Valsartan (Diovan) and combinations with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge)

Published in NPS RADAR

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(val-SAR-tan)

PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues
Information for patients | References

Key points

  • Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor antagonists.
  • If blood pressure is not controlled by valsartan 160 mg, add a second drug rather than increasing the dose to 320 mg. Increasing the dose from 160 mg to 320 mg provides marginal additional blood pressure reduction.
  • Establish the effective dose using individual drugs before prescribing the appropriate combination.
  • Check electrolytes and renal function before and 1–2 weeks after starting valsartan, after each dose increment or if changed clinical circumstances are likely to worsen renal function (e.g. dehydration).
  • Avoid angiotensin II-receptor antagonists (including valsartan) in combination with a nonsteroidal anti-inflammatory drug and a diuretic (including hydrochlorothiazide) — particularly in elderly people or people with pre-existing renal impairment — because combining these three drug classes increases the risk of acute renal failure.

PBS listing

Valsartan (Diovan) — unrestricted benefit

Valsartan is listed on the Pharmaceutical Benefits Scheme (PBS) as an unrestricted benefit1, as are other angiotensin II-receptor antagonists.2

Valsartan with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) — restricted benefit

Valsartan with hydrochlorothiazide (Co-Diovan) or amlodipine (Exforge) is restricted for people with hypertension not controlled with valsartan, hydrochlorothiazide or amlodipine monotherapy.3,4

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended valsartan for listing on a cost-minimisation basis — that is, similar efficacy and cost — with irbesartan. The equi-effective doses were taken to be valsartan 320 mg and irbesartan 300 mg.1

The PBAC recommended valsartan with hydrochlorothiazide or amlodipine for listing on a cost-minimisation basis compared with the corresponding strengths of the individual drugs given concomitantly.3,4

Place in therapy

Valsartan is an angiotensin II-receptor antagonist that has been available overseas for several years.

Angiotensin II-receptor antagonists have similar blood pressure reducing effects to those of other major antihypertensive drug classes.5,6 This class of drugs is an option for initial therapy for people with hypertension and may be useful for those with particular comorbidities (e.g. diabetic nephropathy) or intolerances (e.g. angiotensin-converting enzyme [ACE] inhibitor-induced cough). Other options for initial therapy include low-dose thiazide diuretics, dihydropyridine calcium-channel blockers or angiotensin-converting enzyme inhibitors.7

If blood pressure is not controlled by valsartan 160 mg, add a second drug from a different pharmacological class rather than increasing the valsartan dose to 320 mg,7 and consider comorbidities when choosing the second drug (see Add a second drug for people with hypertension not controlled by monotherapy).

For more information about managing hypertension as a cardiovascular risk factor, refer to NPS News 52 and Prescribing Practice Review 38.8,9

Valsartan is also indicated for people with heart failure (New York Heart Association Class II–IV) unable to tolerate an angiotensin-converting enzyme inhibitor, and to improve survival after myocardial infarction in people who are clinically stable and have left ventricular failure or dysfunction.10 For more information about treating people with heart failure, refer to NPS News 57 and Prescribing Practice Review 41.11,12

Valsartan reduces blood pressure to a similar extent as other angiotensin II-receptor antagonists

A meta-analysis of 46 short-term trials showed that all 9 angiotensin II-receptor antagonists assessed — including valsartan — reduced trough blood pressure to a similar extent: on average, systolic blood pressure was reduced by about 8 mmHg and diastolic blood pressure by about 5 mmHg. However, the true blood pressure reduction may be less because the meta-analysis showed some publication bias. Up to 70% of trough blood pressure reduction achieved by angiotensin II-receptor antagonists occurs at the recommended starting doses.13

Increasing the dose of valsartan from 160 mg to 320 mg provides marginal additional blood pressure reduction

Valsartan reduces blood pressure across its dose range, though an 80 mg dose achieves near maximal blood pressure reduction.13 Increasing the valsartan dose from 160 mg to 320 mg provides marginal additional blood pressure reduction (see Figure 1). This is unlikely to be clinically meaningful and increasing the dose increases the risk of adverse reactions.13,14

Figure 1.
Mean reduction in trough systolic/diastolic blood pressure (mmHg) with valsartan.13

Figure 1: Mean reduction in trough systolic/diastolic blood pressure (mmHg) with valsartan.[13]

Add a second drug for people with hypertension not controlled by monotherapy

If target blood pressure reduction is not achieved with monotherapy, guidelines suggest adding a second drug (from a different pharmacological class (e.g. thiazide diuretic, calcium-channel blocker) at a low dose rather than increasing the dose of the first drug. This maximises blood pressure reduction while minimising adverse reactions.7 Combining valsartan with hydrochlorothiazide or amlodipine achieves significant additional blood pressure reduction (Figures 2, 3). Consider the combination of an angiotensin II-receptor antagonist (e.g. valsartan) with a:

  • thiazide diuretic (e.g. hydrochlorothiazide) for people with hypertension and heart failure
  • calcium-channel blocker (e.g. amlodipine) for people with hypertension and diabetes.

