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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 medical device or product, e.g. insulin pump, nicotine patch, see combination product (medical).
See also: Codrug § Common codrugs, and Synergy § Drug synergy

A combination drug is a pharmaceutical formulation combining multiple active ingredients into a single dosage form. Sub-types:

  • A fixed-dose combination combines two or more specific substances at predetermined, exactified, and unchanging doses, mass-produced and mass-marketed to a large patient population, based on the concept of reducing the pill burden of patients, trying to size a product similar to an effective one size fits all comprehensive treatment plan, involving the use of pharmaceutical-grade, standardized medications capable of treating multiple and differing symptoms, often co-occuring with each other The ideal is to find the perfect mix at the ideal doses to effectively treat symptoms of any person seeking treatment of multiple concerns with one solution. This combination has a long history of use and, while side effects are unavoidable, fixed-dose combination are unlikely to elicit adverse reactions, or contribute to drug interactions or contraindicateds due to the rigorous process of getting a drug approved to be marketed, distributed, prescribed, and sold. Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicatedfor treatment of AIDS.[citation needed] FDC drugs may also target multiple symptoms and medical conditions, often comorbid to each other, yet requiring different treatments.[citation needed]
  • A combopill is a polypill (tablet or capsule intended for oral administration) composed of four or more active ingredients[1] and often, but not always, a fixed-dose combination.[citation needed] While all fixed-dose combination drugs and polypills are "combination drugs" by definition, a "combination drug" is not necessarily a polypill. In contrast to a fixed-dose combination, polypill formulations are custom-prepared and compounded, with ingredients and dosing catered to an individual patient's needs and their personalized medical prescription, including prescription drugs, over the counter drugs, and a variety of nutritional or dietary supplements, like essential minerals, multivitamin complex, amino acids, antioxidants, enzymes, and/or hormones.

Concept of treating multiple symptoms with one combination drug

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Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most widely used class of pain relieverss in the world, indicated for the temporary relief of minor aches and pain caused by, or co-occurring with, inflammation. NSAIDs are typically sold over the counter including ibuprofen (Advil, Motrin), Aspirin, and naproxen (Aleve). Aspirin has additional anticoagulant cardioprotective properties, reducing blood clotting and lowering one's risk of heart attack or stroke. Paracetamol (acetaminophen) is mainly a fever reducer and does not possess anti-inflammatory properties, yet some patients find it to work equally to, or better than, NSAIDs and other angelsics with regard to easing aches, an effect that may be potentiated, boosted, or strengthened when it is used with another analgesic, whether NSAIDs or celecoxib, gabapentin or duloxetine (off-label for nerve pain); all of them are indicated for pain relief of some sort, whether a headache, arthritis pains, or nerve pain, or chronic widespread pain, both chronic and acute. Theoretically, the combination will potentiate and strengthen the efficacy of each other. A combination such as Advil Dual Action with Acetaminophen can simplify treatment for a patient experiencing body aches and joint pain from inflammation, or are suffering fever and related lethargy and fatigue. Caffeine is a common choice for this type of FDC as it can counteract lethargy by mildly boosting wakefulness, alertness, and mood, in addition to hsving proven efficacy treating tension headaches, due to its vasoconstricting profile, plus its synergistic activity between caffeine and other analgesics.[2] As such, the FDC drug Excedrin happens to work for many of such symptoms.

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 generally available by prescription only in most areas of the world; specific circumstances pertaining to accessibility and availability of these products will vary, contingent upon the national, regional (provincial, state, county, or territorial), tribal, and local, municipal jurisdictions:

Indications: ADHD, Obesity, Narcolepsy, Fatigue, Lethargy

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Indications: Cold, Flu, GI Distress, Severe Cough, and COVID-19

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Rondec, Coldec, Ceron () - a combination

Indication: Opthalmalogic Preservation of eye sight, Retinal-protectant

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Indication: Antibiotic Treatment

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Indication: Hypertension, Stroke, Heart Disease, Heart Failure, Cholesterol disorder

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Amlodipine/valsartan, sold under the brand name Exforge

Indications: Psychiatric, Depression, Anxieties, Bipolar I and II, Psychosis, Schizoid, Insomnia

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Indications: Analgesia, Chronic, Severe Pain

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Opioid as the primary therapeutic component, with a non-opioid

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Non-Opioids as the primary therapeutic analgesic

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Over-the-counter (OTC) Combination Drugs

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

Indications: Nausea and vomiting

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

Indications: Insomnia and/or concurrent aches and pain

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Indications: Heartburn, Acid Reflux, GERD

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Indications: Cough, cold, congestion, flu, allergy

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The following medications consist of a variety of active ingredients indicated for cough (cough suppressants), congestion (expectorants and nasal decongestant, antihistamines, and/or an antipyretic (fever-reducing agent]]. 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:[4]

Combinations for Veterinary Use (including OTC and RX)

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Indication: antipruritic, antihistamine

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Titezol' Tiletamine major antipsychotic neuroleptic tranquilizer) and zolazepam (benzodiazepine-like major tranquilizer) combination of medicines used to tranquilize [[[9]

Limitations of currently-available combination drugs

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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 (often a neuroleptic) and/or generalized or social anxiety (e.g. benzodiazepines or SSRIs) and/or obsessive-compulsive disorder (OCD) (nearly always fluvoxamine or clomipramine and anxiety-like compulsions such as 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 9grogginess 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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CNS stimulants or sympathomimetics and CNS depressants

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[12][13]https://www.usitc.gov/publications/docs/tata/hts/bychapter/0800chemappx.pdf Dextroamphetamine tannate was still listed as an activeely imported product according to this tariff list from 2008, albeit very rarely.

