Fixed-Dose Combinations

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.

Q: Despite criticism, some data have suggested that compliance is increased. Could you explain why you agree or disagree with this statement?

Gupta: I agree that there is a significant body of evidence confirming directly or indirectly that the use of an FDC is associated with improvement in compliance. Several observational studies have shown an inverse relationship between the number of prescribed medications and concordance with them. A few qualitative surveys on patient perception have largely produced supportive data, suggesting that the use of an FDC would be more convenient for patients, and encourage compliance and adherence with medications. The findings of our meta-analysis, using evidence from cohort studies and clinical trials, have confirmed previous indirect findings: our analyses found that, compared with a free-drug combination, the use of an FDC was associated with a 21% significant increase in compliance and a 54% increase in persistence with therapy.

Udupa/Sreedhar: There are several advantages offered by FDCs. Many studies have shown that FDCs increase both patient compliance and adherence. FDCs also simplify treatment regimens. Physicians feel that it is convenient to prescribe FDCs rather than single component products, and this sentiment is often shared by patients. It is also generally believed that FDCs are cheaper and reduce the costs of logistics, which is especially important when FDCs need to be distributed to remote places.

Q: Can you give examples of successful, rational FDCs?

Gupta: Currently there are numerous examples of success stories with FDCs. An FDC of antituberculosis medications, compared with the corresponding free-drug combinations, was associated with significantly higher treatment rates and significantly lower adverse effects. Similarly, among those with HIV, the use of an FDC of anti-HIV drugs has shown greater rates of remission. In comparison to these examples, the success stories with the use of FDC in the field of cardiovascular medicine are not that dramatic. However, there is a rapidly growing body of data, suggesting that the usefulness of FDCs in cardiovascular and metabolic medicine is likely to be no different than that seen in other fields of medicine.

In cardiovascular medicine, the main utility of FDCs is mediated through improved compliance, which in turn may increase the treatment efficacy and decrease the outcomes. This hypothesis is partially supported by findings of our meta-analyses: the use of FDCs (compared with the use of corresponding free-drug combination) was associated with a greater (albeit statistically insignificant) reduction. Elsewhere, a few observational studies have shown that the improved adherence with medications is likely to be associated with greater cardiovascular benefits.

Another potential advantage with the use of FDC is a possible reduction in adverse effects. In our meta-analysis, compared with the corresponding free-drug combination given separately, allocation to FDC was associated with lower adverse event rates. The use of a low-dose FDC of two drugs as an initial therapy (in several situations) may have significantly lower adverse events and a better tolerability, than either of the medication alone.. A classic example of this is an FDC combination of an angiotensin-converting enzyme (ACE) inhibitor and a calcium-channel blocker (CCB) is likely to be associated with lower incidence of ankle swelling, compared with the same dose of CCB alone.

Udupa/Sreedhar: Fixed dose combinations are especially useful when treating diseases like human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS), malaria and tuberculosis where more than one drug is usually recommended. There are also certain other conditions and diseases, such as cancer, cardiovascular diseases, diabetes, neuropsychiatry and pain where FDCs may offer benefits. Some successful and rational FDCs include:

• Antiretroviral combinations: abacavir+lamivudine, tenofovir disoproxil fumarate+emtricitabine and efavirenz + tenofovir+emtricitabine.

• Antimalarial combinations: artesunate+amodiaquine, artemether+lumefantrine and amodiaquine+sulphadoxine+pyrimethamine.

• Antitubercular combinations: Rifampicin+Isoniazid+Pyrazinamide.

• Hypertensive combinations that provide better blood pressure control: Amlodepine+Atenolol, Amlodepine+Losatan and Irbesartan+Hydrochlorthiazide.

• Antidiabetic combinations that provide better glycaemic control: Glibenclamide+Metformin, Glipizide+Metformin and Pioglitazone+Metformin.

Q: How do you think the benefits and disadvantages of FDCs shape up against one another? Should the pharma industry pay more attention to potential FDCs or would the time be better spent on other areas of innovation?

Gupta: This is an interesting question, but there is no readily available answer. In my opinion, each new FDC formulation should be based on a thorough understanding of disease mechanism, as well as the mechanism of action, pharmacokinetics and pharmacodynamics of each constituent component—separately and in combination.

There are a few FDCs that are more frequently prescribed over the other because of the prevalence of the clinical situations that they are most effective in. However, given the numerous clinical prescribing situations, I believe all FDCs will have their own niche in treatment settings. Having said that, I believe that there are only a finite number of possible FDCs and with the rapid introduction of new FDCs, the market will probably be saturated in the next few years or so. For long-term sustainability, the pharma industry should spend a significant amount of time on other areas of innovation, including the development of new drugs and effective drug delivery mechanisms.

Udupa/Sreedhar: Benefits and disadvantages should be looked at simultaneously and not individually when evaluating an FDC. If there is considerable evidence that the proposed FDC has more benefits than disadvantages, then it's a definite 'go' situation.

The pharma industry should definitely explore the potential benefits FDCs offer over their individual component products. It is difficult for small- to medium-scale companies to bear R&D costs and even larger companies are finding it risky to develop new drugs and so most pharma companies are now in search of new business models. One of these options is to develop FDCs of existing individual components that are co-prescribed in order to help preserve patents.

When developing FDCs, however, companies must consider the safety and efficacy of the active components in combination, the benefits of simultaneous use of active ingredients and possible interaction between the components. Fixed-ratio combination products are usually considered for marketing approval by regulatory authorities only when the dosage of each ingredient meets the requirements of a defined population group and when the combination has a proven advantage over single compounds administered separately in its therapeutic effects, safety or compliance.

Dr Ajay K Gupta is based at the International Centre for Circulatory Research, Imperial College London (UK).

Dr N. Udupa is Professor and Principal at Manipal College of Pharmaceutical Sciences, Manipal University (India).

Dr D. Sreedhar is Assistant Professor in the Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University (India).

References

1. A.K. Gupta, S. Arshad and N.R. Poulter, Hypertension, 55(2), 399–407 (2010).

2. K. Jamerson et al., N Engl J Med., 359, 2417–2428 (2008).

3. ADVANCE, "ADVANCE Trial — Blood pressure lowering arm results". www.advance-trial.com

4. R.D. Feldman et al., presentation at Scientific Sessions 2007 of the American Heart Association (Orlando, FL., USA, 2007).