Combination drug

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 a tablet or capsule to be administered orally, an elixir or tincture (sublingual), an injectable suspension (intramuscular administration or intravenous therapy), or a suppository (rectal). A legitimate combination drug that exceeds rigorous laboratory quality standards and is approved for medical use is a safe option for treating multiple symptoms or diseases amongst various patients within a large population–and this includes combinations of over-the-counter medicine and/or of prescription drugs. When medications are paired with supplements^{[disambiguation needed]}, consumers can be certain of accurate dosing and ingredient labeling, as well as product quality as it would be regulated and manufactured as a medication and must meet rigorous standards of pharmaceutical quality.

A polypill is specifically formulated as a pill 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]

History

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]

• amitriptyline (tricyclic antidepressant) and perphenazine (typical antipsychotic), brand name Triavil
• amitriptyline and chlordiazepoxide (benzodiazepine), Limbitrol-H, available in the United States, India,^[6][7][8] and Bangladesh
• amlodipine (calcium channel blocker) and benazepril (ACE inhibitor), Lotrel
• amlodipine and atorvastatin (statin), Conduet
• amlodipine and celecoxib (nonsteroidal anti-inflammatory drug), Consensai
• amlodipine and lisinopril (ACE inhibitor), Lisonorm
• amlodipine and olmesartan (ACE inhibitor), Azor
• amlodipine and valsartan (ACE inhibitor), Exforge
• amphetamine (stimulant) racemic salt mixture, combining the enantiomer dextroamphetamine (sulfate ans saccharate bonds) and the stereoisomer levoamphetamine (sulfate and aspartate monohydrate bonds), Adderall by Shire Pharmaceuticals, MyDayis with slightly varying formulation
• bupropion (norepinephrine-dopamine reuptake inhibitor) and naltrexone (opioid antagonist), Contrave
• butalbital (barbiturate) and caffeine (methylxanthine, Butapap
• butalbital, caffeine, and aspirin (nonsteroidal anti-inflammatory), Fiorinal
• butalbital, caffeine, and acetaminophen, Fioricet
• butalbital, caffeine, acetaminophen, and codeine (opioid), Fioricet with Codeine
• calcipotriol/ betamethasone dipropionate, Dovobet by LEO Pharma.
• chlordiazepoxide (benzodiazepine) and clidinium bromide (anticholinergic), Librax^[9][10]
• ephedrine (sympathomimetic) and ethylmorphine (opioid) Lephotan
• flupentixol (typical antipsychotic) and melitracen (tricyclic antidepressant), available outside of the U.S. as Deanxit by Lundbeck
• hydrocodone bitartrate (opioid agonist, tablet) and acetaminophen, Vicodin by AbbVie contains 325 mg acetaminophen as a tablet, currently the only brand form in the United States. Norco is a tablet containing 300 mg acetaminophen, with limited availability in select countries.^[11] LorTab by UCB is now solely available as a syrup in the U.S.^[12]
• hydrocodone and aspirin, Azdone
• hydrocodone and guaifenesin (expectorant), Obedron, Flowtuss
• hydrocodone and ibuprofen (nonsteroidal anti-inflammatory]])NSAID), Ibudone
• ibuprofen and acetaminophen intravenous solution, Maxigesic IV^[13]
• nirmatrelvir (antiviral) and ritonavir (antiviral), combination drug for treatment and management of COVID-19), Paxlovid^[14]
• omeprazole (proton pump inhibitor), amoxicillin (antibiotic), and rifabutin (anti-tuberculosis), Talicia
• olanzapine (atypical antipsychotic) and fluoxetine (selective serotonin reuptake inhibitor), Symbyax
• oxycodone (opioid) and acetaminophen, Percocet
• oxycodone and aspirin, Percodan
• oxycodone and ibuprofen (nonsteroidal anti-flammatory), Combunol
• phentermine (substituted amphetamine, amphetamine derivative) and topiramate (antimigraine) Qsymia by Vivus
• phenylephrine (sympathomimetic) and ketorolac (NSAID), Omidria^[15]
• pseudoephedrine (sympathomimetic) and carbinoxamine (anticholinergic), Rondec elixir^[16]
• tramadol and paracetamol, Ultram

Combination drugs accessible over the counter

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:

