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Combination drug

Drug with two or more active ingredients From Wikipedia, the free encyclopedia

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This article is about 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.

A combination drug is most simply defined as a chemical composition of at least two drugs combined in a single dosage form, typically as one tablet or one capsule, or a single serving in the case of an elixir or tincture–all of which are intended for oral administration, where as the latter two liquid formulations are designed to be taken orally, but specifically under the tongue. Other forms of such medication include injectable suspensions (e.g. intravenous therapy) or suppository intended for rectal administration. A legitimate, mainstream combination drug that exceeded rigorous laboratory quality standards and been approved for medical use as a pharmaceutical-grade medication is a safe option for treating multiple symptoms or diseases amongst various patients within a large population–and this includes combinations of solely over-the-counter medicine, solely prescription drugs, or any combination of both types. When the pharmaceutical-quality ingredients are supplemented with active ingredients that are relatively unregulated in the United States; as a consequence of the Dietary Supplement and Health Act of 1994, supplements may be of questionable product quality, doubtful accuracy of dosing measurements, mislabeled ingredients, deceptive sourcing claims, and may not fully disclose the relative the true bioavailability of vitamins and minerals (for example, vitamin d3 is superior in efficacy than vitamin d2, whereas forms of magnesium like magnesium glycinate, malate, and magnesium taurate|taurate]] are absorbed much better than magnesium oxide); finally, herbs, herbal extracts, and alkaloids may offer therapeutic benefits, as well as adverse effects pertaining to uncertain toxicity ranges.


A polypill is a specific type of combination drug exclusively in the form of a "pill<" whether a tablet, capsule, caplet, or softgel, containing four or more active ingredients,[1][2] frequently requiring custom preparation at a compounding pharmacy in order to meet the personalized specifications deemed necessary by a patient's medical prescription. Such specificities may include uncommon, unconventional, or unavailable dosage, dosage form, a modified release mechanism, and necessity for a particular speed of onset and/or duration of action. Polypills can encompass four or more of any combination of approved prescription drugs and over the counter drugs, and may also include nutritional supplements, amino acids, enzymes, hormones, vitamins and/or essential minerals.[3]

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Background context

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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] Combination drug treatment conceptually emphasizes simplified treatment plans, reduced pill burden and increased patient compliance by offering accessible and affordable ingredients, generally generic drugs with established therapeutic efficacy, and the ability to treat a variety of symptoms and conditions amongst a large patient population with varying treatment needs.

Current prescription combination drugs

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

The combination drugs listed below are universally 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:[5]

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Combination drugs accessible over the counter

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Combination drugs for sale over the counter (OTC) exist around the world, constituting doses that are tolerable to a mainstream consumer population. In the United States, items containing ephedrine, pseudoephedrine, or phenylpropanolamine can be purchased without a prescription, albeit under strict oversight and from behind the pharmacy counter, per the U.S. Federal drug law titled the Combat Methamphetamine Epidemic Act of 2005.[17] The following combination drugs are accessible OTC in nearly all locations:

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Combination drugs under development

Combinations drugs for veterinary use

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Combination drugs no longer available

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Organized according to the pharmaceutical manufacturer responsible for production and distribution at the time, virtually of which have since been acquired and consolidated by the major pharmaceutical conglomerates of 2025.

Produced by:

Abbott Laboratories, AbbVie

  • Obetrol by Abbott Laboratories was a mixture of methamphetamine and dextroamphetamine salts, discontinued 1973,[32] later re-branded Oby-Rex, swapping methamphetamine for levoamphetamine, the (s) isomer of racemic amphetamine.
  • Tuinal by AbbVie was a capsule containing amobarbital and secobarbital (double barbiturate); voluntarily discontinued by AbbVie in 2008, citing widespread substance abuse as well as declining sales due to a decrease in prescriptions, and thus, demand.[33]

Fisons, Inc. (acquired PennWalt-RJS, hostile takeover by R-P-Rorer; now Sanofi-Aventis