Figure 2.
Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and hydrochlorothiazide*.15,16

Figure 3: Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and amlodipine.[15,16]

Figure 3.
Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and amlodipine.17

Figure 3: Placebo-adjusted mean reduction in sitting systolic and diastolic blood pressure (mmHg) at week 8: valsartan and amlodipine.[17]

Consider a fixed-dose combination for people on stable doses of the individual drugs

Fixed-dose combination therapy may be a more convenient option for people who have inadequate blood pressure control with monotherapy and whose doses of the individual drugs in combination are stable. Compared with taking valsartan, hydrochlorothiazide or amlodipine as separate tablets, the combination tablets allow people to take fewer tablets each day and are cheaper because only one co-payment is required for both medicines. However, the usual considerations that apply to combination tablets remain important.18Do not start valsartan, amlodipine or hydrochlorothiazide therapy with a fixed-dose combination. Establish the effective dose using the individual drugs before prescribing the appropriate combination.7 Consider whether the available strengths of the combination allow the same doses of valsartan, hydrochlorothiazide or amlodipine to be given: not all strengths of each drug are available in a combination tablet (see Table 1).

Safety issues

Some common adverse effects for valsartan include dizziness, hypotension and hyperkalaemia.10

As for all angiotensin II-receptor antagonists:

  • stop potassium supplements and potassium-sparing diuretics before starting valsartan5
  • valsartan can worsen renal impairment10 and increase the risk of renal failure5
  • check electrolytes and renal function before and 1–2 weeks after starting valsartan, after each dose increment or if changed clinical circumstances are likely to worsen renal function (e.g. dehydration)6
  • valsartan is contraindicated in pregnant women and women planning to become pregnant because it may cause foetal and neonatal morbidity and death10
  • avoid valsartan in breastfeeding women (there are no data for this group)5
  • avoid angiotensin II-receptor antagonists (including valsartan) in combination with a nonsteroidal anti-inflammatory drug and a diuretic (including hydrochlorothiazide) — particularly in elderly people or those with pre-existing renal impairment — because combining these three drug classes increases the risk of acute renal failure.19,20

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

Dosing issues

In hypertension, the usual dose of valsartan is 80 mg once daily. Maximum blood pressure reduction is seen after 4 weeks: if necessary, increase to 160 mg once daily.

Add a second drug for people whose blood pressure is not controlled by valsartan 160 mg once daily. Increasing the once daily dose from 160 mg to 320 mg provides marginal additional blood pressure reduction.

Lower starting doses and maximum doses are recommended for people aged over 75 years, people with mild to moderate hepatic impairment or a creatinine clearance < 30 mL/minute.5,10

Consider prescribing the appropriate combination when valsartan has been added to hydrochlorothiazide or amlodipine and the effective doses have been established and are stable (Table 1).

In heart failure or after myocardial infarction, valsartan is given twice daily, usually starting with a lower dose than for hypertension.5,10

Table 1.
Dose strengths, appearance and availability on the PBS of valsartan, valsartan with hydrochlorothiazide and valsartan with amlodipine10,21,22

Doses

Packet colour

Tablet colour, shape

valsartan

40 mg

light blue

yellow, oval, scored

80 mg

light medium blue

pale red, round, scored

160 mg

medium blue

grey-orange, oval, scored

320 mg

dark medium blue

grey-violet, oval

valsartan with hydrochlorothiazide

80 mg/12.5 mg

pink

light orange, oval

160 mg/12.5 mg

red

dark red, oval

160 mg/25 mg

red

brown-orange, oval

valsartan with amlodipine

80 mg/5 mg

dark blue with an orange stripe

dark yellow, round

160 mg/5 mg

dark blue with a light blue stripe

dark yellow, oval

160 mg/10 mg

dark blue with a red stripe

light yellow, oval

Information for patients

Advise patients:

  • to take valsartan or valsartan-containing combination tablets at about the same time each day
  • which of their existing medicines are being replaced by valsartan or valsartan-containing combination tablets and to discard the unneeded medicines
  • that some common adverse effects for valsartan include dizziness, hypotension and hyperkalaemia
  • to have their renal function and electrolytes (including potassium) checked 1–2 weeks after starting therapy and at each dose change
  • to tell their doctor or pharmacist that they are taking valsartan with hydrochlorothiazide if they need medicines to treat pain (e.g. nonsteroidal anti-inflammatory drugs).

Discuss the Diovan, Co-Diovan or Exforge consumer medicine information (CMI) leaflet with the patient.

