®

MOXONIDINE

®

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

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

Please see Summary of Product Characteristics before prescribing moxonidine

Details of formulations and dosage recommendations may vary between countries Trade names include: Physiotens ® , Cynt ® , Fisiotens ® , Moxon ® , Norcynt ® and Normatens ® References cited in this slide set are numbered to correspond with those in the companion moxonidine e-monograph

Metabolic syndrome

•

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

Sympathetic overactivity

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

Link with hypertension

•

In animal models, sympathetic overactivity can initiate and maintain elevated blood pressure 2

•

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 patients 4 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

Link with hypertension

•

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

Link with obesity

•

Raised BMI is associated with an increased rate of sympathetic nerve discharge in skeletal muscle 5

•

There is a correlation between BMI, body fat distribution and urinary norepinephrine excretion 6 5. Scherrer U et al. Circulation 1994;89:2634-2640., 6. Landsberg L. Cardiovasc Risk Factors 1993;3:153-158

Link with insulin resistance and diabetes

•

Sympathetic activation is a major component of insulin resistance in clinical experiments 7 and in humans with type 2 diabetes 8

•

Cardiac autonomic dysfunction occurs in: - 30-50% of patients with diabetes - 40% of obese patients without diabetes 9 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)

Link with other risk factors

•

Sympathetic overactivity is also implicated in: - renal disease 10 - left ventricular hypertrophy 11 - congestive heart failure 12 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

Incidence of metabolic syndrome

13 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 Risk of CHD, stroke and CV mortality was higher in people with metabolic syndrome (p<0.001) 13. Isomaa B et al. Diabetes Care 2001;24:683-689 Metabolic syndrome was defined as the presence of at least two of: obesity, hypertension, dyslipidaemia, microalbuminuria

Origin of cardiovascular symptoms

9 Endothelial dysfunction Atherothrombosis Lifestyle Adiposity

inflammation

INSULIN RESISTANCE / METABOLIC SYNDROME - free fatty acids - oxidative stress Arterial rigidity hypertension Relative sympathetic overactivity Arrhythmias LVH Cardiovascular complications 9. Valensi P et al. Presented at a satellite symposium at the ESC Congress 2004, Munich, Germany.

Treatment strategy

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

Rationale for moxonidine

•

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

•

This region contains imidazoline I 1 -receptors and

a

2 -adrenoceptors which regulate sympathetic activity Moxonidine binds selectively and with high affinity to I 1 -receptors in the RVLM 16 thus reducing peripheral sympathetic activity 15. Hamilton CA. In: van Zwieten PA et al (eds). The I 1 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

Overview of moxonidine - 1

•

Lowers peripheral arterial resistance without significant effects on cardiac output 17

•

Relatively little affinity for

a

2 -receptors in the brainstem 16 (adverse events such as sedation and dry mouth are infrequently reported during prolonged therapy) 28

•

Low potential for drug interactions 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

Overview of moxonidine - 2

•

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 The above studies are described in later slides

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 hydrochlorothiazide

19

•

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

Moxonidine versus atenolol

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

% responders 100 80 60 40 20 0 68% (17/25) 71% (20/28) moxonidine 0.2-0.4mg/day atenolol 50-100mg/day 20. Prichard BNC et al. J Cardiovasc Pharmacol 1992;20(suppl 4):S45-S49 Response was defined as DBP <90 mmHg

Moxonidine versus captopril

21 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 Mean blood pressure (mmHg) 200 160 systolic moxonidine (n=25) captopril (n=25) 120 diastolic 80 0 week 1 21. Lotti G, Gianrossi R. Fortschr Med 1993;111(27):429-432 week 2 week 3 week 4

Moxonidine versus captopril

22

•

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 enalapril

23

•

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 as DBP <90 mmHg or >10 mmHg reduction

