Multilayer Tablets: Key Challenges and Trends - Pharmaceutical Technology

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Multilayer Tablets: Key Challenges and Trends
Experts in solid dosage discuss the formulation and manufacture of multilayer tablets.

Pharmaceutical Technology
Volume 36, Issue 3, pp. s22-s33

Fixed-Dose Combinations

A single dosage form that combines two or more active ingredients is known as a combination drug or fixed-dose combination (FDC). One benefit of an FDC is that it reduces the number of pills that must be taken, which can lead to improved patient compliance. However, FDCs have also been a topic of concern, mainly because of the perceived potential for increased adverse events. Pharmaceutical Technology speaks with researchers to explore the benefits and concerns of FDCs, and some of the challenges involved in their formulation. Participants include Dr. Ajay K. Gupta of International Center for Circulatory Research, Imperial College London; Dr. N. Udupa, professor and principal at Manipal College of Pharmaceutical Sciences, Manipal University in India; and Dr. D. Sreedhar, assistant professor in the Department of Pharmacy Management, Manipal College of Pharmaceutical Sciences, Manipal University in India.

PharmTech: Why have FDCs been criticized in the past?

Gupta (Imperial College London): The use of FDCs 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 (Manipal University): 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.

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

Gupta (Imperial College London): 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 (Manipal University): 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.


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