New fixed-dose antihypertensive combination tablets — including the first triple therapy — were listed on the Pharmaceutical Benefits Scheme (PBS) on 1 November 2010. The new combinations are:

  • olmesartan with amlodipine (Sevikar)
  • valsartan with amlodipine and hydrochlorothiazide (Exforge HCT).1

The new listings are restricted to people whose hypertension is inadequately controlled with one of the component drugs at equivalent doses (for dual therapy) or any two of the component drugs (for triple therapy). Neither combination therapy is PBS subsidised for initial treatment of hypertension.

Fixed-dose combination products may be a convenient option for some people, as they reduce the number of tablets to be taken each day, can increase patient adherence and reduce out-of-pocket costs.2,3

Combining antihypertensives is more effective than increasing the dose of current therapy

Most people will require more than one drug to control their blood pressure. Adding a second or third drug from a different pharmacological class at low doses can significantly improve blood pressure, and minimise adverse effects, compared with increasing the dose of a single drug.4–6

Combination therapies have been shown to provide additional blood pressure-lowering:

  • olmesartan with amlodipine combination therapy reduced blood pressure more than monotherapy7–11
  • triple therapy with valsartan, amlodipine and hydrochlorothiazide reduced blood pressure more than any of the dual therapy combinations.12–14

Minimise patient confusion

With multiple single and combination products now available (see Table 1), there may be potential for patient confusion, particularly when a new brand or combination is prescribed. This is because the brand names of some combination products do not clearly indicate that these are combinations.

If prescribing fixed-dose combination therapy, ensure that patients and carers stop their previously prescribed single-ingredient medications and return them to their pharmacist for safe disposal. Advise them to become familiar with the active ingredients, dose, appearance and packaging of the new combination tablets.

Olmesartan fixed-dose combination products

Olmesartan is available in three formulations (Table 1):

  • as a single active ingredient (Olmetec)
  • in combination with hydrochlorothiazide (Olmetec Plus)
  • in the new combination with amlodipine (Sevikar).

Note that the fixed-dose combination of olmesartan 20 mg / amlodipine 10 mg is not available in Australia. For patients whose hypertension is not adequately controlled with olmesartan 20 mg / amlodipine 5 mg, the dose can only be increased by moving to olmesartan 40 mg / amlodipine 5 mg.

Table 1.
Olmesartan and valsartan products

Product Brand name Doses available*

Olmesartan preparations

Olmesartan

Olmetec

20 mg, 40 mg

Olmesartan with hydrochlorothiazide

Olmetec Plus

20 mg / 12.5 mg

40 mg / 12.5 mg

40 mg / 25 mg

Olmesartan with amlodipine

Sevikar

20 mg / 5 mg

40 mg / 5 mg

40 mg / 10 mg

Valsartan preparations

Valsartan

Diovan

40 mg, 80 mg,160 mg, 320 mg

Valsartan with hydrochlorothiazide

Co-Diovan

80 mg / 12.5 mg

160 mg / 12.5 mg

160 mg / 25 mg

320 mg / 12.5 mg

320 mg / 25 mg

Valsartan with amlodipine

Exforge

80 mg / 5 mg

160 mg / 5 mg

160 mg / 10 mg

Valsartan with amlodipine
and hydrochlorothaizide

Exforge HCT

160 mg / 5 mg / 12.5 mg

160 mg / 5 mg / 25 mg

160 mg / 10 mg / 12.5 mg

160 mg / 10 mg / 25 mg

320 mg / 10 mg / 25 mg


* Note that the fixed-dose combination of olmesartan 20 mg / amlodipine 10 mg is not available in Australia

Valsartan fixed-dose combination products

Valsartan is available in four formulations (Table 1):

  • as a single active ingredient (Diovan)
  • in combination with hydrochlorothiazide (Co-Diovan)
  • in combination with amlodipine (Exforge)
  • in the new triple combination with amlodipine and hydrochlorothiazide (Exforge HCT).

If blood pressure is not controlled adequately with valsartan 160 mg monotherapy, consider adding an antihypertensive drug from a different class. Increasing the valsartan dose to 320 mg provides only marginal additional blood pressure reduction, which is unlikely to be clinically meaningful, and increases the risk of adverse reactions.15

Choosing a combination therapy

There are a number of factors to consider before prescribing combination therapy (Table 2). Ideally, first establish the effective dose of, and patient response to, each individual drug in the combination.4 Discuss the consumer medicine information leaflet of the combination product with the patient.

Monitor patients for electrolyte status and renal function before and after starting any antihypertensive combination therapy, after each dose increment or if clinical circumstances change and are likely to worsen renal function (e.g. dehydration).

