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.

Lifestyle

Adiposityinflammation

INSULIN RESISTANCE /METABOLIC SYNDROME

Arterial rigidity hypertension

Cardiovascular complications

Atherothrombosis ArrhythmiasLVH

- free fatty acids- oxidative stress

Endothelial dysfunction

Relative sympathetic overactivity

Treatment strategy

14. Hansson L. Blood Press 1998;7(suppl 3):20-22

Autonomic dysfunction appears to have an important role in many

patients with metabolic syndrome

Treatment of patients with hypertension should take account of associated metabolic conditions14

Rationale for moxonidine

15. Hamilton CA. In: van Zwieten PA et al (eds). The I1 Imidazoline Receptor Agonist Moxonidine. 2nd Ed, London: Roy Soc Med,1996:7-30., 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

Moxonidine binds selectively and with high affinity to I1-receptors in the RVLM16

thus reducing peripheral sympathetic activity

• Sympathetic tone is regulated centrally in the rostral ventrolateral medulla (RVLM)15

• This region contains imidazoline I1-receptors and 2-adrenoceptors which regulate sympathetic activity

Overview of moxonidine - 1

16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10., 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972., 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

• Lowers peripheral arterial resistance without significant effects on cardiac output17

• Relatively little affinity for 2-receptors in the brainstem16 (adverse events such as sedation and dry mouth are infrequently reported during prolonged therapy)28

• Low potential for drug interactions

Overview of moxonidine - 2

The above studies are described in later slides

• Effective when used as monotherapy

• An effective adjunct to other first-line therapies such as diuretics and ACE-inhibitors

• Linear dose-response effect allows dose titration

• Improves glucose metabolism / insulin resistance

• Neutral effect on the lipid profile

• Renal protective effect

Efficacy studies reviewed in this slide set

• Monotherapy versus active comparators

• Dose response

• Long-term efficacy

• Combination with other antihypertensives

• Diabetic / prediabetic hypertensive patients

• Obese hypertensive patients

• Postmenopausal hypertensive women

• Hypertensive patients with LVH

• Role in renal protection

Moxonidine versus active comparators

Moxonidine has been found to be similarly effective to other first-line antihypertensive agents in reducing blood pressure including:

• Diuretics (hydrochlorothiazide - HCTZ)

• Beta-blockers (atenolol)

• ACE inhibitors (captopril and enalapril)

• Calcium-channel blockers (nifedipine)

Moxonidine versus hydrochlorothiazide19

• Double-blind, placebo-controlled parallel group, randomised study in general practice (n=160)

• Moxonidine (0.4mg/day) compared with HCTZ (25mg /day) in mild-to-moderate hypertension

• After 8 weeks of monotherapy, moxonidine and HCTZ both gave significant reductions in BP compared with placebo (p<0.05)

• No significant differences between the drugs

19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

Results using the two active agents in combination are described on a later slide

Response after 8 weeks of moxonidine or atenolol in a randomised, double-blind study in mild-moderate hypertension

Moxonidine versus atenolol20

20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49

% responders

moxonidine0.2-0.4mg/day

atenolol50-100mg/day

71%(20/28)

68%(17/25)

100 -

80 -

60 -

40 -

20 -

0 -

N.S.

Response was defined as DBP <90 mmHg

Mean sitSBP and sitDBP during 4 weeks of treatment with moxonidine (0.2-0.4mg/day) or captopril (25-50mg/day) in a randomised, double-blind study

Moxonidine versus captopril21

21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432

Mean blood

pressure (mmHg)

200 -

160 -

120 -

80 -

week 1 week 2 week 3 week 4

captopril (n=25)

moxonidine (n=25)

0

systolic

diastolic

Moxonidine versus captopril22

• A randomised, double-blind, 4-week study compared moxonidine (0.2mg bd) versus captopril (25mg bd)

• 26 patients with mild-to-moderate hypertension (over 80% also had evidence of endocrine or metabolic diseases)

• Both drugs reduced BP by similar amounts

• No evidence of rebound hypertension with moxonidine on withdrawal of therapy

22. Kraft K, Vetter H. J Cardiovasc Pharmacol 1994;24(suppl 1):S29-S33

Moxonidine versus enalapril23

• 8-week, double-blind, placebo-controlled study of moxonidine (0.2-0.4mg/day, n=47) versus enalapril (5-10mg/day, n=47) in outpatients with mild-to-moderate hypertension

