View source for Category:Fixed-dose combinations

A '''fixed-dose combination''' (FDC) is a single dosage form (tablet, capsule, inhaler, transdermal patch, injectable) that contains two or more active medicines in fixed proportions. The category is structural rather than mechanistic: an FDC is defined by the formulation, not by the pharmacology of its components, and FDCs exist across essentially every therapeutic area. The clinical rationale is consistent across the category: simplification of a multi-medicine regimen into a single daily intake, with corresponding improvement in adherence; a defined ratio between two components that produces complementary or additive effects; and (in selected cases) regulatory or pricing simplification.

The pharmacology of combination medicines has a long pre-history. Galenic pharmacy combined active substances with vehicles, solvents, and other actives in proportions chosen by the prescriber, and the resulting compounded preparations were the rule rather than the exception in medical practice up to the mid-twentieth century. The shift toward proprietary single-active medicines after the [[wikipedia:Pure Food and Drug Act|1906 Pure Food and Drug Act]] made combination products a regulated subset of the pharmacopoeia, requiring justification of both the choice of components and the chosen ratio. The modern fixed-dose combination is therefore a deliberate clinical-pharmacology product, in contrast to the historical compounded mixture.

The transformative event of the FDC was probably the antitubercular combination tablet. The standard four-medicine intensive-phase regimen for [[wikipedia:Tuberculosis|tuberculosis]] (rifampin, isoniazid, pyrazinamide, ethambutol) involved a pill burden of more than ten tablets per day taken for two months, with the recognised risk that any one component might be missed and that selective monotherapy would rapidly produce resistance. The WHO endorsed in 1994 a single-tablet four-medicine FDC (Rifater plus ethambutol, then later the unified Rifater-E and successor formulations) and a two-medicine continuation tablet, and the combination tablets became the global standard for first-line tuberculosis treatment. The adherence and resistance benefit was substantial.

The HIV story is parallel and even more striking. Triple-combination [[wikipedia:Antiretroviral therapy|antiretroviral therapy]] had been the standard of care since 1996 but required, in the first decade, the swallowing of fifteen or more tablets per day on a complex schedule with multiple food restrictions. The first complete-regimen single-tablet FDC, [[wikipedia:Atripla|Atripla]] (efavirenz/emtricitabine/tenofovir disoproxil fumarate, Gilead/BMS, 2006), simplified HIV treatment to one tablet once daily.<ref name="airoldi2006">Airoldi M, Zaccarelli M, Bisi L, Bini T, Antinori A, Mussini C, Bai F, Orofino G, Sighinolfi L, Gori A, et al. One-pill once-a-day HAART: a simplification strategy that improves adherence and quality of life of HIV-infected subjects. ''Patient Preference and Adherence''. 2010 Jul 21;4:115-125. PMID 20694047.</ref> Subsequent single-tablet regimens (Complera, Stribild, Genvoya, Triumeq, Biktarvy, Dovato) refined the chemistry, reduced the toxicity profile, and now define the contemporary standard of care; the related two-medicine maintenance combinations (Juluca: dolutegravir/rilpivirine; Cabenuva: long-acting injectable cabotegravir/rilpivirine) extend the concept.

The cardiovascular polypill is a more recent and ongoing project. The 2003 proposal of [[wikipedia:Nicholas Wald|Nicholas Wald]] and [[wikipedia:Malcolm Law|Malcolm Law]] that a single tablet containing a statin, three half-dose antihypertensives, low-dose aspirin, and folic acid could reduce cardiovascular events by approximately 80 percent in primary prevention populations was provocative;<ref name="wald2003">Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. ''British Medical Journal''. 2003 Jun 28;326(7404):1419. PMID 12829553.</ref> the subsequent SECURE and TIPS trials in 2015-2022 demonstrated meaningful but more modest cardiovascular benefit in secondary prevention with combination tablets of aspirin, atorvastatin, and an ACE inhibitor (Sincro, the polypill product approved in Europe and several other jurisdictions). The cardiovascular FDC field is now extensive: the antihypertensive combinations ([[wikipedia:Lisinopril/hydrochlorothiazide|lisinopril/HCTZ]], [[wikipedia:Valsartan/hydrochlorothiazide|valsartan/HCTZ]], amlodipine/valsartan, and the triple amlodipine/valsartan/HCTZ); the cardiovascular-prevention combinations sacubitril/valsartan ([[wikipedia:Entresto|Entresto]], the first ARNI for heart failure) and ezetimibe/atorvastatin and ezetimibe/rosuvastatin.

The diabetes FDC pharmacopoeia has expanded equivalently. Combinations of metformin with sulfonylureas, with DPP-4 inhibitors (Janumet: sitagliptin/metformin; Komboglyze: saxagliptin/metformin), with SGLT2 inhibitors (Synjardy: empagliflozin/metformin; Xigduo: dapagliflozin/metformin), and with GLP-1 receptor agonists (Soliqua: insulin glargine/lixisenatide; Xultophy: insulin degludec/liraglutide) reduce the polypharmacy of contemporary diabetes care. The asthma and COPD inhaled FDC category (LABA + inhaled corticosteroid; LABA + LAMA; triple LABA/LAMA/ICS) has been described in the [[:Category:Bronchodilators|bronchodilators]] page; the analgesic FDCs (the codeine-containing combinations, [[wikipedia:Vicodin|Vicodin]] and [[wikipedia:Percocet|Percocet]] and Ultracet, the migraine combinations Fioricet and Fiorinal) and the hormonal contraceptives are also major FDC subsets.