Moxonidine versus enalapril

24

– high dose

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 0.6mg/day placebo enalapril 20mg/day Mean change in DBP from baseline (mmHg) - 0 - 4 - 8 - 12 - 16 - 13.2

p<0.001

- 2.3

p<0.001

-11.9

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

Moxonidine versus enalapril

25

– 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

Moxonidine versus nifedipine

26 Mean SBP and DBP after 0.2-4mg/day moxonidine (n=116) and 20-40mg/day nifedipine (n=113) in a double-blind study Mean blood pressure (mmHg) 180 160 140 120 100 80 systolic diastolic moxonidine nifedipine 0 4 8 12 19 week 26 26. Wolf R. J Cardiovasc Pharmacol 1992;20(suppl 4):S42-S44

Moxonidine versus nifedipine

27

•

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;68:862866

Dose-response with moxonidine

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 % patients requiring dose doubling 100 80 60 40 20 0 28% (8/29) Prichar d 1992 56% (14/25) Lotti 1993 42% (49/116) 10% (3/30) Wolf 1992 Mangiameli 1992 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

Linear dose-response

25 Dose-response of moxonidine in reducing office sitDBP at trough from three double-blind, placebo-controlled trials Mean placebo adjusted reduction in sitDBP (mmHg) 15 10 5 0 4.65

7.01

0.2mg

0.4mg

0.6mg

moxonidine dosage (mg/day) 10.5

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

Long-term efficacy of moxonidine

28 Change in mean sitSBP and sitDBP during up to two years of treatment with moxonidine (week 3 = end of dose titration) Change in mean blood pressure (mmHg) 180 160 140 120 100 80 systolic diastolic 1 year (n=141) 2 years (n=49) 0 26 52 78 weeks of moxonidine treatment 104 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620., 44. Prichard BNC. In: van Zwieten PA et al, editors. The I 1 Imidazoline Receptor Agonist Moxonidine. 2 nd Edition. London: Roy Soc Med, 1996:49-75

Long-term efficacy of moxonidine

29

•

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

Moxonidine in combination with HCTZ

19 Mean reduction in sitDBP after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study - 0 placebo moxonidine (0.4mg/day) HCTZ 25mg/day moxonidine + HCTZ (0.4/25mg/day) Mean reduction in diastolic blood pressure from baseline (mmHg) - 10 - 20 9mmHg (n=41) 12mmHg n=37 13mmHg (n=40) * * *p<0.05 vs placebo **p<0.05 vs placebo and monotherapies 16mmHg (n=42) ** 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28

Moxonidine in combination with HCTZ

19 Percentage response for all patients after 8 weeks of moxonidine and HCTZ as monotherapy or in combination in a double-blind study % patients with response 100 80 60 40 20 0 44% (n=41) 70% (n=37) 70% (n=40) 88% (n=42) placebo moxonidine (0.4mg/day) HCTZ (25mg/day) moxonidine + HCTZ (0.4/25mg/day) 19. Frei M et al. J Cardiovasc Pharmacol 1994;24 (suppl 1):S25-S28 Intent-to-treat analysis. Response defined as DBP <90 mmHg or >10 mmHg decrease

Combination therapy – TOPIC study

30 Mean change in SBP and DBP after 4 weeks of combination therapy in patients who had not responded to previous moxonidine monotherapy 0 moxonidine 0.4mg

+ amlodipine 5mg (n=81) Change in mean BP from baseline (mmHg) - 4 - 8 - 12 - 16 -10.7

* -7.3

* - 20 moxonidine 0.4mg

+ enalapril 10mg -5.5

(n=82) -7.9

sitSBP -4.8

moxonidine 0.4mg

sitDBP + HCTZ 12.5mg

(n=90) -4.4

-3.2

* p<0.05 versus the other combinations 30. Waters J et al. J Clin Basic Cardiol 1999;2:219-224

Diabetic/prediabetic hypertensive patients

•

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

Effects on insulin resistance

31 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 % change from baseline 25 20 15 10 5 0 - 5 -10 GLUCOSE INFUSION RATE p=0.026

p=0.004

21% - 6.0% N.S.

