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Combination drug

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(Redirected from Fixed-dose combination)
This article is about fixed drug combinations as treatments. For two synergistic drugs chemically linked together, see codrug.

A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form.[1] Terms like "combination drug" or "combination drug product" can be common shorthand for an FDC product (since most combination drug products are currently FDCs), although the latter is more precise if in fact referring to a mass-produced product having a predetermined combination of drugs and respective dosages (as opposed to customized polypharmacy via compounding[2]). And it should also be distinguished from the term "combination product" in medical contexts, which without further specification can refer to products that combine different types of medical products—such as device/drug combinations as opposed to drug/drug combinations.[3] When a combination drug product (whether fixed-dose or not) is a "pill" (i.e., a tablet or capsule), then it may also be a kind of "polypill" or combopill.

Initially, fixed-dose combination drug products were developed to target a single disease (such as with antiretroviral FDCs used against AIDS). However, FDCs may also target multiple diseases/conditions. In cases of FDCs targeting multiple conditions, such conditions might often be related—in order to increase the number of prospective patients who might be likely to use a given FDC product. This is because each FDC product is mass-produced, and thus typically requires having a critical mass of potentially applicable patients in order to justify its manufacture, distribution, stocking, etc.

Common combination drugs

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See also: Codrug § Common codrugs, and Synergy § Drug synergy
For more common combination drugs, see WHO Model List of Essential Medicines.

Over-the-counter (OTC) medicines

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For sale over the counter to any adult of legal age.

Behind-the-counter medicines

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In the United States, all combination drugs containing ephedrine or pseudoephedrine are stored behind the pharmacy counter per the Combat Methamphetamine Epidemic Act of 2005. Such products are indicated for treating congestion, cough, cold, flu, and allergy, and include:

Prescription drugs

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The following are prescription drugs in most countries, although the specific accessibility of a given product may vary by country, as noted.

Formerly Available Combination Drugs

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CNS stimulant(s) and CNS depressant(s)

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  • Appetrol – 5mg dextroamphetamine and 400mg meprobamate
  • BamaDex – 6mg dextroamphetamine and 400mg meprobamate

CNS Stimulants

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CNS Depressants

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CNS Stimulant and Typical Antipsychotic

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  • Eskatrol was commonly prescribed in the U.S. as a weight loss aid comprising dextroamphetamine and prochlorperazine, discontinued 1981

CNS Stimulant and First Generation Antihistamine

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Less Common FDCs with Analgesics, Hormones, Vitamins, Minerals, or Supplements

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CNS Depressant and First Generation Antihistamine

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Medical Use and Justification of Discontinued Combination Drugs

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Most of the combination drugs which have been discontinued since the twentieth century were simultaneously indicated and utilized for treatment of various conditions, with medical use justified as part of a multifaceted, comprehensive approach to patient health care and medical treatment. Central nervous system stimulants (colloquially called "uppers") were used as appetite suppressants, antidepressants, and wakefulness-promoting agents, and further effects include increased mental alertness and concentration/focus, as well as physical energy and motivation. The addition of a CNS depressant mitigated the stimulant's adverse effects without eliminating therapeutic benefits. In most cases, the "upper" component of these combination drugs was a salt, or mixed salts, of racemic amphetamine, dextroamphetamine, or methamphetamine, while the "downer" was typically one or more barbiturates (most commonly amobarbital, phenobarbital, pentobarbital, and/or secobarbital) or similar GABAergic, non-barbiturate tranquilizers or sedatives, frequently meprobamate or methaqualone, respectively, which provided anxiolytic, muscle relaxant, and hypnotic effects. Upper and downer combination drugs were often capable of substituting for Monoamine Oxidase Inhibitors (MAOIs) in patients with treatment-resistant depression where MAOIs are indicated, but where patients were unlikely to comply with dietary restrictions on tyramine necessary the MAOI class of medications.

Advantages and Disadvantages
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Fixed-dose combination (FDC) drug products, or combination drugs and polypills generally, include such advantages and disadvantages as:

  • Combination drugs are reviewed by regulatory agencies, such as the U.S. Food and Drug Administration (FDA) before receiving approval to be marketed, thus reducing the probability of adverse drug interactions among a combination product's individual ingredients.
  • FDC drug products may be developed by a pharmaceutical company as a way to effectively extend proprietary rights, if not exclusivity or a monopoly, on producing a specific formulation or product, even if individual active ingredients may be off-patent.
  • There may not be an FDC available with the appropriate drug strengths/dosages for a given patient, which risks some patients getting too much of an ingredient and others getting too little. As noted by the American Association of Optometry (AAO) notes, fixed-dose combinations "limit clinicians' ability to customize dosing regimens."[8] A potential solution to this includes custom-compounded FDC drugs and/or polypills prepared via pharmaceutical compounding, allowing a compounding pharmacist to prepare and dispense drug products specifically tailored for individual patients, assisting polypharmacy.
  • If an FDC results in an adverse drug reaction, it may be difficult to identify the active ingredient responsible for causing the reaction. This can be avoided by starting each medication individually and monitoring for reactions, prior to transitioning to an FDC.
  • Scientists formulating combination drugs face challenges in the development stages of multi-drug formulations such as compatibility issues among active ingredients and excipients affecting solubility and dissolution[9]
  • For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[10]
  • A patient's drug and dosage counts may vary depending on whether the patient or clinician counts a combination product as a single drug, or if a formulation's individual active ingredient are accounted. A patient ingesting numerous active ingredients might not be considered to be engaged in [[polypharmacy if they use a combination product consisting of multiple ingredients, but counted as one drug.[11]

References

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  1. ^ Collier, Roger (2012). "Reducing the "pill burden"". Canadian Medical Association Journal. 184 (2): E117 – E118. doi:10.1503/cmaj.109-4076. PMC 3273525. PMID 22231682.
  2. ^ "5-in-1 PolyPill Treatment May Prevent Heart Disease"[1] Archived 2014-02-27 at the Wayback Machine, BAYVIEW PHARMACY'S PRESCRIPTION COMPOUNDING BLOG,Apr 01, 2009 @ 08:09 AM.
  3. ^ Combination Products-U.S. Food and Drug Administration
  4. ^ added citation for Ebselcaps
  5. ^ https://www.reddit.com/r/ObscureDrugs/comments/hk0tlu/crazy_old_amphetamines_combinations_this_ones_was/ a polypill
  6. ^ https://www.worthpoint.com/worthopedia/amphaplex-10-methamphetamine-1825423307 antique vial
  7. ^ https://www.jodrugs.com/tradenames/167408-vernate.aspx
  8. ^ Peter A. Netland,"Glaucoma Medical Therapy-Principles and Management"
  9. ^ Mitra, Amitava; Wu, Yunhui (September 2012). "Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products". The AAPS Journal. 14 (3): 646–655. doi:10.1208/s12248-012-9378-x. ISSN 1550-7416. PMC 3385830. PMID 22684403.
  10. ^ Kennedy Seele, 2020 [full citation needed]
  11. ^ Lee, GB; Hosking, SM; Etherton-Beer, C; Pasco, JA; Williams, LJ; Holloway-Kew, K; Page, AT (February 2025). "Defining polypharmacy in older adults: a cross-sectional comparison of prevalence estimates calculated according to active ingredient and unique product counts". International Journal of Clinical Pharmacy. doi:10.1007/s11096-025-01882-7.
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