• Anacin (aspirin; caffeine) tablet widely available since 1916^[18]
• chlorpheniramine (first-generation antihistamine) and phenylpropanolamine (sympathomimetic), Vernate Injection by Tutag Pharmaceuticals of New Jersey, liquid for intramuscular injection;^[19][20][21] available as the tablet Tri-Nefrin, and a syrup elixir Altec Syrup, all available in Asia, all discontinued in U.S. by 2007.
• Coricidin by Bayer, a line of cough medicine combining chlorpheniramine and dextromethorphan; chlorpheniramine, dextromethorphan, guaifenesin, and acetaminophen is Coricidin Cold + Cough; chlorpheniramine, phenylephrine, guaifenesin, and acetaminophen is Coricidin HBP High Blood Pressure^[22]
• aspirin, caffeine, and acetaminophen, Excedrin by Bayer^[23]
• diphenhydramine and 8-chlorotheophylline as an ionic bond produce the compound dimenhydrinate, Dramamine by GlaxoSmithKline.^[24][25]
• fenproporex and diazepam, Esbelcaps available in Central and South America^[26]
• fexofenadine and pseudoephedrine, Allegra-D
• glucose, fructose, and phosphoric acid, Emetrol for Nausea
• ibuprofen and famotidine (proton pump inhibitor), Duexis^[27]
• ibuprofen and diphenhydramine citrate, Advil PM
• loratadine and pseudoephedrine, Claritin-D by AstraZeneca
• naproxen sodium and diphenhydramine hydrochloride, Aleve PM by Bayer^[28]
• naproxen and pseudoephedrine, Aleve-D
• Toplexil by Aventis, available in dosage forms including tablet, tincture, elixir and suppository, oxomemazine and guaifenesin, approved and available in France, Algeria, and Morocco^[29]
• Robitussin, a line of cough medicine encompassing various combinations including dextromethorphan, acetaminophen, chlorpheniramine, doxylamine succinate, and/or guaifenesin.
• guaifenesin and phenylephrine, Sudafed PE by Merck

Combination drugs under development

• MDMA/citalopram, combination of MDMA (an entactogen informally called "molly" and/or "ecstasy) and citalopram (an SSRI antidepressant), under development without a trade name in FDA Phase II clinical trials and being studied for treatment of post-traumatic stress disorder.^[30]

Combination drugs for veterinary use

• Temaril-P combines alimemazine (antitussive) and prednisolone (antipruritic), approved for use in dogs, generic drug since 2024, and substitutes alimemazine for trimeprazine, leaving in place prednisolone, equivalent to branded formula in efficacy
• Titzeol combines tiletamine and zolazepam, large animal tranquilizer^[31]

Combinations no longer available

• 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 per widespread substance abuse and decrease in prescriptions.^[33]
• Phenephen by A.H. Robins combined hyoscyamine sulfate, phenacetin, and aspirin; a separate formulation, Phenephen with Codeine contained the identical formula with the addition of codeine as a fourth active ingredient.
• Pondimin ("fen-phen") combined fenfluramine and phentermine, discontinued 1997^[34]
• Anxine^[35][36] 120 mg mephenesin (muscle relaxant), 35 mg cyclobarbital, and 2.5 mg dextroamphetamine

• Bama-Dex combined 5 mg dextroamphetamine and 400 mg meprobamate^[37]

• Acutran (amfecloral) by G.W. Carnrick Laboratories, dextroamphetamine sulfate and chloral hydrate,^[38] discontinued 1973^[32]

• Bontril Timed No. 1 combined 2.5 mg dextroamphetamine and 7.5 mg butabarbital^{[citation needed]}
• Bontril Timed No. 2 5 mg dexamphetamine and 15 mg butabarbital^[39]
• Bontril Timed No. 3 10 mg dexamphetamine and 30 mg butabarbital^{[citation needed]}
• Bontril Timed No. 4 15 mg dexamphetamine with 60 mg butabarbital. ^{[citation needed][40]}

• Delcobese, racemic amphetamine molecule with each enantiomer bonded to sulfate and adipate, "withdrawn voluntarily in 1984, unrelated to safety or legal concerns"^[41]
• Mandrax, a tablet combining methaqualone and diphenhydramine (first-generation antihistamine), only available in South Africa until 1993, "Lemmon (drug)" was a street name for diverted methaqualone
• Dexytal by Eli Lilly, combination dextroamphetamine and amobarbital elixir^{[dubious – discuss][citation needed]}
• Mediatric combined two hormones (0.25 mg Premarin and 2.5 mg methyltestosterone) with 100 mg vitamin c, b vitamins, and 1 mg methamphetamine
• Eskatrol by Smith, Kline & French combined dextroamphetamine and prochlorperazine (typical antipsychotic, discontinued 1981
• Daprisal tablet combined dextroamphetamine, amobarbital, and aspirin
• Dexamyl tablet combined dextroamphetamine and amobarbital, discontinued 1982
• Durophet was a racemic mixture of amphetamine salts combining combined 12.5 mg amphetamine and 400 mg methaqualone (sedative-hypnotic), discontinued 1984
• 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)""General Practice American Academy(20)". 1959.
• Desbutal combined 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) ^[42][43]
• 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)^[44]
• OboTan-S: formerly SynaTan-S^[45][46][47]) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital^[48]
• Obolip combined dextroamphetamine, phenobarbital, choline, dimethionine, 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 (laxative),^[49] 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.
• Phelantin combined 100 mg phenytoin (anticonvulsant), 32 mg pentobarbital, and 2.5 mg methamphetamine^[50]