CNS stimulants

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CNS stimulants and first generation antihistamines (FGAs)

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CNS stimulant and typical antipsychotics

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CNS depressants

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CNS 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 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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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. Polypharmacy, however, is the recommended starting practice, as taking individual forms (pills, capsules, tincture, etc.) of distinct medication allows the patient to see what the specific direct results and adverse effects from a single active ingredient may be. After the titration period of at least 4 weeks, the patient is likely safe to begin taking a fixed-dose combination pill or a polypill; it's worth nothing that even patient who have used a specific for months, years, or even decades can theoretically develop an adverse drug reaction at any time, at which point the situation is further complicated because the patient may not recall the difference life before and after consistent dosing of the combo, and if they attempt to discontinue use abruptly, there is the risk of withdrawal symptoms.

The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."[21] 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[22] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[23]

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.[24]

Illicit drug combinations

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Practically illicit "street" drugs are composed of varying, inconsistent, combination of cutting agents, research chemicals, designer drugs, and/or counterfet ingredients effectively functioning as placebo. Ingredient listings may be purposely or mistakenly inaccurate, misstated, and/or deceptive, and can include toxic, if not lethal, doses, of ingredients; one never knows what they will get when ingesting a non-standardized combination of potentially any substance or chemical available to the amateur chemists who formulate these combinations via clandestine chemistry, in clandestine, "underground" laboratories in less than sterile conditions using base ingredients, raw materials, congeners, fillers, binders, and active ingredients of varying quality, quantity, dosage, and purity levels.

Stimulant-based

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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 and research chemicals, including synthetic cathinone; methamphetamine and varying mixtures of racemic amphetamine, its components, derivatives and analogues; MDMA, caffeine powder, ephedrine or pseudoephedrine, fenproporex; levamisole, a flesh-eating veterinary antibiotic[25] sibutramine, yohimbe; a minority of samples products contained over 5% of genuine cocaine, or coca leaf extract.

Depressant-based and/or Opioid-based

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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 CNS 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.[26] 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,[27] a direct response to its implication in overdose deaths featured in products alongside fentanyl and other power CNS depressants; xylazine is currently a controlled substance at the state level in Michigan and New York.[28]

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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  1. ^ "5-in-1 PolyPill Treatment May Prevent Heart Disease", BAYVIEW PHARMACY'S PRESCRIPTION COMPOUNDING BLOG,Apr 01, 2009 @ 08:09 AM.
  2. ^ Caffeine has demonstrated efficacy in relieving tensions headaches: https://www.uclahealth.org/news/article/caffeine-connection-between-coffee-and-headaches
  3. ^ https://www.drugs.com/duexis.html
  4. ^ https://www.deadiversion.usdoj.gov/meth/combat-methamphetamine-epidemic-act.html
  5. ^ "Chlorpheniramine and Phenylpropanolamine Drug Information - Indications, Dosage, Side Effects and Precautions". Medindia. Retrieved 2025-04-15.
  6. ^ https://entertainment.ha.com/itm/music-memorabilia/memorabilia/elvis-presley-owned-prescription-bottle-and-box-1976-total-2-items-/a/7081-46290.s Photograph of a prescription vial containing Vernate Liquid dispensed to Elvis Presley in 1976
  7. ^ https://www.jodrugs.com/tradenames/167408-vernate.aspx
  8. ^ "Label: Coricidin HBP Cold and Flu". DailyMed. December 30, 2021.
  9. ^ https://www.revisor.mn.gov/rules/6800/date/2002
  10. ^ https://www.drugs.com/international/esbelcaps.html?utm_source=chatgpt.com product believed to be largely discontinued
  11. ^ https://www.worthpoint.com/worthopedia/pharmacy-drugstore-obotan-forte-292341330 A picture of OboTan in extended release form at the maximum dose called OboTan Forte for example
  12. ^ https://pubchem.ncbi.nlm.nih.gov/compound/Dextroamphetamine-tannateBig text Tanphetamin brand of dexamfetamine tannate
  13. ^ 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
  14. ^ https://www.worthpoint.com/worthopedia/amphaplex-10-methamphetamine-1825423307 antique vial
  15. ^ https://www.nytimes.com/1997/09/23/science/how-fen-phen-a-diet-miracle-rose-and-fell.html New York Times "How Fen-Phen Rose and Fell" December 1997
  16. ^ https://pmc.ncbi.nlm.nih.gov/articles/PMC2377281/
  17. ^ https://ia601401.us.archive.org/10/items/in.ernet.dli.2015.145028/2015.145028.Side-Effects-Of-Anti-Obesity-Drugs_text.pd Pfizer acquired Roerig in 1953
  18. ^ https://pubchem.ncbi.nlm.nih.gov/compound/Dextroamphetamine-tannate
  19. ^ https://upload.wikimedia.org/wikipedia/commons/9/98/Notices_of_judgment_under_the_Federal_food%2C_drug%2C_and_cosmetic_act_...Drugs_and_devices_%28IA_CAT11088280015%29.pdf
  20. ^ https://sciencehistory.pastperfectonline.com/webobject/4319798D-5DB1-4B3A-92E4-665749368298
  21. ^ Peter A. Netland,"Glaucoma Medical Therapy-Principles and Management"
  22. ^ 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.
  23. ^ Kennedy Seele, 2020 November 12
  24. ^ 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.
  25. ^ https://abcnews.go.com/Health/Wellness/flesh-eating-cocaine-laced-veterinary-drug-levamisole/story?id=13902353
  26. ^ https://www.unodc.org/LSS/Announcement/Details/b47cf39e-f557-4001-98a8-536af5673e9e Nitazene-class substances have more potency than fentanyl and its analogues
  27. ^ https://www.health.ny.gov/publications/12044.pdf
  28. ^ https://www.deadiversion.usdoj.gov/drug_chem_info/xylazine/xylazine.html
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