Fixed dose drug combinations – are they pharmacoeconomically sound? Findings and implications especially for lower- and middle-income countries

Figures & data

Table 1. Published pharmacoeconomic studies of FDCs in LMICs.

Author, year and country	FDCs and methods	Principal findings
Non Communicable Diseases
Cardiovascular disease
Gaziano et al (2006) – multiple countries [329]	2 FDCs – one containing aspirin, lovastatin lisinopril, and amlodipine (forerunner to the polypill) for primary prevention and a similar FDC for secondary prevention with metoprolol replacing amlodipine among six regions involving LMICs Costings based on the International Drug Price Indicator Guide	Preventive strategies could result in a 2-year gain in life expectancy ICERs for secondary prevention ranged from 306 USD/QALY to 388 USD/QALY gained.
Sing et al (2018) – India [38]	Polypill for secondary prevention in India versus usual care groups The price of the polypill was constructed using a range of scenarios: $0.06 to $0.94/day.	The mean cost per patient was significantly lower with the polypill strategy at -203 USD per person (95% CI: −286, −119, p < 0.01) ICERs ranged from a cost-saving to $75 per 10% increase in adherence for the polypill priced at $0.94/day
Lin et al (2019) – multiple countries [40]	Polypill containing aspirin, lisinopril, atenolol, and simvastatin Microsimulation models used to assess its cost-effectiveness for secondary prevention versus current care in China, India, Mexico, Nigeria, and South Africa Variety of sources used for prices including retail market prices	At public-sector prices, the ICER was Int168 USD per DALY averted in China, Int$154 in India, Int$88 in Mexico, Int$364 in Nigeria, and Int$64 in South Africa, amounting to 0·4–6·2%/capita GDP in these countries The ICER increased to 3·3–14·6%/capita GDP at retail market prices
T2DM	None identified
Respiratory Diseases – Altaf et al (2015) – India [242]	Prospective observational study undertaken to evaluate the clinical and economic consequences of salmeterol/fluticasone (SF) – Group I, formoterol/budesonide (FB) – Group II, and formoterol/fluticasone (FF) – Group III – in severe and very severe chronic obstructive pulmonary disease patients 90 COPD patients were divided into three groups[NB – No longer recommended [23,245,246]].	The 3% and 2% increase in FEV1 in Groups I and II, respectively, was highly significant vs. 0.2% increase in Group III The mean total costs over 6 months was Rs. 29,725/- for Group I, Rs. 32,602/- for Group II, and Rs. 37,155/- for Group III The incremental cost-effectiveness of FB versus SF was Rs. 37,781/- per avoided exacerbation and Rs. 661/-per symptom-free day
Pain management – Cristancho et al (2013) – Colombia [265]	The cost-effectiveness of three different FDCs indicated for moderate and severe acute pain – acetaminophen 500 mg + codeine 30 mg (AC), acetaminophen 500 mg + hydrocodone 5 mg (AH) and acetaminophen 325 mg + tramadol 37.5 mg (AT) Prices typically Institutional prices	The prices/numbers needed to treat were $1816Colombian pesos/2.2 for AC, $4772 Colombian peso/2.3 for AH and $5342/2.6 for AT Using AC as the comparator, the ICER for AT from a payer’s perspective was $8790 Colombian pesos and $29,460 Colombian pesos for AH
Infectious diseases
Malaria
Mori et al (2016) – Tanzania [281]	Dynamic Markov decision model developed Model based on clinical and epidemiological estimates to predict the budget impact of DP as either first- or second-line treatment alongside AL	Prescribing AL and DP as first- and second-line treatment, respectively, will save approximately $64,423/year whilst achieving a 3% reduction in the number of malaria cases versus AL + quinine Prescribing DP as first line will add $780,180/year but achieve a further 5% reduction in the number of malaria cases vs. AL followed by DP
TB	None identified
HIV
Zheng et al (2018) - India [316]	1 FDC (EFZ/TDF/3TC) vs. TLD (DTG + TDF/3TC) Microssimulation model	DTG + TDF/3TC is cost-effective with an ICER = 130 US$/life year saved
Costa (2019) – Brazil [326]	1 FDC (EFZ/TDF/3TC) vs. multiple tablet regimens with the same formulation of the FDC and other multiple tablet regimens Cost per responder at 52 weeks Adjusted for loss to follow-up	FDC was cost-effective with an ICER of US$19583 for multiple tablet regimens with the same composition of the FDC and US$41,128 for other multiple tablet formulations

