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Combination drug

From Wikipedia, the free encyclopedia
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.

United States

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India

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Discontinued Combination Drugs

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CNS stimulant(s) and CNS depressant(s)

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Duplicate CNS Stimulants

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  • Amphaplex 10 (methamphetamine saccharate, 2.5mg/methamphetamine Hcl, 2.5mg/amphetamine sulfate, 2.5mg/dextroamphetamine sulfate, 2.5mg)[5]
  • Amphaplex 20 (methamphetamine saccharate, 5mg/methamphetamine Hcl, 5mg/amphetamine sulfate, 5mg/dextroamphetamine sulfate, 5mg)
  • Obetrol (methamphetamine/dextroamphetamine), discontinued 1973
  • Pondimin, informally "fen-phen" (fenfluramine/phentermine), discontinued 1998 – treatment of obesity

Duplicate CNS Depressants

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  • Tuinal (secobarbital/amobarbital), discontinued 1999[citation needed] – treatment of insomnia
  • Mandrax (methaqualone/diphenhydramine)

CNS Stimulant and First Generation Antipsychotic

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CNS Stimulant and First Generation Antihistamine

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CNS Stimulant and CNS Depressant with Analgesic (pain reliever)

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  • Artogesic (dextroamphetamine/mephobarbital/phenacetin/salicylamide)
  • Dysonil (methamphetamine hydrochloride/pentobarbital sodium/salicylamide)
  • Lamital by Teva Pharmaceuticals (methamphetamine hydrochloride/acetaminophen/amobarbital)
  • Edrisal (Aspirin 160mg, Phenacetin 160mg, and Amphetamine Sulfate 2.5mg
  • Edrisal with Codeine - Aspirin 160mg, Phenacetin 160mg, Amphetamine Sulfate 2.5mg, and Codeine 16mg

Stimulant-Depressant with Vitamins, Amino Acids, Alkaloids, Enzymes, and Hormones

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Medical Use of Discontinued Combination Drugs

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Most of the combination drugs which have been discontinued since the twentieth century had diverse indications for treatment and were justified for medical use in the context of a multifaceted, comprehensive approach to patient treatment. CNS stimulants (colloquially called "uppers") were used as appetite suppressants, antidepressants, wakefulness-promoting agents, in addition to improving and increasing alertness, energy, motivation, and focus. Meanwhile, the CNS depressants mitigated the stimulant's adverse effects without eliminating therapeutic benefits.

The "upper" component of most stimulant-depressant combinations was typically racemic amphetamine, dextroamphetamine, or methamphetamine in the form of either a single hydrochloride salt or mixed salts. The "downer" component was usually a single barbiturate salt (often pentobarbital sodium or amobarbital), albeit some combination formulations similar-acting, non-barbiturate, tranquilizers like meprobamate) or sedatives including methaqualone or chloral hydrate.

Such combinations were found able to of replacing Monoamine Oxidase Inhibitors in patients with treatment-resistant depression where MAOIs are indicated but compliance with necessary MAOI-related dietary restrictions was unlikely. Non-barbiturate Sedative-Hypnotic with a first-generation antihistamine, e.g. Mandrax (methaqualone/diphenhydramine) in South Africa

Advantages

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In addition to simply being a means of facilitating the general advantages of combination therapy, specific advantages of fixed-dose combination (FDC) drug products include:

  • Improved medication compliance by reducing the pill burden of patients. Pill burden is not only the number of pills needing to be taken, but also the associated burdens such as keeping track of several medications, understanding their various instructions, etc.
  • Ability to compose combined profiles of for example pharmacokinetics, effects and adverse effects that may be specific for the relative dosages in a given FDC product, providing a simpler overview compared to when looking at the profiles of each single drug individually. Such combined profiles can also include effects caused by interaction between the individual drugs that may be omitted in individual drug profiles.
  • Since FDCs are reviewed by regulating agencies (such as the Food and Drug Administration in the United States), the active ingredients used in the FDCs are unlikely to exhibit adverse drug interactions with each other. However, FDCs may interact with other drugs that a patient is taking, so the usual medical and pharmaceutical precautions against drug-drug interactions or DDIs remain warranted.
  • FDC drug products may be developed by a pharmaceutical company as a way to in effect extend proprietary rights and marketability of a drug product. Since FDCs may be protected by patents, a company may obtain exclusive rights to sell a particular FDC or formulation thereof, even though the individual active ingredients and many therapeutic uses thereof may be off-patent.

Disadvantages

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  • There may not be an FDC available with the appropriate drugs and/or in the most appropriate respective strength(s) for a given patient, which can lead to some patients getting too much of an ingredient and others getting too little, as the AAO notes that FDCs "limit clinicians' ability to customize dosing regimens."[7] In such cases an alternative possibility (instead of an FDC) is to use custom-compounded polypills prepared by a compounding pharmacist according to a prescription. (Pharmaceutical compounding is the practice of preparing individualized drug products for individual patients, which can aid with polypharmacy.)
  • If an adverse drug reaction occurs from using an FDC, it may be difficult to identify the active ingredient responsible for causing the reaction. This problem might be alleviated by starting the medications individually and monitoring for reactions, and then switching to an FDC when no problems have been observed (assuming of course that it's the active ingredient causing the problem).
  • Formulation scientists experience challenges in the development stages of multi-drug formulations such as compatibility issues among active ingredients and excipients affecting solubility and dissolution[8]
  • If one drug is contraindicated for a patient, whole FDC cannot be prescribed.[9]
  • Those who used combination drugs may have different total drug counts depending on whether unique preparations or active ingredients are counted. As such, someone who takes five or more active ingredients may not be captured as having polypharmacy if they use combination drugs and only the number of preparations is counted.[10]

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. ^ https://www.reddit.com/r/ObscureDrugs/comments/hk0tlu/crazy_old_amphetamines_combinations_this_ones_was/ alternatively referred to as "Diacels," this FDC qualifies as a polypill
  5. ^ https://www.worthpoint.com/worthopedia/amphaplex-10-methamphetamine-1825423307 antique vial
  6. ^ https://www.jodrugs.com/tradenames/167408-vernate.aspx
  7. ^ Peter A. Netland,"Glaucoma Medical Therapy-Principles and Management"
  8. ^ 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.
  9. ^ Kennedy Seele, 2020 [full citation needed]
  10. ^ 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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