• Both drugs were significantly superior to placebo at week 8 for sitBP (p<0.001), 24hr SBP (p=0.002) and 24hr DBP (p<0.001)

• Response rates were comparable between moxonidine and enalapril (66% vs 60%)

23. Küppers HE et al. J Hypertens 1997;15:93-97 Response was defined asDBP <90 mmHg or >10 mmHg reduction

Change in DBP at week 8 with moxonidine (n=51) and enalapril (n=53) in a randomised, double-blind, placebo-controlled study in mild-to-moderate hypertension

Moxonidine versus enalapril24 – high dose

24. Prichard BNC et al. Blood Press 2002;11:166-172

p<0.001

moxonidine0.6mg/day

enalapril20mg/day

p<0.001

Mean change in DBP from

baseline (mmHg)

-11.9

- 0 -

- 4 -

- 8 -

- 12 -

- 16 -

placebo

- 2.3

- 13.2

Moxonidine versus enalapril25 – low dose

• 8-week, double-blind, randomised, placebo-controlled study in mild-to-moderate hypertension

• Moxonidine 0.2mg/day (n=54) versus enalapril 5mg/day (n=59)

• Both gave significant reductions in DBP versus placebo (p<0.001)

• No significant difference between moxonidine and enalapril in their effects on blood pressure

25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

Mean SBP and DBP after 0.2-4mg/day moxonidine (n=116) and 20-40mg/day nifedipine (n=113) in a double-blind study

Moxonidine versus nifedipine26

26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44

Mean blood

pressure (mmHg)

180 -

160 -

140 -

120 -

100 -

80 -

4 8 12 19

nifedipine

moxonidine

0 week 26

systolic

diastolic

Moxonidine versus nifedipine27

• 4-week, randomised, double-blind study in 60 patients aged 45-71 years

• Compared moxonidine (0.2-0.4mg/day) versus

sustained-release nifedipine (20-40mg/day)

• Mean BP reductions after 4 weeks:

- moxonidine ... from 167/100 to 132/83 mmHg

- nifedipine ... from 167/99 to 134/83 mmHg

27. Mangiameli S et al. Z Allg Med 1992;68:862 866

Percentage of patients requiring a moxonidine dose increase from 0.2mg to 0.4mg daily after two weeks of treatment in four clinical trials 20,21,26,27

Dose-response with moxonidine

20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49., 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432., 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44., 27. Mangiameli S et al. Z Allg Med 1992;68:862-866

Prichard 1992

42%(49/116)28%

(8/29)

100 -

80 -

60 -

40 -

20 -

0 -

% patients

requiring dose

doubling

56%(14/25)

10%(3/30)

Lotti 1993

Wolf 1992

Mangiameli 1992

Dose-response of moxonidine in reducing office sitDBP at trough from three double-blind, placebo-controlled trials

Linear dose-response25

25. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

0.2mg

15 -

10 -

5 -

0 -

Mean placebo-adjusted

reduction in sitDBP

(mmHg)

0.4mg 0.6mg

moxonidine dosage (mg/day)

4.65

7.01

10.5

Change in mean sitSBP and sitDBP during up to two years of treatment with moxonidine (week 3 = end of dose titration)

Long-term efficacy of moxonidine28

28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., 44. Prichard BNC. In: van Zwieten PA et al, editors. The I1

Imidazoline Receptor Agonist Moxonidine. 2nd Edition. London: Roy Soc Med, 1996:49-75

Change in mean

blood pressure (mmHg)

180 -

160 -

140 -

120 -

100 -

80 -

2 years (n=49)

1 year (n=141)

26 52 78 1040

systolic

diastolic

weeks of moxonidine treatment

• Open, multicentre study of 223 outpatients with mean sitBP >160/95 to <240/114 mmHg

• Moxonidine (0.2-0.6mg/day) was given for 12 months, with a supplementary diuretic if required