ACE, angiotensin-converting enzyme; AL, artemether–lumefantrine; DALY, disability-adjusted life-year; DP, dihydroartemisinin-piperaquine; DTG, dolutegravir; EFZ, Efavirenz; FDC, Fixed dose combinations; ICER, incremental cost-effectiveness ratio; QALY, quality-adjusted life year; TDF, tenofovir disoproxil fumarate; 3TC, lamivudine.

Table 2. Availability of FDCs among the various LMICs (Public sector only and only oral medicines apart from inhalers).

	Albania	Botswana	Brazil	Bulgaria	Cameroon	Estonia	Ghana
Infectious diseases
Antibiotics (Prevention malaria, etc)
sulfamethoxazole + trimethoprim	Yes	Yes	Yes	Yes	Yes	Yes	Yes
HIV FDCs
abacavir + lamivudine	No	Yes	No	Yes	Yes	Yes	Yes
dolutegravir + lamivudine + tenofovir	Yes	Yes	No	No	No	No	No
efavirenz + emtricitabine + tenofovir	No	Yes	No	No	Yes	No	Yes
efavirenz + lamivudine + tenofovir	No	Yes	Yes	No	Yes	No	Yes
emtricitabine + tenofovir	No	Yes	Yes	Yes	Yes	Yes	Yes
lamivudine + nevirapine + zidovudine	No	Yes	No	No	Yes	No	Yes
lamivudine + zidovudine	No	Yes	Yes	Yes	Yes	Yes	Yes
	6 other FDCs available	3 other FDCs	2 other FDCs available	5 other INNs of FDCs are		4 other FDCs	4 other FDCs
Anti TB Medicines
isoniazid + pyridoxine + sulfamethoxazole + trimethoprim	No	No	No	No	Yes	No	No
ethambutol + isoniazid + pyrazinamide + rifampicin	No	Yes	Yes	No	Yes	No	Yes
ethambutol + isoniazid + rifampicin	No	Yes	No	No	Yes	No	Yes
isoniazid + pyrazinamide + rifampicin	No	Yes	Yes	No	Yes	No	Yes
isoniazid + rifampicin	No	Yes	Yes	No	Yes	Yes	Yes
Antimalarial medicines including prevention
artemether + lumefantrine	No	Yes	Yes	No	Yes	No	Yes
artesunate + amodiaquine	No	Yes	No	No	Yes	No	Yes
artesunate + mefloquine	No	No	Yes	No	No	No	No
artesunate + pyronaridine tetraphosphate	No	No	No	No	No	No	No
dihydroartemisinin + piperaquine phosphate	No	No	No	No	Yes	No	Yes
sulfadoxine + pyrimethamine	No	Yes	No	No	Yes	No	Yes
Non-communicable diseases
Cardiovascular – Hypertension, etc
lisinopril + amlodipine	No	No	No	Yes	No	Yes	No
lisinopril + hydrochlorothiazide	No	Yes	No	Yes	No	No	No
telmisartan + amlodipine	No	Yes	No	Yes	No	Yes	No
telmisartan + hydrochlorothiazide	Yes	Yes	No	Yes	No	No	No
		12 other FDCs		24 INNs of FDCs are available		26 other FDCs	2 other FDCs
Diabetes
None	No	1 FDC available	No	10 INNs of FDCs are available		9 FDCs available	No
Respiratory
budesonide + formoterol	Yes	Yes	Yes	Yes	No	Yes	Yes
	Other FDCs also reimbursed	1 other FDC		10 other FDCs are available		10 other FDCs	1 other FDC
Pain
None	No	1 FDC available	No	No	5 other FDCs available	No	No
	Iran	Kenya	Kosovo	Latvia	Nigeria	Romania
Infectious diseases
Antibiotics (Prevention malaria, etc)
sulfamethoxazole + trimethoprim	Yes	Yes	Yes	Yes	Yes	Yes
HIV FDCs
abacavir + lamivudine	No	Yes	Yes	Yes	No	Yes
dolutegravir + lamivudine + tenofovir	No	Yes	No	No	No	No
efavirenz + emtricitabine + tenofovir	Yes	No	Yes	Yes	No	Yes
efavirenz + lamivudine + tenofovir	No	Yes	No	No	No	No
emtricitabine + tenofovir	Yes	Yes	Yes	Yes	No	Yes
lamivudine + nevirapine + zidovudine	No	Yes	No	No	Yes	No
lamivudine + zidovudine	Yes	Yes	Yes	Yes	Yes	Yes
	10 other FDCs					5 other FDCs
Anti TB Medicines
