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Combination drug

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This article is about fixed-dose combination drugs and polypills as treatments. For two synergistic drugs chemically linked together, see codrug. For use of multiple separate and individual drugs for treatment, see polypharmacy. For drug combined with a separate device or form, see combination product (medical).

A combination drug is a medication composed of two or more prescription or over the counter drugs as active ingredients in a single dosage form, generally in the form of a fixed-dose combination, whereby each active component comprises an exact, standardized dosage with the combination. Fixed-dose combination drugs are produced and marketed on a grand scale, intended to serve as a near universal treatment for a large patient population with diverse medical histories, conditions, predisposition thereof, and treatment requirements. A polypill is a pharmacy or capsule containing four or more active ingredients[1][2], often needing to be compounded at a specialized pharmacy in order to satisfy a patient's medical prescription (e.g. dosage form, dose, and/or mechanism/action of release ias part of the individual's overall care and personalized treatment plan. Polypills encompass approved prescription drugs, over the counter drugs, as well as nutritional supplements, amino acids, vitamins, minerals, and hormones as necessary.[3]

Background and concept of plural medication in singular form

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Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV.[4]

The concept of combination drugs has come to include reducing pill burden for patients, thereby encouraging patient compliance, and generally simplifying treatment plan with one product containing easily accessible (often available over the counter without a prescription requirement), relatively affordable (often generic drugs) ingredients with established therapeutic efficacy and a broad capacity for treating a variety of symptoms and conditions, thus ensuring maximum appeal to a majority of patients amongst a large population with varying needs.

Common combination drugs currently used worldwide

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Examples of over the counter (OTC), thus easily accessible, combination drugs able to relieve multiple symptoms often include, at minimum, a nonsteroidal anti-inflammatory drug (NSAID), a chemical class of drugs with anti-inflammatory and analgesic effects, able to temporarily alleviate mild pain from osteoarthritis, inflammation, and swelling, and to a lesser degree, localized pain, such as neck, shoulder, back, and joint pains, as well as various forms of headache. Excedrin is an OTC fixed-dose combination drug specifically marketed as a treatment for tension and cluster headaches, and it pairs aspirin (an NSAID) with caffeine (a mild psychostimulant with headacheache-relieving properties in its own right,[5] along with paracetamol (also known as acetaminophen), primarily a fever reducer without anti-inflammatory properties, with limited and inconsistent analgesic effect on its own). With aspirin fighting inflammation, caffeine causing vasoconstriction of blood vessels in the brain, and acetaminophen exhibiting synergy and potentiating the other two substances, this combination is a well-known, easily accessible, OTC, and commonly-used fixed-dose combination.

Amongst the NSAID class of drugs, aspirin is particularly cardioprotective, with proven efficacy as an anticoagulant blood thinner and associated with lower risk of cardiovascular disease, heart attack, and stroke.[6] It could therefore be argued that the inclusion of aspirin, in particular, in products like Excedrin or Anacin (a combination of 400mg aspirin and 32mg caffeine, sans acetaminophen), may further work as a preventative or treatment in patients with headaches and inflammation, in addition to cardiovascular issues.

Current prescription combination drugs

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For more common combination drugs, see WHO Model List of Essential Medicines.

The combination drugs listed below are typically available by prescription only, but specific circumstances regarding a given combination's legal accessibility, or any specific regulation pertinent to ingredient quality, quantities, production standards, sourcing, etc. will vary by jurisdictions, and include:








Over-the-counter combination drugs

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Fixed-dose combination drugs for sale over the counter internationally, including medicine indicated for various purposes:

Indications: GI upset, GERD, nausea, vomiting, acid reflux, heartburn

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treating motion sickness, nausea, and vomiting, and well as allergy symptoms, including:

In the United States, any of the products listed below containing ephedrine or pseudoephedrine are not prescription drugs, but they are stored behind the pharmacy counter, and requires additional steps to complete purchase of these products per U.S. federal law, the Combat Methamphetamine Epidemic Act of 2005:[13]