• Mean sitBP was reduced by 25/15 mmHg at week 12 and by 27/16 mmHg at week 52

• Response was 82% at week 12 and 85% at week 52

29. Trieb G et al. Eur J Clin Res 1995;7:227-240 Response defined as DBP <90 mmHg or a reduction of >10 mmHg

Long-term efficacy of moxonidine29

Mean reduction in sitDBP after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study

Moxonidine in combination with HCTZ19

19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

Mean reduction

in diastolic blood

pressure from

baseline (mmHg)

13mmHg(n=40)

*16mmHg

(n=42)***p<0.05 vs placebo

**p<0.05 vs placebo and monotherapies

- 0 -

- 10 -

- 20 -

placebomoxonidine(0.4mg/day)

HCTZ25mg/day

moxonidine+ HCTZ

(0.4/25mg/day)

12mmHgn=37

*

9mmHg(n=41)

Percentage response for all patients after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study

100 -

80 -

60 -

40 -

20 -

0 -

% patients with

response

moxonidine+ HCTZ

(0.4/25mg/day)

HCTZ(25mg/day)

moxonidine(0.4mg/day)

placebo

44%(n=41)

70%(n=37)

70%(n=40)

88%(n=42)

Intent-to-treat analysis. Response defined as DBP <90 mmHg or >10 mmHg decrease

Moxonidine in combination with HCTZ19

19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

Mean change in SBP and DBP after 4 weeks of combination therapy in patients who had not responded to previous moxonidine monotherapy

Combination therapy – TOPIC study30

30. Waters J et al. J Clin Basic Cardiol 1999;2:219-224

0 -

- 4 -

- 8 -

- 12 -

- 16 -

- 20 -

Change in mean BP from baseline (mmHg) -10.7

*

-7.3*

-7.9

-5.5 -3.2-4.4

* p<0.05 versus the other combinations

-4.8

moxonidine 0.4mg+ amlodipine 5mg

(n=81)

moxonidine 0.4mg+ enalapril 10mg

(n=82)

moxonidine 0.4mg+ HCTZ 12.5mg

(n=90)

sitDBPsitSBP

• Prediabetic conditions include insulin resistance, hyperinsulinaemia and hyperglycaemia

• Long-term benefits of antihypertensive therapy may be compromised if the drugs chosen have adverse effects on insulin sensitivity

• In hypertensive patients, moxonidine has been shown to reduce plasma glucose levels and increase insulin sensitivity

Diabetic/prediabetic hypertensive patients

Effects of moxonidine (0.4mg/day for 8 weeks) in hypertensive patients with reduced insulin sensitivity in a double-blind, placebo-controlled, randomised, parallel group study

31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35

% change

from baseline

GLUCOSE INFUSION RATE

INSULIN SENSITIVITY INDEX

25 -

20 -

15 -

10 -

5 -

0 -

- 5 -

-10 -

- 6.0%

p=0.004

N.S.

p=0.026

21%

- 6.0%

p=0.027

21%

p=0.056

N.S.

placebo (n=13)

moxonidine (n=25)

Effects on insulin resistance31

Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state

• 30 patients with mild-to-moderate hypertension and normal glucose tolerance

• Insulin sensitivity was studied after 6 months of treatment with moxonidine (0.2-0.6mg/day)

• Following oral GTT, the 2-hour plasma insulin level was statistically significantly reduced by moxonidine compared with pretreatment (18% reduction, p<0.05)

32. Almazov VA et al. J Hypertens 2000;18(suppl 2):12

Patients with normal glucose tolerance32

• Open, randomised study of 202 mildly hypertensive, insulin-resistant, overweight patients

• Moxonidine (0.2mg bd) or metformin (500mg bd) for 16 weeks

• Insulin AUC after OGTT was 14.7% lower with moxonidine than metformin (p=0.052)

• Difference in AUC between treatments was 23.8% in patients with high sympathetic activity at baseline (p<0.05)

33. Betteridge J. ESC 2004 (www.solvaycardio.com)

Insulin-resistant hypertensive patients33

High sympathetic activity was defined as heart rate of >80 beats per minute

• 12-week study in hypertensive patients with type 2 diabetes

• Moxonidine (0.2-0.6mg/day as an adjunct to stable antihypertensive therapy) versus metoprolol

• Moxonidine significantly improved fasting plasma glucose levels compared with metoprolol