  • BiPhetamine was introduced and patented by Pennwalt, Inc. in 1964, and manufactured and marketed by its R.J. Strausenburgh division as shiny black, oblong softgels inscribed RJS and comprising 50% dextroamphetamine and 50% levoamphetamine).[34] Fisons, Inc. acquired Pennwalt, Inc.-RJS in 1966, rebranded BiPhetamine to Biphetamine-T and maintaining the same dosages, while adding 40 mg methaqualone to distinguish its product and avoid patent infringement, as well as reformulating it as dual-colored black and burgundy red capsule. Negative publicity regarding methaqualone had become so widespread that the manufacturer of brand name Quaalude (methaqualone hydrochloride), the Lemmon Drug Company voluntarily discontinued its own product in 1982, followed soon after by Fisons withdrawing their

Over the next decade, Fisons began to experience diminishing profit margins, increasingly negative financial forecasts, and was being pressured throughout 1995 to sell to the French pharmaceutical conglomerate Rhone-Poulenc Rorer;[35] to sell, which Fisons refused and poor forecasts. Despite initially turning down an offer from French pharmaceutical conglomerate trade name]] Biphetamine. It was hostile takeover in 1996.[36][37]

G.W. Carnrick Laboratories, acquired by Élan Pharmaceuticals of Ireland

  • Acutran by G.W. Carnrick Laboratories is composed of amfecloral, a compound molecule pairing dextroamphetamine sulfate and chloral hydrate,[38] discontinued 1973[32]
  • Bontril Timed No. 1 combined 2.5 mg dextroamphetamine and 7.5 mg butabarbital; Bontril Timed No. 2 5 mg dexamphetamine and 15 mg butabarbital; Bontril Timed No. 3 10 mg dexamphetamine and 30 mg butabarbital; Bontril Timed No. 4 15 mg dexamphetamine with 60 mg butabarbital, all manufactured and marketed by G.W. Carnrick Laboratories.[39]

Laderle, Roehrig, and Wyeth, all now divisions of Pfizer

  • Amphaplex 10 by Laderle Laboratories combined 2.5 mg methamphetamine saccharate, 2.5 mg methamphetamine hydrochloride, and 5 mg racemic amphetamine sulfate; Amphaplex 20 combined 5 mg methamphetamine saccharate, 5 mg methamphetamine hydrochloride, and 10 mg racemic amphetamine sulfate.[40]
Roehrig
Wyeth

Behlen Manufacturing

  • Anxine by Behlen Manufacturing[46][47] 120 mg mephenesin (muscle relaxant), 35 mg cyclobarbital, and 2.5 mg dextroamphetamine
  • Bama-Dex combined 5 mg dextroamphetamine and 400 mg meprobamate[48]

Lemmon Drug Company

Eli Lilly & Company

  • Dexytal by Eli Lilly, combination dextroamphetamine and amobarbital elixir;
Irwin, Neisler & Co. (D/B/A Neisler), acquired by Mallinckrodt and sold to Union Carbide
  • Durophet (racemic amphetamine salts) became generized as "biphetamine" due to the nationwide ubiquity of colloquially "viphetamine]]comparable to Biphetamine by Fisons, see above) brand the former combined 12.5 mg amphetamine and 400 mg methaqualone (sedative-hypnotic), discontinued 1984 due to global convention banning methaqualone; Durabond, tablet combining 8 mg chlorpheniramine tannate (first-generation antihistamine/FGA), 25 mg pyrilamine tannate (first-generation antihistamine), and "10 mg Tanphetamin (racemic amphetamine tannate) [also by Neisler]""General Practice American Academy(20)". 1959.
  • Edrisal by Wyeth, combined 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine /sulfate; Edrisal with Codeine included an additional 16 mg codeine[citation needed]
  • Ethobral by Wyeth, Triple-Barbiturate Tablets quinalbarbitone sodium (rapid-acting barbiturate), butobarbitone (intermediate-acting barbiturate), and phenobarbital (long-acting)[50][51]
  • Desbutal by Union Carbide doing business as Neisler Labs, 5 mg methamphetamine and 30 mg pentobarbital, discontinued 1973[32]
  • NalerTan combined 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate (first-generation antihistamine) [52][53]
  • dextroamphetamine, amobarbital, methylcellulose, and nutritional supplements, brandedNexorin
  • Obocell combined 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate (antihistamine); Obocell-TF was identical in composition with the addition of a high-viscosity methylcellulose supplement, also by Neisler and listed as "160 mg Nitrin on the label)[54]