INSULIN SENSITIVITY INDEX p=0.056

p=0.027

21% - 6.0% N.S.

moxonidine (n=25) placebo (n=13) 31. Haenni A, Lithell H. J Hypertens 1999;17(Suppl 3):S29-S35 Insulin sensitivity evaluated by hyperinsulinaemic euglycaemic clamp test. Insulin sensitivity index = glucose infusion rate/mean insulin concentration at steady-state

Patients with normal glucose tolerance

32

•

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

Insulin-resistant hypertensive patients

33

•

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

Hypertensive diabetic patients

34

•

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

Obesity and hypertension

•

Hypertension in obese patients may be related to activation of renal sympathetic nerves and stimulation of the renin-angiotensin system 45,46

•

Urinary norepinephrine levels increase with rising BMI 49

•

Most obese subjects and obese hypertensive patients have high circulatory levels of the hormone leptin 50,51 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

Moxonidine in obese hypertensives

37 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 Change in sitDBP from baseline (mmHg) - 0 - 10 - 20 moxonidine week 12 week 24 -10.2

* -12.7

* amlodipine week 12 week 24 -14.7

-15.9

* * *p<0.05 vs baseline (no significant difference between active treatments) 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 BP was controlled in 58% patients on moxonidine and 52% on amlodipine

Metabolic effects in obese hypertensives

37 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) reduction of standing norepinephrine (pg/ml) 100 ** 90.7

50 57.3

0 reduction of plasma leptin (pg/ml) 6 * 5.5

3 0 4.3

reduction of fasting insulin (U/ml) 10 * 9.6

5 4.7

0 responders non-responders 37. Sanjuliani AF et al. J Clin Basic Cardiol 2004;7:19-25 ** p<0.003 responders vs non-responders * p<0.05 responders vs non-responders

Moxonidine in obese hypertensives

38

•

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

Postmenopausal hypertension

•

SBP tends to increase in women after the menopause

•

The prevalence of hypertension in women after the menopause is similar to that in men 52

•

‘Menopausal metabolic syndrome’ describes comorbidities such as hypertension, abdominal obesity, insulin resistance, type 2 diabetes, and changes in the lipid profile 53,54 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 syndrome

55 MENOPAUSE Estrogen deficiency Regional fat metabolism Energy expenditure Insulin resistance Metabolic syndrome Central adiposity Hypertension and endothelial dysfunction Vascular inflammation Impaired glucose tolerance Type 2 diabetes Atherosclerosis 55. Sjoberg L et al. Int J Clin Pract 2004;suppl 139:4-12

Moxonidine in postmenopausal women

35 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 Plasma glucose (mmol/L) 0.2 0 - 0.2 - 0.4 - 0.6 - 0.8 * * - 1.0 0hr 1hr 2hr Hours after oral glucose tolerance test moxonidine atenolol * AUC *p<0.01 versus pretreatment 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 Intention to treat analysis

Moxonidine in postmenopausal women

35 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 Plasma insulin (mU/L) 6 4 2 0 - 2 - 4 - 6 0hr 1hr 2hr Hours after oral glucose tolerance test moxonidine atenolol 35. Kaaja R et al. Int J Clin Pract 2004;suppl 139:26-32 AUC

LVH and hypertension

•

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 mortality 62,63

•

Sympathetic overstimulation may play an important role in the development of myocardial hypertrophy 64 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

Moxonidine in LVH

11 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 Interventricular septum end-diastolic diameter (cm) 1.8 1.6 1.4 1.2 1.0 p<0.05

p<0.05

baseline 3 p<0.05

months 6 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65 9

Moxonidine in LVH

11 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 Left ventricular mass (g) 400 350 300 250 200 150 baseline p<0.05

p<0.05

3 months 6 9 11. Haczynski J et al. J Clin Basic Cardiol 2001;4:61-65

Renal protection in hypertension

•

Increased sympathetic activity leads to renal vasoconstriction, stimulation of renin release, and stimulation of sodium reabsorption 10