• No significant differences between treatments in the change in insulin sensitivity from baseline

34. Jacob S et al. Exp Clin Endocrinol Diabetes 2004;112(6):315-322

Hypertensive diabetic patients34

• Hypertension in obese patients may be related to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system45,46

• Urinary norepinephrine levels increase with rising BMI49

• Most obese subjects and obese hypertensive patients have high circulatory levels of the hormone leptin50,51

45. Hall JE. Am J Hypertens 1997;10: S49-S55., 46. Tuck ML et al. N Engl J Med 1981;304:930-933., 49. Landsberg L. J Cardiovasc Pharmacol 1994;23(suppl 1):S1-S8., 50. Barroso SG et al. Trace Elem Electrolytes 2003;20:134-139., 51. Masuo K et al. Am J Hypertens 2001;14:530-538

Obesity and hypertension

Effects of moxonidine 0.2-0.4mg/day and amlodipine 5mg/day on office sitDBP after 12 and 24 weeks in an open study of 40 obese patients with mild-to-moderate hypertension

Moxonidine in obese hypertensives37

37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25

Change in sitDBP

from baseline (mmHg)

*p<0.05 vs baseline (no significant difference between active treatments)

- 0 -

- 10 -

- 20 -

week 12 week 24 week 12 week 24

-10.2

*

moxonidine amlodipine

-12.7

*-14.7

*

-15.9

*

BP was controlled in 58% patients on moxonidine and 52% on amlodipine

Effect of 24 weeks of moxonidine 0.2-0.4mg/day. Subgroup analysis according to blood pressure response (response was defined as achieving office BP <140/90mmHg)

Metabolic effects in obese hypertensives37

37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25

non-responders

responders

reduction of standing norepinephrine (pg/ml)

100 -

50 -

0 -

90.7

57.3

reduction of plasma leptin (pg/ml)

5.54.3

reduction of fasting insulin (U/ml)

9.6

4.7

6 -

3 -

0 -

10 -

5 -

0 -

** p<0.003 responders vs non-responders* p<0.05 responders vs non-responders

** * *

• Moxonidine (0.4mg/day) was added to the current antihypertensive treatment of 112 obese patients with uncontrolled hypertension

• Open, multicentre study in primary care, which included 25 patients with type 2 diabetes

• After 6 months of treatment, there were mean decreases in SBP and DBP of 23.0 and 12.9 mmHg, respectively

• Overall, SBP and DBP were controlled in 63% and 86% of patients, respectively

38. Abellán J et al. Kidney Int 2005;67(suppl 93):S20-S24

Moxonidine in obese hypertensives38

• SBP tends to increase in women after the menopause

• The prevalence of hypertension in women after the menopause is similar to that in men52

• ‘Menopausal metabolic syndrome’ describes comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile53,54

Postmenopausal hypertension

52. Burt VL et al. Hypertension 1995;25:305-313., 53. Tong PL et al. Atherosclerosis 2002;161(2):409-415., 54. Mercuro G et al. Ital Heart J 2001; 2(10):719-727

Menopausal metabolic syndrome55

55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12

MENOPAUSE

Regional fat metabolism

Estrogen deficiency

Central adiposity

Insulin resistance Hypertension and endothelial dysfunction

Metabolic syndrome

Vascular inflammationImpaired glucose tolerance

Type 2 diabetes Atherosclerosis

Energy expenditure

Change from baseline in plasma glucose during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women

Moxonidine in postmenopausal women35

35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32

Plasma glucose

(mmol/L)

0hr 1hr 2hr

AUCHours after oral glucose tolerance test

0.2 -0 -

- 0.2 -- 0.4 -- 0.6 -- 0.8 -- 1.0 -

atenololmoxonidine *p<0.01 versus pretreatment

* *

*

Intention to treat analysis

35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32

Plasma insulin (mU/L)

0hr 1hr 2hrAUCHours after oral glucose tolerance test

6 -4 -2 -0 -

- 2 -- 4 -- 6 -

atenololmoxonidine

Change from baseline in plasma insulin during OGTT following treatment with moxonidine (0.6mg/day) and atenolol (50mg/day) (n=109): double-blind study in hypertensive, obese, postmenopausal women