Jannsen Pharmaceuticals

Smith, Kline & French, acquired by GlaxoSmith Kline

Teva Pharmaceuticals

Parke-Davis

  • Phelantin by Parke-Davis combined 100 mg phenytoin (anticonvulsant), 32 mg pentobarbital, and 2.5 mg methamphetamine[59]

Winston Pharmaceuticals

A.H. Robins

AstraZeneca

  • Obolip combined dextroamphetamine, phenobarbital, choline, di-methionine, and methylcellulose
  • Euphoramin, 5 mg methamphetamine and 300 mg meprobamate (non-barbiturate, barbiturate-adjacent GABergic minor tranquilizer
  • Dysonil combined methamphetamine, pentobarbital, and salicylamide (analgesic)
  • Direcel combination dextroamphetamine, butabarbital, carboxymethylcellulose
  • DuoDex, combination barbaloin (stimulant-laxative),[62] dextroamphetamine (stimulant), pentobarbital (barbiturate), thyroid (hormone); The U.S. FDA declared in May 2002 that "aloin-containing laxatives are no longer GRAS [nor] effective for OTC use" upon the IARC classifying whole-leaf herbal extracts of aloe vera as "possibly carcinogenic to humans" due to presence of latex.

Polish swlzki Farmc

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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 were versatile as anorectic, antidepressant, and eugeroic (wakefulness-promoting) agents, boosting mental alertness and physical stamina, as well as the ability to maintain focus and motivation. Theoretically, when combined with a CNS depressant, a stimulant's adverse effects (primarily overstimulation, paranoia, and/or anxiety) could be mitigated or reduced/balanced without eliminating the stimulant's therapeutic benefits. The stimulating component was almost always of the substituted amphetamine chemical class or an amphetamine derivative or analog; the tranquilizing component was either one or more barbiturate salts, or non-barbiturate GABAergic drugs (e.g. meprobamate, methaqualone) with a similar mechanism of action, with tranquilizing, muscle relaxant, and sedating effects.

Patients are empowered with the capability of alleviating symptoms of multiple medical conditions with the ingestion of a single dosage form, reducing the patient's pill burden and consistently showing improved medication compliance scores. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens,"[64] despite conceding that these combinations were often capable of replacing Monoamine Oxidase Inhibitors (MAOIs) in patients with treatment-resistant depression where MAOI treatment is appropriate, but where the MAOI-related dietary restrictions would otherwise hinder patient compliance.

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.[65] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[66][67]

Limitations of polypharmacy for multi-faceted disorders

Examples including neurological disorders, excessive motor activity

The limitations of combination formulations currently available for treating the large number of overlapping neurological symptoms inherent to most neurological conditions is a hindrance to properly treating disruptive, concurrent symptoms. Tourette's is a stellar example of this dilemma, because the minimum diagnostic criteria is habitual, repeated physical movements, muscle spasms, the compulsive need to repeat motions and succumb to the premonitory urge to release perform needless, disruptive central nervous system] motor activity (physical "motor tics"). Pimozide and off-label medications canhelp reduce those symptoms.

obsessive-compulsive anxiety, social anxiety, generalized anxiety, are very likely to concur with with tics; as such, polypharmacy necessitates secondary or even tertiary solutions to treat these aspects of the broader condition: OCD alone is often resolved clomipramine (a tricyclic antideresant) anxietys 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's Syndrome is a neurological disorder, idand is ideallt diagnosed and, to the extent possible and treated by a medical specialis trained in the field of neurologyin with neurologt tresatmentand by a neurologistideally treated by a neurologists. Tourette's is almost universally viewed as a tic disorder]], while neurotypicasl observers are unlikely to conjure the word "Tourette," or consider other forms of presentation, much less to anakyze and compare existenceunlikely to even consider the condition, but to the general public there is a conviction that use is routinely and uncontrollably engaging in disruptive, unmistakable, physical movements ("motor tics") and/or spending nearly every waking hour producing loud, disruotive, unmistkable, clearly uncmfortbe or ainful noises, grunts, grws or which treatment options are currently limited; only the typical antipsychotics, pimozide and haloperidol are specifically approved for treating the tic component of Tourette's;[68] clonidine and guanfacine are approved for ADHD, which often comorbid to Tourette's, but not necessarily guaranteed to reduce tics.