isoniazid + pyridoxine + sulfamethoxazole + trimethoprim	No	No	No	No	No	No
ethambutol + isoniazid + pyrazinamide + rifampicin	Yes	Yes	No	No	No	Yes
ethambutol + isoniazid + rifampicin	Yes	Yes	No	No	No	No
isoniazid + pyrazinamide + rifampicin	Yes	Yes	No	No	No	Yes
isoniazid + rifampicin	Yes	Yes	Yes	No	Yes	Yes
	4 other FDCs					1 other FDC
Antimalarial medicines including prevention
artemether + lumefantrine	Yes	Yes	No	No	Yes	No
artesunate + amodiaquine	No	No	No	No	Yes	No
artesunate + mefloquine	No	No	No	No	No	No
artesunate + pyronaridine tetraphosphate	No	No	No	No	No	No
dihydroartemisinin + piperaquine phosphate	No	Yes	No	No	No	No
sulfadoxine + pyrimethamine	Yes	Yes	No	No	Yes	No
	7 other FDCs				1 other FDC	1 other FDC
Non-communicable diseases
Cardiovascular – Hypertension, etc
lisinopril + amlodipine	No	No	No	Yes	No	No
lisinopril + hydrochlorothiazide	Yes	No	No	No	No	No
telmisartan + amlodipine	No	No	No	Yes	No	No
telmisartan + hydrochlorothiazide	No	No	No	Yes	No	Yes
	10 other FDCs				2 other FDCs	22 other FDCs
Diabetes
None	5 FDCs available	No	No	No	No	7 FDCs available
Respiratory
budesonide + formoterol	Yes	Yes	Yes	Yes	No	Yes
	23 other FDCs					5 other FDCs
Pain
None	No	No	No	No	No	1 FDC available
	South Africa	Srpska	Sudan	Vietnam	Zambia	Zimbabwe
Infectious diseases
Antibiotics (Prevention malaria, etc)
sulfamethoxazole + trimethoprim	Yes	Yes	Yes	Yes	Yes	Yes
HIV FDCs
abacavir + lamivudine	Yes	Yes	No	No	Yes	Yes
dolutegravir + lamivudine + tenofovir	Yes	No	No	No	Yes	Yes
efavirenz + emtricitabine + tenofovir	Yes	No	No	No	Yes	Yes
efavirenz + lamivudine + tenofovir	No	No	No	Yes	Yes	Yes
emtricitabine + tenofovir	Yes	Yes	No	No	Yes	Yes
lamivudine + nevirapine + zidovudine	No	No	No	Yes	Yes	Yes
lamivudine + zidovudine	Yes	Yes	No	Yes	Yes	Yes
	2 other FDCs	1 other FDC		2 other FDCs	1 other FDC
Anti TB Medicines
isoniazid + pyridoxine + sulfamethoxazole + trimethoprim	No	No	No	No	No	No
ethambutol + isoniazid + pyrazinamide + rifampicin	Yes	Yes	Yes	Yes	Yes	Yes
ethambutol + isoniazid + rifampicin	No	Yes	Yes	Yes	Yes	Yes
isoniazid + pyrazinamide + rifampicin	Yes	No	Yes	Yes	Yes	Yes
isoniazid + rifampicin	Yes	Yes	Yes	Yes	Yes	Yes
				1 other FDC	1 other FDC
Antimalarial medicines including prevention
artemether + lumefantrine	Yes	No	Yes	Yes	Yes	Yes
artesunate + amodiaquine	No	No	No	Yes	No	Yes
artesunate + mefloquine	No	No	No	Yes	No	No
artesunate + pyronaridine tetraphosphate	No	No	No	No	No	No
dihydroartemisinin + piperaquine phosphate	No	No	No	Yes	No	No
sulfadoxine + pyrimethamine	No	No	No	Yes	Yes	Yes
			2 other FDCs
Non-communicable diseases
Cardiovascular – Hypertension, etc
lisinopril + amlodipine	Yes	No	No	Yes	No	No
lisinopril + hydrochlorothiazide	Yes	Yes	No	Yes	No	No
telmisartan + amlodipine	Yes	No	No	Yes	No	Yes
telmisartan + hydrochlorothiazide	Yes	No	No	Yes	Yes	Yes
	17 other FDCs	7 other FDCs	1 other FDC	16 other FDCs	2 other FDCs	5 other FDCs
Diabetes
None	2 FDCs available	7 FDCs available	NA	7 FDCs available	No	1 FDC available
Respiratory
budesonide + formoterol	Yes	Yes	Yes	Yes	No	No
	2 other FDCs	4 other FDCs	1 other FDC	5 other FDCs
Pain
None	3 FDCs available	No	No	15 FDCs available	No	No