•

Moxonidine may be renoprotective by: - reducing sympathetic output centrally - direct renal effects (independent of blood pressure lowering) via imidazoline binding sites in the kidney 10. Ritz E et al. Blood Press 1998;7(suppl 3):14-19

Renal protective effects

39 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) Mean MSNA (burst/min) 50 40 30 20 10 0 p<0.05

p<0.05

baseline eprosartan eprosartan + moxonidine healthy controls 39. Neumann J et al. J Am Soc Nephrol 2004;15:2902-2907

Improved allograft survival

40

•

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

Effect on microalbuminuria

•

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

•

12.8% of people with metabolic syndrome are estimated to have microalbuminuria 52

•

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 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 on serum creatinine

43 Effect of moxonidine (0.3mg/day, n=89) and nitrendipine (20mg/day, n=82) on serum creatinine in patients with advanced renal failure moxonidine nitrendipine p<0.05

serum creatinine (µmol/L) 500 400 300 200 100 0 0 1 2 3 months 4 5 6 43. Vonend O et al. J Hypertens 2003;21:1709-1717

Moxonidine - adverse events

24 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 (n=51) enalapril (n=53) placebo (n=50) % patients reporting adverse events 20 10 0 24. Prichard BNC et al. J Clin Basic Cardiol 2003;6:49-51

Tolerability in a 52-week study

28 Treatment-emergent adverse events affecting >2% of patients in a long-term, open-label study of moxonidine % patients reporting adverse events 20 15 10 13% 5 3% 2% 0 week 3 week 12 week 52 DRY MOUTH 5% week 3 0% week 12 0% week 52 TIREDNESS 28. Schwarz W, Kandziora J. Fortschr Med 1990;32:S616-S620

Moxonidine - contraindications

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

•

Known hypersensitivity to any of the components of the product

•

Sick sinus syndrome

•

Bradycardia (resting heart rate <50bpm) * Please see National Prescribing Information or SmPC, as licence details may vary between countries

Chemical structure of moxonidine

The coloured area identifies the imidazoline part of the structure H 3 C N N OCH 3 NH Cl H N N 71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Mode of action of moxonidine

•

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 I 1 -receptors in the RVLM 16

•

This causes inhibition of sympathetic activity and reduced peripheral resistance 16. Ernsberger PR et al. J Cardiovasc Pharmacol 1992; 20(suppl 4):S1-S10

Acts within the RVLM

•

Microinjection of moxonidine into the RVLM of spontaneously hypertensive rats produces rapid, dose-dependent reductions of arterial blood pressure 72

•

There is no effect on blood pressure if moxonidine is injected into adjacent (non-RVLM) areas of the medulla 72. Haxhiu MA et al. J Cardiovasc Pharmacol 1992; 20 (suppl 4):S11S15

Selective for I

1

receptors

•

The blood pressure-lowering effect of moxonidine is reversed by injection of efaroxan (an I 1 -receptor antagonist) into the RVLM 73

•

In vitro, moxonidine has an approximately 70-fold greater affinity for I 1 -receptors compared with

a

2 -receptors 16 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)

Moxonidine is highly selective

16 Selectivity of moxonidine for imidazoline (I 1 ) and

a

2 -receptors (K i = affinity constant). Affinity for I 1 versus

a

2 -receptors (log K i at I 1 receptors divided by K i at

a

2 -receptors) -5 -4 -3 -2 -1 0 1 2 3 moxonidine rilmenidine clonidine norepinephrine epinephrine guanabenz

a

2 > I 1 I 1 >

a

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

Actions of centrally-acting agents

71

a

-methyldopa

a

2 - adrenoceptor clonidine (non selective) MOXONIDINE selective I 1 - imidazoline receptor Salivary glands Nucleus coeruleus Nucleus tractus solitarii Rostral ventrolateral medulla (RVLM) Inhibition of sympathetic nerve activity Inhibition of norepinephrine release Peripheral vasodilation Dry mouth Sedation Lowering of blood pressure 71. van Zwieten. J Hypertens 1999;17(suppl 3):S15-S21