Combinations drugs for veterinary use

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Limitations of currently-available combinations

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The limitations of combination formulations currently available for treating a widely-inclusive collection of symptoms such as Tourette's is highlighted by there not being a polypill or any combination formula period approved for treating the condition. Medication available, and sometimes used in the context of polypharmacy involves various individual medicines for treating tics and/or generalized anxiety or social anxiety disorder and/or obsessive-compulsive anxieties with use of individual benzodiazepines or SSRIs for the former two conditions, and fluvoxamine or clomipramine first-line treatments for OCD and related disorders, such as hoarding or compulsive decluttering. But, where Attention-Deficit Hyperactivity Disorder, depression, or insomnia become a primary concern to the patient, it is only through polypharmacy (in this case, adding another antidepressant or a "booster, alongside a hypnotic soporific agent, and/or psychostimulants to both treat ADHD and counteract the sleep inertia, grogginess or hangover caused by the other evening medications).

Tourette syndrome is a neurological tic disorder whose only FDA-approved treatment is the neuroleptic pimozide, a drug only used for tics due Tourette's disorder; every other treatment is an off-label use. While Tourette's is typically identified by chronic motor and vocal tics–"semi-voluntary" movements and noises made in response to a "premonitory urge," an internal buildup of compulsive tension that can only be temporarily upon performing/making the motion/sound demanded by compulsion. Tourette's, however, is an all-encompassing umbrella term that includes not just chronic physical and phonic tics, but also presents with such comorbid symptoms as anxiety (often OCD, social anxiety, schizoid personality, avoidant personality disorder, or generalized anxiety), ADHD, insomnia, depression, and traits of high-functioning autism formerly called Asperger syndrome.

Formerly available, discontinued combination drugs

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Central nervous system stimulants or sympathomimetics and central nervous system depressants

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Central nervous system stimulants

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Central nervous system stimulants and first generation antihistamines

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Central nervous system stimulant and typical antipsychotics

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Central nervous system depressants

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Central nervous system depressants and first generation antihistamines

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Other formulations

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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 central nervous system 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 MAOI-related dietary restrictions would impact patient's life.

Advantages and disadvantages

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There are advantages and disadvantages of combination drug therapy, including using fixed-dose combination drugs and/or polypills, as opposed to partaking in polypharmacy and increasing one's pill burden by keeping track of an organized schedule or any FDCD with 2, 3, or 4 active ingredients, relative to the concept of polypharmacy. Overall, giving patients the ability to take control and alleviate symptoms, and potentially treat or cure multiple conditions by consuming all of their medical treatments efficacious treatment options by the ingestion of a single pill, which consistently improves patient medication compliance by reducing their pill burden. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."[34] AAO states their organizational position is that custom-compounded fixed-dose combination drugs, as well as compounded polypills are superior to mass-marketed, mass-manufactured, one size fits all style treatment. 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[35] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[36][37]

Illicit streets as de facto drug combinations

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Illicit stimulants

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Illicit combination drugs are often formulated as a powder, paste, or counterfeit "pressed" pills intended to resemble their pharmaceutical-grade counterparts. Since 2018, ABC News of Houston reports that product described as "powder cocaine" originating from a clandestine laboratory are increasingly analyzed and found to contain other stimulants, in order to mimic cocaine's effects in a cost-effective, deceptive manner; many of the batches analyzed did not contain any cocaine or coca alkaloids whatsoever; instead, they were blends of various designer drugs, research chemicals, methamphetamine, and/or various amphetamines, derivatives, analogues; MDMA, caffeine powder, ephedrine or pseudoephedrine; levamisole, a flesh-eating veterinary antibiotic[38]