FDC, Fixed dose combination; HIV, Human immunodeficiency virus; INN, International non-proprietary name; TB, tuberculosis

Table 3. Positive clinical and economic (general) considerations associated with FDCs.

Clinical benefits associated with FDCs (general)

Economic benefits (general) associated with FDCs

Simplifies the treatment schedule – which can be particularly important in LMICs where there are low literacy levels as seen in a number of sub-Saharan African countries Easier to prescribe Improved adherence with reduced pill burden Minimal frequency of medicine consumption and reduced chances of patients missing doses Potential to attain clinical goals more rapidly through complimentary additive effects of the components and/or reduced titration times Potential for increased tolerability and/or fewer side-effects through the combination of synergistic medicines Reduced chances of stockouts with FDCs versus the components especially for FDCs containing multiple medicines; consequently, potentially improving clinical outcomes

Potential for reduced overall costs enhanced by synergism with lower doses – potential for lower costs than the components enhanced if FDCs are produced and procured at low cost aided by mass approaches to production, packaging, and distribution Reduced space for storage and distribution/potentially reduced logistical costs Potential for improved shelf life Now seeing in countries that prices of FDCs cannot be higher than the costs of the individual components (e.g. Slovenia) and may even be lower (e.g. India and Zambia)

FDC, Fixed dose combination; HIV, Human immunodeficiency virus; INN, International non-proprietary name; TB, tuberculosis

Table 4. Positive clinical considerations with FDCs across disease areas.