Moxonidine in postmenopausal women35

• LVH in hypertensive patients is an adaptation response to try and overcome increased peripheral vascular resistance

• LVH is a major independent risk factor for cardiovascular morbidity and mortality62,63

• Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy64

LVH and hypertension

62. Levy D et al. N Engl J Med 1990;322:1561-1566., 63. Koren MJ et al. Ann Intern Med 1991;114:345-352., 64. Trimarco B et al. Circulation 1985;72:38-46

Interventricular septum end-diastolic diameter at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF

Moxonidine in LVH11

11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

baseline

1.8 -

1.6 -

1.4 -

1.2 -

1.0 -

Interventricular septum

end-diastolic diameter (cm)

3 6 9

p<0.05

p<0.05

p<0.05

months

Left ventricular mass at baseline and after 3, 6 and 9 months of moxonidine monotherapy (0.2-0.6mg/day) in 20 hypertensive patients with LVF

11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

400 -

350 -

300 -

250 -

200 -

150 -

Left ventricular

mass (g)

p<0.05p<0.05

monthsbaseline 3 6 9

Moxonidine in LVH11

• Increased sympathetic activity leads to renal vasoconstriction, stimulation of renin release, and stimulation of sodium reabsorption10

• Moxonidine may be renoprotective by:

- reducing sympathetic output centrally

- direct renal effects (independent of blood pressure lowering) via imidazoline binding

sites in the kidney

Renal protection in hypertension

10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19

Mean muscle sympathetic nerve activity (MSNA) in nine hypertensive patients with chronic renal failure given eprosartan alone or with moxonidine. Controls were healthy age-matched persons (n=22)

Renal protective effects39

50 -

40 -

30 -

20 -

10 -

0 -

Mean MSNA

(burst/min)

healthy controls

eprosartan +

moxonidine

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

eprosartanbaseline

p<0.05 p<0.05

• Predictors of allograft survival were evaluated in 601 renal transplant patients

• A number of factors increased the relative risk of allograft loss, the most important being renal vascular resistance

• Another risk factor was high heart rate (pulse>80 beats/min) which suggests increased sympathetic activity

• The use of moxonidine was associated with an approximately 70% reduction of allograft failure

Improved allograft survival40

40. Radermacher J et al. New Engl J Med 2003;349:115-124

• Microalbuminuria is predictive of retinopathy, LVH, CV events and all-cause mortality

• 12.8% of people with metabolic syndrome are estimated to have microalbuminuria52

• Moxonidine reduces urine albumin excretion in:

- non-obese hypertensive patients with microalbuminuria (p<0.001 vs baseline)41

- normotensive patients with well controlled type 1 diabetes (p<0.006 vs placebo)42

Effect on microalbuminuria

41. Krespi PG et al. Cardiovasc Drugs Ther 1998;12:463-467., 42. Strojek K et al. 36th Ann Meeting of the EASD (2000), Jerusalem, Israel, 17-21 September., 52. Burt VL et al. Hypertension 1995;25:305-313

Effect of moxonidine (0.3mg/day, n=89) and nitrendipine (20mg/day, n=82) on serum creatinine in patients with advanced renal failure

Effect on serum creatinine43

43. Vonend O et al. J Hypertens 2003;21:1709-1717

serum creatinine

(µmol/L)

500 -

400 -

300 -

200 -

100 -

0 - 1 2 3 4

nitrendipinemoxonidine

65 0months

p<0.05

Treatment-emergent adverse events affecting > 4% patients after monotherapy with moxonidine 0.6mg/day, enalapril 20mg/day, or placebo in an 8-week randomised, double-blind trial

Moxonidine - adverse events24

24. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

dry m

outh

diarrh

oea

headac

he

bronch

itis

% patients

reporting adverse

events

enalapril(n=53)

placebo(n=50)

nause

a

back

pain

gastro

-

ente

ritis

moxonidine(n=51)

dizzin

ess

20 -

10 -

0 -

Tolerability in a 52-week study28

28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

13%

week3

% patients

reporting adverse

events

20 -

15 -

10 -

5 -

0 -

DRY MOUTH TIREDNESS

3% 2%

week12

week52

5%

week3

0% 0%

week12

week52

Treatment-emergent adverse events affecting >2% of patients in a long-term, open-label study of moxonidine