Effects on catecholamine levels

•

Single oral doses of moxonidine reduce plasma norepinephrine levels in patients with hypertension 74

•

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 moxonidine 37 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

Haemodynamic effects of moxonidine

17 Effect of moxonidine on cardiac output and systemic vascular resistance dyn.sec/cm 5 2000 cardiac output 1800 1600 1400 systemic vascular resistance 1200 0 * * * p<0.01

1 2 3 Hours post-administration * L/min - 8 - 6 - 4 - 2 - 0 4 17. Mitrovic V et al. Cardiovasc Drugs Ther 1991;5:967-972

Neutral effect on lipid profile

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In a study of 20 hypertensive patients, moxonidine produced no statistically significant changes in HDL, LDL or total cholesterol, or triglycerides 75

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There were no significant changes in these lipid parameters in an analysis of pooled results from several placebo-controlled trials 70 70. Data on file, Solvay Pharmaceuticals GmbH., 75. Elisaf MS et al. J Hum Hypertens 1999;13:781-785

Pharmacokinetics of moxonidine

78 Parameter Time to peak plasma concentration (hr) Peak plasma concentration (ng/ml) Area under the curve (0-infinity) (ng.hr/ml) Terminal half-life (hr) Total clearance (ml/min) Renal clearance (ml/min) Single dose* 0.74

1.29

4.18

2.12

830 530 Multiple dose 0.67

1.33

4.02

1.97

863 522 78. Weimann H-J, Rudolph M. J Cardiovasc Pharmacol 1992;20(suppl 4):S37-S41 * oral dose 0.2mg bd (n=12)

Pharmacokinetics of moxonidine

76,77

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80-90% of an oral dose is absorbed

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Bioavailability = 88%

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Protein binding = 7%

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

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

Pharmacokinetics of moxonidine - 2

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Does not accumulate in plasma with repeated dosing 77,78

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Pharmacokinetics are not significantly affected by food 78

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

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No evidence of moxonidine accumulation after multiple dosing in older subjects 78 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

Plasma profile of moxonidine

77 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 concentration mcg/L 2000 1000 600 300 single dose multiple dose 100 0 1 2 3 4 5 6 Time after administration (hours) 7 8 77. Trenk D et al. J Clin Pharmacol 1987;27:988-993

Plasma profile in renal impairment

79 Plasma concentration-time profile of moxonidine (0.3mg once-daily for 7 days) in patients with and without renal impairment (n=8 per group) Log plasma concentration mcg/L 4.0 1.0 0.4 0.1 0.04 0.01 0 79. Kirch W et al. Clin Pharmacokinet 1988;15:245-253 GFR <30ml/min 3 GFR 30-60ml/min GFR >90ml/min 6 9 12 15 18 21 Time after administration (hours) 24

Low likelihood of drug interactions

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

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No substantial pharmacokinetic interaction with digoxin, HCTZ or glibenclamide

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Has been co-administered with hypolipidaemic agents

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Effect of sedatives/hypnotics may be intensified

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Avoid use with alcohol or tricyclic antidepressants

Dosage of moxonidine

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0.2mg, 0.3mg, 0.4mg tablets

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0.2mg usual starting dose

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

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Can be increased to 0.6mg daily after a further 2-3 weeks Usual maintenance dose is 0.4mg per day Appearance of pack varies between countries

Administration

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May be taken with or without food

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Stop treatment gradually over two weeks

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

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No dose adjustment required in the elderly

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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

Summary - 1

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

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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 - 2

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Moxonidine acts centrally to reduce sympathetic stimulation

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

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

Summary - 3

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

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diabetics

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impaired glucose tolerance / insulin resistance

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obese

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postmenopausal metabolic syndrome

Summary - 4

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

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Moxonidine has been shown to have renoprotective properties

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Moxonidine is well tolerated

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

Physio

tens

®

Cynt

® Solvay Pharmaceuticals

December 2005