Disease area	Benefits of FDCs
Cardiovascular diseases including hypertension	Improved dose frequency and ease of administration help improve adherence especially where patients are on multiple medicines due to existing co-morbidities – potentially improving disease management Potential for improved effectiveness by combining different treatments with different mechanisms of action, e.g. different lipid-lowering treatments One component of an FDC may offset the side-effects seen with other components, e.g. ACE inhibitors offsetting one of the major side effects associated with calcium channel blockers Potential for minimal adverse effects alongside improvement in disease management Improved long-term adherence through reduced pill burden especially important among aging populations, e.g. European LMICs
Type 2 Diabetes Mellitus (T2DM)	Potential for improved adherence through reduced pill burden – especially important in T2DM patients with multiple co-morbidities to enhance adherence rates Improved disease control for patients with T2DM as well as potentially reducing complications through using medicines with different mechanisms of action In some countries, helps increase the prescribing of metformin where this is a concern and SUs available in combination with metformin
Respiratory diseases	FDCs containing ICS/LABAs are seen as a standard of care for the maintenance of patients with asthma Improved acceptance of FDCs versus separate inhalers helped by easier administration Reduced doses of steroids where there are concerns with continued high doses of steroids for maintenance among patients with asthma FDCs seen to improve the quality of life of patients with asthma through improved adherence and better maintenance of disease targets
Pain	Improved potential for pain management with FDCs with different mechanisms of action where concerns with abuse or increased side-effects if the dose of one component is increased to manage the pain Multiple mechanisms for a broader effect
Malaria	Improved effectiveness and treatment success Improved adherence to prescribed medicines enhanced by the potential for shortened duration of treatment Potential for decreased resistance using medicines with different mechanisms of action Potential for reduced costs
Tuberculosis (TB)	FDCs may help prevent the emergence of resistant strains especially given the length and complexity of the treatment regimens involved Increased effectiveness against resistant cases with medicines with different mechanisms of action Reduces the incidence of MDR-TB Synergism at lower doses Complex treatment regimen eased by FDCs thereby enhancing completion rates Dispersible FDCs for children easing administration
Human immunodeficiency virus (HIV)	FDCs containing medicines with different mechanisms of action typically improves treatment outcomes Synergism at lower doses FDCs may help prevent the emergence of resistant strains Increased effectiveness against resistant cases Combining tablets simplifies treatment regimens and standardizes doses prescribed aiding subsequent quality of care Patients are unable to default on specific medicines believed to be causing side-effects such as dizziness and drowsiness seen with efavirenz

ACE, angiotensin-converting enzyme; FDC, Fixed Dose Combination; ICS/LABAs, Inhaled corticosteroids/long-acting β agonists; MDR-TB, Multidrug resistant TB; SU = sulfonyl urea.

Table 5. General concerns regarding FDC.

Clinical concerns associated with FDCs (general)

Economic concerns (general) associated with FDCs

Reduces the ability to titrate individual doses to the specific needs of patients Potential for overtreatment if physicians and patients are not fully aware of the constituents of FDCs – especially important if patients are switched to different FDCs FDCs can increase polypharmacy especially in patients with chronic NCDs Issues of pharmacokinetics in some FDCs including issues of dissolution, absorption and drug:drug interactions Missing doses of an FDC has a greater impact than missing doses of one of the medicines in the FDC Challenging to ascertain responsible medicine for ADRs – especially important for pharmacovigilance

Potentially appreciably higher prices for the FDC versus the cost of the components combined Typically only available as ‘branded’ medicines in some countries and consequently only available in private pharmacies rather than public facilities and not in rural areas, e.g. Cameroon

ADRs, Adverse Drug Reactions; FDC, Fixed Dose Combination

Table 6. Clinical concerns regarding FDCs across disease areas.

