Place in therapy of fixed-dose combination medicines

Do fixed-dose combination medicines (FDCs) improve adherence or provide better health outcomes?

Fixed-dose combination medicines are designed to help patients adhere to medicine regimens and improve health outcomes.1

There is evidence that fixed-dose combination medicines improve outcomes for patients with:

  • communicable diseases such as HIV or tuberculosis (TB)
  • other chronic diseases, such as hypercholesterolaemia.

For communicable diseases that require treatment over a long period, irregular adherence can cause drug resistance. This affects treatment options for individual patients and constitutes a public health problem.2,3 The availability of fixed-dose combinations of common HIV and TB medicines effectively reduces the considerable pill burdens for these diseases and improves adherence.2,4

For chronic diseases, there have been serious outcomes associated with non-adherence such as increased incidence of cardiac events5 and cardiovascular morbidity and mortality.6,7  A systematic review of FDC formulations for diabetes reported improved satisfaction, lower medical costs and 10% to 13% improved adherence (although one included trial reported no adherence advantage).8

One meta-analysis of people taking medicines for HIV, hypertension, tuberculosis and diabetes estimated that FDC preparations reduced the risk of non-adherence by about 25%.9

Evidence for improved adherence with combination medicines is strongest when the reduction in pill burden is greatest.2

Factors contributing to non-adherence

While combining medicines into a simplified dosing regimen is associated with a significant improvement in adherence,9-11 use of combination medicines does not by itself ensure improved adherence in every individual, as many factors contribute to non-adherence.1

There is limited evidence that fixed-dose combinations are better than other dosing aids. Although one systematic review concluded that both fixed-dose combination medicines and dosing aids improved adherence it was noted that the quality and quantity of the studies performed in this area was poor.12

To date, improved adherence with co-packs has not been directly demonstrated. There is some evidence that reminder packaging, normally included in co-packs, improves clinical targets such as blood pressure.13 However, more research is needed to fully understand the effect of reminder packaging.13

For more information

  1. Australian Government Department of Health and Ageing. Compliance Medicines Working Group Report to Pharmaceutical Benefits Advisory Committee. April 2010. [Online] (accessed 11 December 2012).
  2. Llibre JM, Arribas JR, Domingo P, et al. Clinical implications of fixed-dose coformulations of antiretrovirals on the outcome of HIV-1 therapy. AIDS 2011;25:1683–90. [PubMed]
  3. Blomberg B, Spinaci S, Fourie B, et al. The rationale for recommending fixed-dose combination tablets for treatment of tuberculosis. Bull World Health Organ 2001;79:61–8. [PubMed]
  4. Moulding T, Dutt AK, Reichman LB. Fixed-dose combinations of antituberculous medications to prevent drug resistance. Ann Intern Med 1995;122:951–4. [PubMed]
  5. Bouchard MH, Dragomir A, Blais L, et al. Impact of adherence to statins on coronary artery disease in primary prevention. Br J Clin Pharmacol 2007;63:698–708. [PubMed]
  6. Hilleman DE, Monaghan MS, Ashby CL, et al. Physician-prompting statin therapy intervention improves outcomes in patients with coronary heart disease. Pharmacotherapy 2001;21:1415–21. [PubMed]
  7. Compliance and adverse event withdrawal: their impact on the West of Scotland Coronary Prevention Study. Eur Heart J 1997;18:1718–24. [PubMed]
  8. Hutchins V, Zhang B, Fleurence RL, et al. A systematic review of adherence, treatment satisfaction and costs, in fixed-dose combination regimens in type 2 diabetes. Curr Med Res Opin 2011;27:1157–68. [PubMed]
  9. Bangalore S, Kamalakkannan G, Parkar S, et al. Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007;120:713–9. [PubMed]
  10. Simons LA, Ortiz M, Calcino G. Persistence with a single pill versus two pills of amlodipine and atorvastatin: the Australian experience, 2006–2010. Med J Aust 2011;195:134–7. [PubMed]
  11. Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010;55:399–407. [PubMed]
  12. Connor J, Rafter N, Rodgers A. Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review. Bull World Health Organ 2004;82:935–9. [PubMed]
  13. Mahtani KR, Heneghan CJ, Glasziou PP, et al. Reminder packaging for improving adherence to self-administered long-term medications. Cochrane Database Syst Rev 2011:CD005025. [PubMed]