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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.

A combination drug, broadly, is a medicine formulated to include two or more active ingredients (e.g. over-the-counter (OTC) or prescription drugs and hormones; vitamins, minerals, supplements, herbs, alkaloids) in a single dosage form (e.g. one tablet, capsule, softgel, elixir, tincture, or suppository). Combination drugs may further be classified a fixed-dose combination and/or a polypill, whereby the former frequently include mass-products, mass-marketed as versatile, multi-purpose treatment options, and distributed to large patient populations, with each person carrying unique genetic factors that determine their susceptibility to disease or medical symptoms, and with their own personalized health goals and treatment plans, necessitating a variety of treatment options for a wide variety of patient treatment needs. A polypill is a tablet or capsule 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, 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, over the counter drugs, and may also include nutritional supplements, amino acids, enzymes, hormones, vitamins and/or essential minerals.[3]

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

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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:

Combination drugs accessible over the counter (OTC)

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Fixed-dose combination drugs for sale over the counter 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.[13]

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

Combination drugs under development

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Combinations drugs for veterinary use

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Combination drugs no longer widely available

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  • Acutran by G.W. Carnrick Laboratories is composed of amfecloral, a compound molecule pairing dextroamphetamine sulfate and chloral hydrate,[28] discontinued 1973[29]
  • Ambar by Wyeth Pharmaceuticals combined methamphetamine hydrochloride and phenobarbital; Ambar Extentab was the extended-release formulation
  • Amphaplex 10 by Laderle Laboratories (later acquired by Wyeth) 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.[30]
  • Amplus Now by Roehrig Laboratories combined 5 mg dextroamphetamine sulfate with 5 mg hydroxyzine (first-generation antihistamine)[31][32]
  • Amvicel by Roehrig Laboratories combined 10 mg dextroamphetamine, 40 mg amobarbital, 15 mg phenobarbital, 30 mg nicotinamide, plus vitamins and essential minerals[33]
  • Apamead by Laderle Laboratories combined dextroamphetamine sulfate, amobarbital, aspirin, and phenacetin (racetin)
  • ANOX by Winston Pharmaceuticals,encapsulated polypill combining a fixed dose of three barbiturate salts (20 mg each of phenobarbital, butabarbital, and secobarbital) and two amphetamine salts (7.5 mg each of methamphetamine hydrochloride and dextroamphetamine sulfate)[34]
  • Anxine by Behlen Manufacturing[35][36] combined 120 mg mephenesin (muscle relaxant), 35 mg cyclobarbital, and 2.5 mg dextroamphetamine sulfate
  • Bama-Dex by Behlen Manufacturing combined 5 mg dextroamphetamine and 400 mg meprobamate[37]
  • Biphetamine T-12.5 and Biphetamine T-20 by Fisons comprised, respectively, 12.5 mg and 20 mg of racemic amphetamine salts, thereby containing the two enantiomers of racemic amphetamine, dextroamphetamine and levoamphetamine, at respective doses of 6.25 mg of each isomer for the former product, 10 mg of each for the latter.
  • 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.[38]
  • Delcobese by Lemmon Drug Company was a balanced combination of racemic amphetamine sulfate and adipate, "withdrawn voluntarily in 1984, unrelated to safety or legal concerns"[39]
  • Desbutal by Irwin, Neisler & Co. (Neisler Labs), 5 mg methamphetamine and 30 mg pentobarbital, discontinued 1973[29]
  • Dexytal by Eli Lilly, combination dextroamphetamine and amobarbital elixir; Dexamyl by Smith, French & Kline (now GlaxoSmith Kline/GSK), dextroamphetamine and amobarbital as a tablet, discontinued 1982; Daprisal by GSK, dextroamphetamine, amobarbital, and aspirin as a tablet
  • Durophet-M and Durabond, both by Neisler Labs: 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.</ref>
  • Direcel combined dextroamphetamine, butabarbital, carboxymethylcellulose; Direcel-T included additional thyroid hormone
  • DuoDex combined aloin (laxative), dextroamphetamine, pentobarbital, and thyroid hormone
  • Dysonil combined methamphetamine, pentobarbital, and salicylamide (analgesic)
  • Edrisal 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)[40][41]
  • Eskatrol by Smith, French & Kline combined dextroamphetamine and prochlorperazine (first-generation antipsychotic, discontinued 1981
  • Euphoramin, 5 mg methamphetamine and 300 mg meprobamate, Euphoramin
  • Lamital by Teva Pharmaceuticals combines acetaminophen, amobarbital, and methamphetamine
  • Mandrax by Lemmon Drug Company, tablet comprising methaqualone and diphenhydramine (first-generation antihistamine), available in South Africa until 1993
  • Mediatric by Janssen Pharmaceuticals combined two hormones (0.25 mg Premarin and 2.5 mg methyltestosterone) with 100 mg vitamin c, b vitamins, and 1 mg methamphetamine
  • NalerTan by Neisler combined 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate (first-generation antihistamine) [42][43]
  • dextroamphetamine, amobarbital, methylcellulose, and nutritional supplements, brandedNexorin
  • Obocell by Neisler 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)[44]
  • Obetrol by Abbott Laboratories was a mixture of methamphetamine and dextroamphetamine salts, discontinued 1973,[29] later re-branded Oby-Rex, swapping methamphetamine for levoamphetamine, the (s) isomer of racemic amphetamine.
  • Obolip combined dextroamphetamine, phenobarbital, choline, dimethionine, and methylcellulose
  • Phelantin by Parke-Davis combined 100 mg phenytoin (anticonvulsant), 32 mg pentobarbital, and 2.5 mg methamphetamine[45]
  • Phenephen by A.H. Robins combined hyoscyamine sulfate, phenacetin, and aspirin; Phenephen with Codeine was the aforementioned formula with codeine as a fourth active ingredient
  • Pondimin, better known as "fen-phen," a colloquialism for combination fenfluramine and phentermine, discontinued 1997[46]
  • SynaTan-S by Neisler (later acquired by Mallinckrodt and re-branded OboTan-S)[47][48][49]) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital[50]
  • Pre M.T.[citation needed] by Behlen combined racemic amphetamine sulfate, pentobarbital, and pyrilamine maleate with a microdose of theobromine
  • Reladorm combined 100 mg cyclobarbitol and 10 mg diazepam, last available in Russia until it was discontinued in 2019[51]
  • 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.[52]

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,"[53] 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[54] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[55][56]

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 for which treatment options are currently limited; only the typical antipsychotics, pimozide and haloperidol are specifically approved for treating the tic component of Tourette's;[57] 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.[58] 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").

Illicit "street" drug combinations

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So-called "powder cocaine" often contains stimulants meant to mimic cocaine's effects; many batches analyzed did not contain any cocaine or coca alkaloids at all; most frequently, "powder cocaine" is 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."[59]

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.[60] 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.[61][62]

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and the designer drugs (synthetic triazolobenzodiazepines) bromazolam, clobromazolam, phenazolam, and flualprazolam.[63] 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.[64] Xylazine is currently a controlled substance under state statutes in Michigan and New York.[65]

Mandrax is the trade name of a pharmaceutical combination drug consisting of methaqualone and diphenhydramine.,[66] 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".[67]

See also

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References

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  66. ^ South Africa - a Profile of the Drug Trade (PDF). United Nations. pp. 1–3. Retrieved 2025-05-10.
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