Disease area	Concerns with FDCs
Cardio Vascular (CV) diseases including hypertension	Reduces the ability to tailor treatment to individual patients especially where adverse effects are seen with the prescribed FDC More limited options with FDCs versus individual components More difficult to adjust doses when needed potentially enhancing treatment inertia Potential for doubling doses of medicines if patients and prescribers are not fully aware of the constituents of prescribed FDCs Clinical rationality of a number of CV FDCs with the potential for inadequate dosing and increasing costs Concerns with the bioequivalence and pharmacokinetics of some FDCs for CV diseases
Type 2 Diabetes Mellitus (T2DM	More difficult to adjust doses thereby potentially reducing the ability to tailor treatment to individual patients More limited options with FDCs versus individual components Reduced positive effect of metformin on CV events with reduced doses of metformin or with metformin/sulfonyl urea combinations Potential for doubling doses of medicines if patients and prescribers are not fully aware of the constituents of prescribed FDCs Clinical rationality of a number of FDCs, e.g. metformin FDCs in India FDCs enhance the potential for polypharmacy, e.g. in Slovenia many patients with T2DM are typically on 4 or more INN medicines which was not often seen before the availability of FDCs
Respiratory diseases	Reduces the potential for effective management especially where there are concerns with the doses of steroids administered – as a result, potential for over medication with steroids Patients may need to use different inhaler devices with different FDCs impacting on adherence in practice Increasing concerns with prescribing of LABA/ICS combinations in patients with COPD unless asthma-like symptoms
Pain	Reduces the ability to tailor treatment to individual patients More difficult to adjust doses Potential for substance misuse if currently taking FDCs due to the subjective nature of pain Limited clinical justification for FDCs to treat pain among some of the coauthors Potential to enhance irrational prescribing
Malaria	Potential concerns with tolerance to mefloquine FDCs Appreciable number of unapproved FDCs in some LMICs Concerns with the pharmacokinetic profile of some FDCs for malaria impacting on their effectiveness and safety Potential loss of effectiveness Potential development of drug resistance to one or more of the components leading to loss of therapeutic options
Tuberculosis (TB)	Difficult to desensitize patients in the event of adverse effects Potential for increased adverse events Some constituents of FDCs may cause more adverse effects than the originators Potential quality issues when medicines are combined especially with rifampicin in FDCs for TB – consequently vigilance is needed to monitor the quality of rifampicin as a key component of antimalarial FDCs given concerns with certain rifampicin FDCs in countries such as South Africa Potential loss of effectiveness Potential development of drug resistance to one or more of the components leading to loss of therapeutic options The interaction between efavirenz as well as lopinavir, dolutegravir, raltegravir with bedaquiline is a problem for patients with HIV who also have MDR-TB (especially in sub-Saharan Africa) – necessitating a switch to twice daily nevirapine with separate companion tablets – antiretroviral FDCs without bedaquiline drug interactions are strongly recommended in these patients
Human immunodeficiency virus (HIV)	Difficult to desensitize patients in the event of adverse effects, with the potential for increased adverse events with FDCs Some constituents of FDCs may cause more adverse effects than the originators necessitating careful monitoring of patients Potential loss of effectiveness over time Potential development of drug resistance to one or more of the components leading to loss of therapeutic options Currently, no liquid formulation FDCs are available for pediatric patients Imperative to educate patients that FDCs cannot be crushed or dissolved to improve swallowing as bioequivalence will be compromised Supply chain integrity is imperative to ensure a continuous supply of ARV FDCs for patients with interruptions in supply associated with sub-clinical outcomes

CV, cardiovascular; FDC,Fixed Dose Combination; ICS/LABAs,Inhaled corticosteroids/long-acting β agonists; INN, International non-proprietary name; MDR-TB, Multidrug-resistant TB.

BOX 1. Potential initiatives that can be undertaken by key stakeholder groups to enhance the availability and prescribing of valued FDCs.