Moxonidine - contraindications

* Please see National Prescribing Information or SmPC, as licence details may vary between countries

• Known hypersensitivity to any of the components of the product

• Sick sinus syndrome

• Bradycardia (resting heart rate <50bpm)

The following are listed on the Master SmPC for moxonidine:*

The coloured area identifies the imidazoline part of the structure

Chemical structure of moxonidine

H3C

Cl

NH

OCH3

N

NHN

N

71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Mode of action of moxonidine

16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10

• The autonomic nervous system is regulated by cardiovascular control centres in the rostral ventrolateral medulla (RVLM) in the brain stem

• Sympathetic response is mediated through imidazoline binding sites in the RVLM

• Moxonidine has a highly selective agonist effect on imidazoline I1-receptors in the RVLM16

• This causes inhibition of sympathetic activity and reduced peripheral resistance

Acts within the RVLM

72. Haxhiu MA et al. J Cardiovasc Pharmacol 1992; 20 (suppl 4):S11 S15

• Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats produces rapid, dose-dependent reductions of arterial blood pressure72

• There is no effect on blood pressure if moxonidine is injected into adjacent (non-RVLM) areas of the medulla

Selective for I1 receptors

16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10., 73. Haxhiu MA et al. Cardiovasc Drugs Ther 1993;7(suppl 2):155(Abstr 155)

• The blood pressure-lowering effect of moxonidine is reversed by injection of efaroxan (an I1-receptor antagonist) into the RVLM73

• In vitro, moxonidine has an approximately 70-fold greater affinity for I1-receptors compared with 2-receptors16

Selectivity of moxonidine for imidazoline (I1) and 2-receptors (Ki = affinity constant).

Moxonidine is highly selective16

-5 -4 -3 -2 -1 0 1 2 3

2 > I1

16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S1-S10

I1 > 2

moxonidine

rilmenidine

clonidine

norepinephrine

epinephrine

guanabenz

Affinity for I1 versus 2-receptors (log Ki at I1 receptors divided by Ki at 2-receptors)

Actions of centrally-acting agents71

2 - adrenoceptor

Dry mouth Lowering of blood pressure

I1 - imidazoline receptor

71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

-methyldopa

Salivary glands

Nucleus coeruleus

Nucleus tractus solitarii

MOXONIDINEclonidineselective

Rostral ventrolateral medulla (RVLM)

Inhibition of sympathetic nerve activity

Inhibition of norepinephrine release

Peripheral vasodilation

(non-selective)

Sedation

Effects on catecholamine levels

37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25., 74. Kirch W et al. J Clin Pharmacol 1990;30:1088-1095

• Single oral doses of moxonidine reduce plasma norepinephrine levels in patients with hypertension74

• The fall in plasma norepinephrine correlates with the reduction in SBP (p=0.05) and DBP (p=0.02)

• Reductions in plasma catecholamine levels reported in clinical studies with moxonidine37

Effect of moxonidine on cardiac output and systemic vascular resistance

Haemodynamic effects of moxonidine17

17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972

dyn.sec/cm5

2000 -

1800 -

1600 -

1400 -

1200 - 1 2 3 40

cardiac output

systemic vascular resistance

- 8

- 6

- 4

- 2

- 0

Hours post-administration

L/min

*

* *

* p<0.01

Neutral effect on lipid profile

70. Data on file, Solvay Pharmaceuticals GmbH., 75. Elisaf MS et al. J Hum Hypertens 1999;13:781-785

• In a study of 20 hypertensive patients, moxonidine produced no statistically significant changes in HDL, LDL or total cholesterol, or triglycerides75

• There were no significant changes in these lipid parameters in an analysis of pooled results from several placebo-controlled trials70

Pharmacokinetics of moxonidine78

ParameterSingle dose*

Multiple dose

Time to peak plasma concentration (hr) 0.74 0.67

Peak plasma concentration (ng/ml) 1.29 1.33

Area under the curve (0-infinity) (ng.hr/ml) 4.18 4.02

Terminal half-life (hr) 2.12 1.97

Total clearance (ml/min) 830 863

Renal clearance (ml/min) 530 522

78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20(suppl 4):S37-S41 * oral dose 0.2mg bd (n=12)