References

  1. Pharmaceutical Benefits Advisory Committee. Positive recommendations made by the Pharmaceutical Benefits Advisory Committee (PBAC) in July 2008 relating to the listing of drugs on the Pharmaceutical Benefits Scheme (PBS). Canberra: Australian Government Department of Health and Ageing, 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-jul08-positive (accessed 29 October 2008).
  2. Department of Health and Ageing. PBS for Health Professionals. Canberra: Australian Government, 2008. www.pbs.gov.au (accessed 29 October 2008).
  3. Pharmaceutical Benefits Advisory Committee. Public summary document: valsartan with hydrochlorothiazide, tablets, 80 mg-12.5 mg, 160 mg-12.5 mg and 160 mg-25 mg. Canberra: Australian Government Department of Health and Ageing, 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-valsartan-july08 (accessed 6 November 2008).
  4. Pharmaceutical Benefits Advisory Committee. Public summary document: amlodipine besylate with valsartan, tablet, 5 mg-80 mg, 5 mg-160 mg, 10 mg-160 mg. Canberra: Australian Government Department of Health and Ageing, 2008. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbac-psd-amlodipine-july08 (accessed 6 November 2008).
  5. Rossi S, ed. Australian Medicines Handbook. Adelaide: Australian Medicines Handbook Pty Ltd, 2008.
  6. Cardiovascular Writing Group. Therapeutic Guidelines: Cardiovascular. Version 5 Updated June 2008 [eTG complete CD-ROM]. Melbourne: Therapeutic Guidelines Ltd, 2008.
  7. National Blood Pressure and Vascular Disease Advisory Committee. Guide to management of hypertension 2008: assessing and managing raised blood pressure in adults. . Sydney: National Heart Foundation, 2008. http://www.heartfoundation.org.au/Professional_Information/Clinical_Practice/Hypertension/Pages/default.aspx (accessed 29 October 2008).
  8. National Prescribing Service. Managing hypertension as a cardiovascular risk factor. NPS News 52. Sydney: National Prescribing Service, 2007. http://nps.org.au/health_professionals/publications/nps_news/current/nps_news_52/managing_hypertension_as_a_cardiovascular_risk_factor (accessed 29 October 2008).
  9. National Prescribing Service. Managing hypertension as a cardiovascular risk factor Prescribing Practice Review 38. Sydney: National Prescribing Service, 2007. http://nps.org.au/health_professionals/publications/prescribing_practice_review/editions/current/prescribing_practice_review_38/managing_hypertension_as_a_cardiovascular_risk_factor (accessed 29 October 2008).
  10. Novartis Pharmaceuticals Australia Pty Limited. Diovan product information. 21 May 2008. Australia. http://www.novartis.com.au/products_healthcare.html (accessed 3 November 2008).
  11. National Prescribing Service. Improving outcomes in chronic heart failure by early detection, drug therapy and patient support. NPS News 57. Sydney: National Prescribing Service, 2008. http://nps.org.au/health_professionals/publications/nps_news/current/nps_news_57/improving_outcomes_in_chronic_heart_failure_by_early_detection,_drug_therapy_and_patient_support (accessed 29 October 2008).
  12. National Prescribing Service. Improving outcomes in chronic heart failure. Prescribing Practice Review 41. Sydney: National Prescribing Service, 2008. http://nps.org.au/health_professionals/publications/prescribing_practice_review/editions/current/prescribing_practice_review_41/improving_outcomes_in_chronic_heart_failure (accessed 29 October 2008).
  13. Heran BS, Wong MMY, H, I.K., et al. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev 2008; 4:CD003822. http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD003822/frame.html
  14. Medicines and Healthcare Products Regulatory Agency. Diovan 320 mg tablets PL00101/0726 UKPAR. London: MHRA, 2008. http://www.mhra.gov.uk/home/groups/l-unit1/documents/websiteresources/con2033064.pdf (accessed 29 October 2008).
  15. Benz JR, Black HR, Graff A, et al. Valsartan and hydrochlorothiazide in patients with essential hypertension. A multiple dose, double-blind, placebo controlled trial comparing combination therapy with monotherapy. Journal of Human Hypertension 1998;12:861–6. [PubMed]
  16. Pool JL, Glazer R, Weinberger M, et al. Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults. Clin Ther 2007;29:61–73. [PubMed]
  17. Philipp T, Smith TR, Glazer R, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as monotherapy in adult patients with mild to moderate essential hypertension. Clin Ther 2007;29:563–80. [PubMed]
  18. Moulds RFW. Combination products — love them or loathe them? Aust Prescr 2001;24:127–9. http://www.australianprescriber.com/magazine/24/5/127/9/
  19. Adverse Drug Reactions Advisory Committee. Beware the triple whammy! Australian Adverse Drug Reactions Bulletin 2006;25:18. http://www.tga.gov.au/adr/aadrb/aadr0610.pdf
  20. Adverse Drug Reactions Advisory Committee. ACE inhibitor, diuretic and NSAID: a dangerous combination. Australian Adverse Drug Reactions Bulletin 2003;22:14-5. http://www.tga.gov.au/adr/aadrb/aadr0308.pdf
  21. Novartis Pharmaceuticals Australia Pty Limited. Co-Diovan product information. 23 June 2008. Australia. http://www.novartis.com.au/products_healthcare.html (accessed 3 November 2008).
  22. Novartis Pharmaceuticals Australia Pty Limited. Exforge product information. 21 May 2008. Australia. http://www.novartis.com.au/products_healthcare.html (accessed 3 November 2008).