• Reladorm combined 100 mg cyclobarbitol and 10 mg diazepam, previously available in Russia, discontinued 2019^[51]
• Amphaplex 10 by Laderle 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.^[52]
• Amplus Now by Roehrig combined 5 mg dextroamphetamine sulfate with 5 mg hydroxyzine (first-generation antihistamine)^[53][54]
• Amvicel combined 10 mg dextroamphetamine, 40 mg amobarbital, 15 mg phenobarbital, 30 mg nicotinamide, plus vitamins and essential minerals^[55]
• Apamead combined dextroamphetamine sulfate, amobarbital, aspirin, phenacetin
• Ambar by Wyeth Pharmaceuticals combined methamphetamine hydrochloride and phenobarbital; available asAmbar Extentab in extended-release formulation
• Edrisal combined 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine sulfate;
• Edrisal with Codeine 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine sulfate, and 160 mg codeine^{[citation needed]}
• Ethobral Triple-Barbiturate Tablets by Wyeth combined secobarbital, butobarbital, and phenobarbital^[56][57]
• Biphetamine by R.J. Strausenburgh (1964-66), by Fisons (1966-79) (inscribed RJS) containing equal parts dextroamphetamine and levoamphetamine. Later acquired by Fisons, then R.P. Rorer and rebranded Biphetamine-T^{[58][59][60][61]}
• Lamital combined acetaminophen, amobarbital, and methamphetamine
• ANOX capsule 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)^[62]
• ANOX DiAmfet 5 modified-release dosage formulation of the above combination components

Justification of medical use

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. Substituted amphetamines (stimulants) simultaneously functioned as appetite suppressant, antidepressant, and eugeroic agents, also increasing mental alertness and concentration and physical stamina, while a GABAergic depressant (e.g. a barbiturate, benzodiazepine, antipsychotic, or quinazolone) offered tranquilizing, muscle relaxant, sedative properties to ease overstimulation, paranoia, anxiety without eliminating the stimulant's therapeutic benefits. 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."^[63]

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.^[64] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.^[65][66]

Limitations of polypharmacy for multi-faceted disorders

Obsessive-compulsive disorder, social anxiety, and anxiety are all commonly likely to comorbidity with tics; as such, polypharmacy necessitates secondary or even tertiary solutions to treat these aspects of the umbrella term: OCD alone is often resolved clomipramine (a tricyclic antidepressant) 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, generally diagnosed and treated by a neurologist or psychiatrist familiar with tic disorders. Tourette's most often involves 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.^[67], and the typical antipsychotic, pimozide, is specifically approved (as an orphan drug) for this indication.^[68] 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 Asperger syndrome. clonidine and guanfacine are approved for ADHD, which often comorbid to Tourette's, but not necessarily guaranteed to reduce tics.

Illicit drug combinations

Products sold as "powder cocaine" or "crack cocaine" are often found to contain very little, if any, coca alkaloids. ABC News has conducted several investigative journalism analyses and metanalyses and have reported that the greatest concern with any illicit stimulant is that they include undetermined amounts of designer drugs and/or research chemicals; instead of cocaine or pharmaceutical stimulants (e.g. amphetamines, cocaine) products are likely to contain MDMA, crystal meth, and caffeine. Increasingly, the flesh-eating veterinary antibiotic levamisole has been found in "powder cocaine."^[69]

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.^[70] 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. The death of Prince resulted from him unknowingly ingesting fentanyl in the form of counterfeit pills designed to resemble Percocet (oxycodone/acetaminophen) tablets. These "pressed" pills are synthesized via clandestine chemistry by untrained chemists and often cut with agents including fentanyl, carfentanil, and as of September 2024, nitazenes.^[71][72]

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and synthetic triazolobenzodiazepines, bromazolam, clobromazolam, phenazolam, and flualprazolam.^[73] 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.^[74] Xylazine is currently a controlled substance under state statutes in Michigan and New York.^[75] "Mandrax" is a genericized trademark and street name for the illicit combination of methaqualone and diphenhydramine, named after the pharmaceutical brand that was available by prescription in South Africa until 1993.^[76] "Mandrax" is now synthesized via clandestine chemistry as a free base preparation, which is smoked for an intense, short-lived "high".^[77]

See also

• Codrugs
• Synergy#Drug synergy