The clinical use of an FDC is not without its drawbacks. The fixed proportions remove the flexibility to titrate one component independently of the other, which is significant when one of the components has narrow renal-dose-adjustment or hepatic-dose-adjustment requirements (the metformin in metformin-containing combinations must be reconsidered at lower eGFR; the DOAC dose in DOAC combinations must be adjusted for age and weight and renal function). The brand-name FDC is often substantially more expensive than the generic component prescription, with no clinical-outcome benefit beyond the convenience of a single tablet. The adherence benefit of an FDC, although real and consistent across trials, is smaller than the adherence benefit of structural simplifications like once-daily versus thrice-daily dosing.

== Selected combinations indexed ==

Not exhaustive; the category is large. A representative sample by therapeutic area:

* '''Antitubercular''': Rifater (rifampin + isoniazid + pyrazinamide), Rifamate (rifampin + isoniazid), four-medicine regimen combinations
* '''Antiretroviral / single-tablet HIV''': [[wikipedia:Atripla|Atripla]], [[wikipedia:Biktarvy|Biktarvy]] (bictegravir + emtricitabine + tenofovir alafenamide), Triumeq (dolutegravir + abacavir + lamivudine), Genvoya, Stribild, Symtuza, Juluca (dolutegravir + rilpivirine), Dovato (dolutegravir + lamivudine), Cabenuva (long-acting injectable cabotegravir + rilpivirine)
* '''Antihypertensive''': lisinopril/HCTZ, losartan/HCTZ, valsartan/HCTZ, olmesartan/HCTZ, amlodipine/benazepril, amlodipine/valsartan, amlodipine/olmesartan, the triple combinations (amlodipine/valsartan/HCTZ, amlodipine/olmesartan/HCTZ); fixed dose calcium channel blocker + ARB + diuretic combinations
* '''Cardiovascular / heart failure''': [[wikipedia:Sacubitril/valsartan|sacubitril/valsartan]] (Entresto, the ARNI); [[wikipedia:Hydralazine/isosorbide dinitrate|isosorbide dinitrate/hydralazine]] (BiDil, the racially defined heart-failure combination); aspirin/clopidogrel
* '''Lipid-lowering''': ezetimibe/atorvastatin, ezetimibe/rosuvastatin, ezetimibe/simvastatin
* '''Antidiabetic''': Janumet (sitagliptin/metformin), Komboglyze (saxagliptin/metformin), Synjardy (empagliflozin/metformin), Xigduo (dapagliflozin/metformin), Glyxambi (empagliflozin/linagliptin), Soliqua (insulin glargine/lixisenatide), Xultophy (insulin degludec/liraglutide)
* '''Inhaled (asthma, COPD)''': Advair/Seretide (fluticasone/salmeterol), Symbicort (budesonide/formoterol), Anoro Ellipta (umeclidinium/vilanterol), Trelegy Ellipta (fluticasone/umeclidinium/vilanterol), Breztri Aerosphere (budesonide/glycopyrronium/formoterol)
* '''Analgesic''': [[wikipedia:Vicodin|Vicodin]] (hydrocodone + acetaminophen), [[wikipedia:Percocet|Percocet]] (oxycodone + acetaminophen), Percodan (oxycodone + aspirin), Ultracet (tramadol + acetaminophen), [[wikipedia:Tylenol with codeine|Tylenol with Codeine]], Fioricet (butalbital + acetaminophen + caffeine), Fiorinal (butalbital + aspirin + caffeine), Excedrin (aspirin + acetaminophen + caffeine)
* '''Hormonal contraceptives''' (collected separately under [[:Category:Hormonal_contraceptives|hormonal contraceptives]] and at the individual combination-product pages)
* '''Anti-infective combinations''': trimethoprim/sulfamethoxazole (Bactrim, Septra), amoxicillin/clavulanic acid (Augmentin), piperacillin/tazobactam (Zosyn), ceftazidime/avibactam, ceftolozane/tazobactam, imipenem/cilastatin/relebactam, sulbactam/durlobactam
* '''Antiulcer / proton-pump inhibitor combinations''': Vimovo (esomeprazole + naproxen), Yosprala (omeprazole + aspirin, for cardiovascular prevention with gastric protection)
* '''Vaccines and immunisations''': the combined-pediatric and combined-adult vaccines (DTaP, MMR, MMRV, hepatitis A + B, MenACWY, the COVID-influenza combination vaccines under development)

== Notes on scope ==

The boundary of this category is "medicine formulation that contains two or more active medicines in fixed proportions." The compounded prescriptions tailored to an individual patient are not FDCs in this category sense; they are individual-prescriber preparations rather than approved fixed-dose products. The "combination therapy" of two separately prescribed medicines is also not an FDC unless the two medicines have been co-formulated. Multi-vitamin preparations and the various herbal-supplement combinations are not regulated as fixed-dose combination medicines in the United States and are not collected here. The combination contrast media (the iodinated contrast agents that mix two iodine-containing molecules) are diagnostic agents rather than therapeutic medicines and are not in this category. Several FDC products have been withdrawn over the years because of disproportionate toxicity attributed to the combination (the appetite suppressant Fen-phen, the analgesic Darvocet) or because of regulatory restrictions on the components; the historical FDCs are mentioned on their corresponding medicine pages where they illustrate principles of the category.

== About these pages ==

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.

== References ==

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