Table 2.
Combination therapy — factors to consider

Is fixed-dose combination treatment appropriate for this patient?

Take into account:

  • efficacy of mono- or combination therapy
  • adherence to lifestyle advice and current treatments
  • patient response to the individual drugs
  • contraindications
  • associated comorbidities

In patients with comorbidities, what are the potential drug–drug interactions?

Avoid prescribing4,16:

  • NSAIDs for people taking an angiotensin II-receptor antagonist and a diuretic, due to the increased risk of acute renal failure ('triple-whammy')
  • a potassium-sparing diuretic with an angiotensin II-receptor antagonist, due to the risk of hyperkalaemia

Will it be possible to identify which drug in the combination is causing adverse effects?

  • Some adverse effects (e.g. dizziness) are common to olmesartan, amlodipine and valsartan, so it may be hard to identify which drug is responsible
  • Amlodipine may cause mild to moderate oedema
  • Valsartan may cause hyperkalaemia

Is the required dose combination available?

Note that the fixed-dose combination of olmesartan 20 mg / amlodipine 10 mg is not currently available in Australia

What is the potential for patient confusion and medication error?

  • Brand names of some combination products do not clearly indicate that these are combinations
  • The appearance and packaging of the new combination tablets may be similar
  • Ensure that patients and carers know the name and dose of all the active ingredients contained in the combination product and which medicines are being replaced by the combination product
  • Advise patients to return unneeded medicines to their local pharmacy

For more information see:

References

  1. Australian Department of Health and Ageing. July 2010 PBAC outcomes: positive recommendations. 2010. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-jul10 (accessed 1 September 2010).
  2. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-Dose Combinations Improve Medication Compliance: A Meta-Analysis. Am J Med 2007;120:713–9. http://www.sciencedirect.com/science/article/B6TDC-4PBD4YB-G/2/b282461f019924633b49e138ddaf42d4
  3. Gupta AK, Arshad S, Poulter NR. Compliance, Safety, and Effectiveness of Fixed-Dose Combinations of Antihypertensive Agents: A Meta-Analysis. Hypertension;55:399–407. http://hyper.ahajournals.org/cgi/content/abstract/55/2/399
  4. National Heart Foundation of Australia. Guide to management of hypertension 2008: Updated August 2009. Web version. http://www.heartfoundation.org.au/SiteCollectionDocuments/A_Hypert_Guidelines2008_2009Update_FINAL.pdf (accessed 8 September 2010).
  5. Australian Medicines Handbook 2010. Adelaide: Australian Medicines Handbook Pty Ltd, 2010.
  6. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. [PubMed]
  7. Schering-Plough Pty Limited. Sevikar product information, 10 May 2010.
  8. Australian Government Department of Health and Ageing. Australian public assessment report for Olmesartan medoximal and Amlodipine besylate. Proprietary product name: Sevikar. September 2010. http//:www.tga.gov.au/pmeds/auspar/auspar-sevikar.pdf (accessed 3 November 2010).
  9. Chrysant SG, Melino M, Karki S, et al. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther 2008;30:587–604. http://www.sciencedirect.com/science/article/B6VRS-4SJHXW9-2/2/99ced5227e33f76495511c7a060aacee
  10. Barrios V, Brommer P, Haag U, et al. Olmesartan medoxomil plus amlodipine increases efficacy in patients with moderate-to-severe hypertension after monotherapy: a randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009;29:427–39. [PubMed]
  11. Volpe M, Brommer P, Haag U, et al. Efficacy and tolerability of olmesartan medoxomil combined with amlodipine in patients with moderate to severe hypertension after amlodipine monotherapy: a randomized, double-blind, parallel-group, multicentre study. Clin Drug Investig 2009;29:11–25. [PubMed]
  12. Calhoun DA, Lacourciere Y, Chiang YT, et al. Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension 2009;54:32–9. [PubMed]
  13. Australian Government Department of Health and Ageing. Australian public assessment report for Amlodipine (as besylate) and Valsartan and Hydrochlorothiazide. Proprietary product name: Exforge HCT, Ejocia HCT. August 2010. http//:www.tga.gov.au/pmeds/auspar/auspar-exforge.pdf (accessed 3 November 2010)
  14. Novartis Pharmaceuticals Corporation. Prescribing Information, August 2009.
  15. Heran BS, Wong MM, Heran IK, et al. Blood pressure lowering efficacy of angiotensin receptor blockers for primary hypertension. Cochrane Database Syst Rev 2008:CD003822. [PubMed]
  16. Australian Adverse Drug Reactions Bulletin. ACE inhibitor, diuretic and NSAID: a dangerous combination. 2003; 22. http://www.tga.gov.au/adr/aadrb/aadr0308.htm (accessed 14 October 2010).