A) Clinical and other considerations Emphasize the importance of adherence to treatments especially for patients with chronic NCDs and how valued FDCs can help with this. Concurrent with this, improve prescriber education about the benefits of valued FDCs starting in medical school and continuing post qualification – similarly for pharmacists who are increasingly involved with patient education regarding their medicines and the importance of adherence to prescribed doses Possibly linked to this, the development of quality prescribing indicators potentially linked with financial rewards Pharmaceutical companies to provide robust clinical trial data demonstrating improved outcomes and adherence with FDCs versus the components separately to aid listing in country/region reimbursement list/EML (such data when available can be incorporated into robust health technology assessments of new FDCs) Investigate further the clinically meaningful benefits of the polypill especially for sub-Saharan Africa given the appreciable increase in morbidity and mortality due to CV diseases in recent years in these countries Robustly considering any potential drug:drug interactions or increased adverse effects in patients with HIV subsequently developing chronic NCDs (increasingly happening in sub-Saharan Africa) and prescribed FDCs – especially as this co-morbid population is likely to experience challenges with medication adherence/polypharmacy The process from transitioning from individual medicines to FDCs should be carefully managed in terms of supply chain management (where problems currently exist) to facilitate procurement at a central level (and hence procurement at lower prices) and subsequent distribution Appropriate patient counseling also needs to take place to optimize the process – with intensive adherence counseling still needed especially among patients with limited education. In view of this, if appropriate create policies that enhance capacity within health-care systems that help spread correct information and awareness regarding the value and effectiveness of pertinent FDCs as well as use patient organizations where these exist to spread key messages – this can include instigating educational activities among physicians and pharmacists in medical and pharmacy schools and post-qualification Accelerating the registration/pricing procedures for valued FDCs in countries where this is a concern, e.g. Sudan. This can be addressed through the provision of scientifically sound guidelines and robust data supporting their registration as well as a review of reimbursement/pricing procedures where there are concerns More flexible approaches to private pharmacies regarding the availability of FDCs especially in rural areas where this is a concern, e.g. Cameroon

B) Economic Realistic pricing expectations and considerations especially where there are high patient co-payments or strict pricing regulations, e.g. Estonia, to help overcome concerns with the over-pricing of FDCs and enhance their chances of being reimbursed/listed in national/regional EMLs – typically initially robust health technology assessments using cost minimization approaches are needed among LMICs to enhance their listing in national EMLs (progressing to cost-effectiveness analyses as sophistication levels grow) Addressing issues of affordability and access where these exist – including reducing additional patient co-payments for the FDC versus multiple tablets of the same medicines where these exist especially for valued FDCs, e.g. Bulgaria and Poland Concurrent with this, promoting local pharmaceutical company participation in the manufacturing of FDCs to agreed quality standards through incentives and other mechanisms to help address supply chain and affordability/access issues where these exist

Abbreviations: EML = Essential Medicine List; FDC = Fixed Dose Combination; LMICs = Lower- and Middle-Income countries; NCDs = Non-communicable diseases

BOX 2. Potential initiatives that can be undertaken by key stakeholder groups to reduce or negate the availability of FDCs where concerns.

A) Clinical The development of public/private partnerships to help standardize treatment approaches including the prescribing of FDCs Provision of robust health technology assessments to support listing/funding of FDCs in LMICs – especially for more elderly patients with high pill burdens. This includes robust cost-effectiveness analyses across LMICs demonstrating their value versus the prescribing of multiple medicines for the same patient population Concomitant with this – greater focus on issues of potential polypharmacy with FDCs especially in elderly patients with multiple co-morbidities Only register FDCs of proven clinical value, enforced through tighter regulations – especially important in countries with existing high rates of irrational FDCs, e.g. India – although changing – and to prevent the future availability of FDCs where concerns Improved education of undergraduates and physicians where concerns with irrational FDCs, e.g. India. This should be continued with activities after qualification including in-service training/continual professional development to enhance adherence rates among patients to prescribed FDCs given ongoing concerns with long-term adherence to medicines especially in patients with chronic asymptomatic conditions Improve pharmacovigilance activities especially for FDCs where there are safety as well as drug:drug interaction concerns Greater interaction and empowerment of national patient organizations to enhance the appropriate use of valued FDCs and limit the prescribing/use of FDCs where there are clinical and other concerns Enforce legislation and monitor activities to reduce or negate non-prescription sales of FDCs especially where concerns with their rationality

B) Economic Tougher hurdles for pricing/reimbursement considerations to reduce reimbursement/listing of FDCs of limited clinical value as well as unjustifiably higher prices than the components combined

FDC = Fixed Dose Combination; LMICs = Lower- and Middle-Income countries

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