Typically identified by chronic motor and vocal tics (described by NIH as "semi-voluntary" actions performed in response to a premonitory urge, an internal sensory phenomenon akin to a buildup of tension, only able to be alleviated upon releasing a tic.[69] Tourette's, however, is an all-encompassing umbrella term that presents not just as chronic motor/physical and vocal/phonic tics; tics are nearly always comorbid to symptoms of obsessive-compulsive anxiety and/or social anxiety, avoidant personality or schizoid personality, ADHD, as well as insomnia, depression, and traits of high-functioning autism (formerly "Asperger syndrome").

Pimozide (approved); tetrabenazine, topiramate, diazepam, haloperidol (off label) specific to tics

For Tourette's, there is one approved, pharmaceutical directly responsible for blocking the D2 receptor – pimozide. C] and even more so to excessive motor activity (e.g.convulsions; tremors; muscle spasms; and the restlessness inherent to akathisia, the most severe, pervasive, unwaveing obsessive comulsion to move and flail entire portions lest the gradual feelingcompulsion to|general restless, and the and restlessness due to the compulsion to perform a physical motion/motor activity; NOTE: all of the aforementioned symptoms are due to the gradual rise in tension and discomfort until it is painful do without succumbing to the urge. cal tics, sounds grunts, etc. appsroved for medical use by the Food and Drug Administration (FDA), and neither of them are guaranteed to work the same for each individual, thus, treatment options are complex to identify, and difficult in that sense. For decades, the typical antipsychotic, pimozide was the sole treatment with the most targeted effect on symptoms of Tourette's particular motor tics. consist of two, o

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Illicit "street" drug combinations

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Terms for stimulants being sold as "powder cocaine" or crack cocaine have been found to contain as little 15% cocaine hydrochloride or any other form of ingredient with an acceptable amount of coca alkaloids at all. ABC News has conducted several investigative journalism analyses and metanalyses and have reported that the greatest concern for any so-called "cocaine" or amphetamine, methamphetamine powders and mostd found to contain designer drugs and/or research chemicals including synthetic cathinones, MDMA, methamphetamine, caffeine, and increasingly the flesh-eating veterinary antibiotic levamisole have been found in "powder cocaine."[70]

Since the forced closure of so many pill mills in the U.S. beginning in 2007, a black market for opioids has flourished and continuously expanded.[71] As demand increases for relatively mild opioid "pain pills" ranging from codeine, hydrocodone, oxycodone, morphine, diacetylmorphine (Heroin) items being deceptively sold as such are adulterated by undeclared amounts of highly potent synthetic opioids of questionable purity. Prince died in April 2016 from taking pills he thought were "Percocet;" in actuality, the "Percocet" was not relatively mild oxycodone, but counterfeit "presses" or "pressed pills" that resulted in Prince's gradual ingestion of unknown, but lethal, quantities of fentanyl. "Presses" are synthesized via clandestine chemistry by untrained chemists and often cut with agents including fentanyl, carfentanil, and as of September 2024, nitazenes.[72][73]

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and the designer drugs (synthetic triazolobenzodiazepines) bromazolam, clobromazolam, phenazolam, and flualprazolam.[74] In April 2025, U.S. Attorney General Pam Bondi stated a desire to regulate xylazine under U.S. federal drug law) as a Schedule III controlled substance.[75] Xylazine is currently a controlled substance under state statutes in Michigan and New York.[76]

Mandrax is the trade name of a pharmaceutical combination drug consisting of methaqualone and diphenhydramine.,[77] once prescribed in South Africa, but banned in 1993. "Mandrax" is now synthesized via clandestine chemistry as a free base preparation, which is smoked for an intense, short-lived "high".[78]

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