Pharmacokinetics of moxonidine76,77

76. Theodor R et al. Eur J Drug Metab Pharmacokinet 1991;16(2):153-159. 77. Trenk D et al. J Clin Pharmacol 1987;27:988-993

• 80-90% of an oral dose is absorbed

• Bioavailability = 88%

• Protein binding = 7%

• About 10% is metabolised (metabolites have low antihypertensive potency)

• Peak plasma concentrations reached within 60 min; mean plasma half-life is about 2 hours

Pharmacokinetics of moxonidine - 2

77. Trenk D et al. J Clin Pharmacol 1987;27:988-993., 78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20 (suppl 4):S37-S41., 79. Kirch Wet al. Clin Pharmacokinet 1988;15:245-253

• Does not accumulate in plasma with repeated dosing77,78

• Pharmacokinetics are not significantly affected by food78

• No dose adjustment needed in older patients whose renal function is normal for age

• No evidence of moxonidine accumulation after multiple dosing in older subjects78

Plasma concentration-time profile of moxonidine after an oral single dose (0.2mg) and after giving 0.2mg bd for 5 days (n=12)

Plasma profile of moxonidine77

77. Trenk D et al. J Clin Pharmacol 1987;27:988-993

Plasma concentration

mcg/L

2000 -

1 2 3 40

single dose

multiple dose

Time after administration (hours)

100 -

1000 -

600 -

300 -

6 7 85

Plasma concentration-time profile of moxonidine (0.3mg once-daily for 7 days) in patients with and without renal impairment (n=8 per group)

Plasma profile in renal impairment79

79. Kirch W et al. Clin Pharmacokinet 1988;15:245-253

Log plasma concentration

mcg/L

4.0 -

3 6 9 120

Time after administration (hours)

0.01 -

0.4 -

0.1 -

0.04 -

18 21 2415

1.0 -GFR <30ml/min

GFR 30-60ml/min

GFR >90ml/min

Low likelihood of drug interactions

• Only 7% protein binding - interaction with highly protein bound drugs is unlikely

• No substantial pharmacokinetic interaction with digoxin, HCTZ or glibenclamide

• Has been co-administered with hypolipidaemic agents

• Effect of sedatives/hypnotics may be intensified

• Avoid use with alcohol or tricyclic antidepressants

• 0.2mg, 0.3mg, 0.4mg tablets

• 0.2mg usual starting dose

• Can be increased to 0.4mg daily after 2-3 weeks

• Can be increased to 0.6mg daily after a further 2-3 weeks

Dosage of moxonidine

Appearance of pack varies between countries

Usual maintenance dose is 0.4mg per day

• May be taken with or without food

• Stop treatment gradually over two weeks

• If stopping a combined moxonidine/beta-blocker regimen, stop the beta-blocker a few days before moxonidine is gradually stopped

• No dose adjustment required in the elderly

• Starting dose of 0.2mg/day in patients with moderate to severe renal impairment - if necessary and well tolerated the dose can be increased to 0.4mg/day

Administration

• Many patients with hypertension have metabolic syndrome - with one or more conditions such as insulin resistance, impaired glucose tolerance, obesity and altered lipid profile

• When treating these patients it would be appropriate to select an antihypertensive agent with a beneficial or neutral effect on the other components of the metabolic syndrome

Summary - 1

• Moxonidine acts centrally to reduce sympathetic stimulation

• It is as effective as other classes of antihypertensive agents in reducing SBP and DBP

• It may be used as monotherapy, but is a good option for adjunctive therapy in patients with the metabolic syndrome

Summary - 2

• diabetics

• impaired glucose tolerance / insulin resistance

• obese

• postmenopausal metabolic syndrome

Summary - 3

Moxonidine lowers blood pressure and improves the metabolic profile in several types of hypertensive patients:

• Beneficial effects have been seen with moxonidine in hypertensive patients with LVH

• Moxonidine has been shown to have renoprotective properties

• Moxonidine is well tolerated

• A low level of drug interactions, once-daily dosing, and linear dose-response are advantageous when using moxonidine in combination regimens

Summary - 4

Cynt ®

Physiotens ®

Solvay Pharmaceuticals

December 2005