Illicit depressants and opiates

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Due to the crackdown of pill mills between 2007-2012, the opioid epidemic now includes preparations declared to be "heroin" or "pressed" replica pills of hydrocodone (sold Norco or LorTab); oxycodone (sold as Percocet), yet are rarely pure in their ingredient compositions. Cutting agents have grown in proportion to the overall composition of these products, such that "heroin" has been cut and mixed with central nervous system depressants including major tranquilizers such as quetiapine; muscle relaxants like carisoprodol or cyclobenzaprine; first-generation antihistamines like diphenhydramine or hydroxyzine); and benzodiazepine derivative and analogue research chemicals, including gidazepam, pinazepam, clobromazolam, etizolam). Since 2020, there has been a noticeable rise amongst active ingredients in opioid combinations containing fentanyl (more potent than heroin), and increasingly, carfentanil (an elephant and rhinoceros tranquilizer more potent than fentanyl).

Since 2023, worldwide samples of illicit combinations featuring opioids have contained the most lethal known substance to date: those belong to the nitazene chemical class.[39] have been found in these opioid samples– all of which mimic the muscle relaxant, anxiolytic, and analgesic properties of pharmaceutical-grade opioid medications. U.S. Attorney General has indicated interested in federally regulating the relative mild veterinary sedative xylazine, which is currently available by prescription only, as a federally-controlled Schedule III controlled substance per the Controlled Substances Act,[40] a direct response to its implication in overdose deaths featured in products alongside fentanyl and other power central nervous system depressants; xylazine is currently a controlled substance at the state level in Michigan and New York.[41]

See also

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Notes

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  1. ^ Bontril Timed is distinct from, and unrelated to, Bontril and Bontril PDM–common brand names of phendimetrazine.

References

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  3. ^ https://thecompounder.com/amino-acids-minerals-nutrients-vitamins/
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  5. ^ "The caffeine connection between coffee and headaches | UCLA Health". www.uclahealth.org. Retrieved 2025-04-24.
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  20. ^ Bartholomew, Arthur Allen (A.A.) (1970). "Amphetamine addiction". Medical Journal of Australia. 1 (24): pp.1209-1214. {{cite journal}}: |access-date= requires |url= (help); |page= has extra text (help); Check date values in: |access-date= (help)
  21. ^ "Esbelcaps (International database)". Drugs.com. Retrieved 2025-04-24.
  22. ^ "Pharmacy Drugstore Obotan Forte Dextroamphetamine Tannate Mallinckrodt". Worthpoint. Retrieved 2025-04-24.
  23. ^ https://pubchem.ncbi.nlm.nih.gov/compound/Dextroamphetamine-tannateBig text Tanphetamin brand of dexamfetamine tannate
  24. ^ Gilman, A.G., T.W. Rall, A.S. Nies and P. Taylor (eds.). Goodman and Gilman's The Pharmacological Basis of Therapeutics. 8th ed. New York, NY. Pergamon Press, 1990., p. 368
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  26. ^ "Amphaplex 10 methamphetamine amphetamine Palmedics Bottle narcotic empty | #1825423307". Worthpoint. Retrieved 2025-04-24.
  27. ^ "Bontril Timed #1 by CARNRICK Laboratories". JODrugs.
  28. ^ Kolata, Gina (1997-09-23). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". The New York Times. ISSN 0362-4331. Retrieved 2025-04-24.
  29. ^ Rasmussen, Nicolas (June 2008). "America's first amphetamine epidemic 1929-1971: a quantitative and qualitative retrospective with implications for the present". American Journal of Public Health. 98 (6): 974–985. doi:10.2105/AJPH.2007.110593. ISSN 1541-0048. PMC 2377281. PMID 18445805.
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  36. ^ Kennedy Seele, 2020 November 12
  37. ^ 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. PMID 39954222.
  38. ^ "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". ABC News. Retrieved 2025-04-24.
  39. ^ "News: February 2025 – UNODC EWA: Increasing availability of nitazenes calls for global response". www.unodc.org. Retrieved 2025-04-24.
  40. ^ "Xylazine: What Clinicians Need to Know" (PDF). www.health.ny.gov.
  41. ^ "Diversion Control Division | Xylazine". www.deadiversion.usdoj.gov. Retrieved 2025-04-24.
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