Q: Why have FDCs been criticised in the past?
Gupta: The use of FDC was previously discouraged because of cost considerations, lack of flexibility in dose titration and doubts over the bioavailability of the individual components (compared with the bioavailability of the constituent components, when given separately). Another concern was that the use of FDCs would be associated with the increased risk of adverse events. Over the last few years, however, the findings of several clinical trials and observational studies have refuted most of these concerns (1–4).
Findings from recently conducted clinical trials have virtually removed any doubts over the comparative efficacy and safety of an FDC versus its corresponding free-drug combination. Moreover, in several situations, the use of FDC was associated with significantly improved efficacy. For example, in the ACCOMPLISH Trial, blood pressure control rates (within first six months) improved significantly among previously treated hypertensive patients, from 37% to 73%, with the use of a single pill FDC of two antihypertensive agents. Another trial using a low-dose FDC, STITCH Trial (Simplified Treatment Intervention to Control Hypertension), found that those allocated to treatment with an FDC compared with the usual care were more likely to have a better blood pressure control, with no adverse effect on tolerability.Other studies have also shown that the total costs (direct and indirect) related to the use of any FDC is likely to be lower than the use of its corresponding free-drug combination, particularly because of a reduction of indirect costs related to disease complications. Indeed, a quick look at the costs of available FDCs in the UK shows that the direct cost of several FDCs is similar or cheaper than the cost of the two constituent components given separately. Additionally, the cost to patients at the point of delivery is cheaper with an FDC compared with the prescription of two components separately when patients have to pay for prescription. A recent study has also shown that costs incurred by the patient (either as co-payment or otherwise) has an inverse relationship with adherence and concordance with medication. Lastly, the improved and easy availability of several different dose compositions of an FDC have made it easier for physicians to up-titrate medications with little difficulty.
In summary, I believe, it is no longer justified to persist with an attitude of disdain against the use of FDCs.
Udupa/Sreedhar: The single most important factor that FDCs have been criticised for is dose titration. Dose titration of one or all the active ingredients present in an FDC is not possible, which is crucial when both actives require dose titration. However, manufacturers have taken note of this and addressed the problem in certain cases, but the criticism is justified because the very existence of the FDC discourages adjustment of doses to the patient's needs, and may also lead to overdosing or underdosing of one or more of the active ingredients present. Moreover, busy prescribers may not notice the dose of each active ingredient present in an FDC and it could encourage polypharmacy.