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Fixed-dose combinations and adherence

Systematic review

Bandolier has previously examined issues about adherence in its pages and on the Internet version, where there is a small library of evidence. Adherence to long-term therapy is low, perhaps not even 50%. A WHO report in 2003 highlighted that simplicity of dosing regimen and adverse effects were therapy-related factors contributing to adherence (make it easier, with fewer adverse events, and people take the tablets).

Ways of improving adherence include combining several therapies in one pill, or using unit-of-use packaging that puts the medications to be used in fixed combination together. A systematic review [1] has assembled what passes for the evidence.

Systematic review

All randomised or quasi-randomised studies meeting various criteria were sought in five major databases, to mid-2003, were used. Criteria were: adult patients, taking more than one oral medication, intervention of combination pill or unit-of-use packaging compared with usual pill containers, and at least one outcome measure relating to adherence, pharmacological goal of medication, or cost.


No quantitative synthesis was likely to be possible from what was a predictably mixed bag of studies. Fifteen trials were found, with fixed dose combinations in three and unit-of-use packaging in 12. Settings were:

Studies had statistical significance or trends towards better adherence or better clinical outcomes more often than they did not (Table 1). Two of three studies examining combination therapy in one pill versus the same medicines separately in tuberculosis or HIV over four months to two years had statistically better adherence, and one tuberculosis study had significantly better clinical outcomes. Of five studies examining unitary packaging in older people with many medications, three performed since 1987 had significant improvements in adherence, but populations were tiny.

Table 1: Main results of combination therapy systematic review

Improvement trend
Outcome in trials measuring it
Trends to improve clinical and/or adherence outcomes
Significant improvement to adherence
Significant improvement in clinically relevant end-point


This systematic review is a useful resource for thinking about combination therapies, either as one pill, or as unitary packaging of different pills. It tells us that there is precious little information, that the trials are in a mixed bunch of conditions (they include TB, leprosy, malaria, hypertension) and settings from less to most developed countries. But that is what there is, at least up to mid-2003.

On balance, combinations look useful most of the time, both for adherence and clinical outcomes. That is interesting, especially when attitudes to combination therapies are so mixed. Great for tuberculosis or a magic polypill with five ingredients to banish heart disease. Bad for paracetamol and codeine in older people with pain in the community.

We do know that female sex, older age, and increasing numbers of pills increases the risk of serious adverse drug events. We know that these are common, affecting many thousands of older people. What is daft is that we have so little data, when common sense indicates that the combination of adverse drug events and noncompliance has to be a huge cost in resource and human terms.


  1. J Connor et al. Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review. Bulletin of the World Health Organisation 2004 82: 935-939.

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