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, 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 a pill containing four or more active ingredients, ^{[1] [2]} often produced at a compounding pharmacy due to the specific dosage, dosage form, and modified release mechanism. Polypills can encompass four or more of any combination of approved prescription drugs and over the counter drugs, as well as nutritional supplements and hormones, amino acids, enzymes, 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/perphenazine (Triavil)
• amitriptyline/chlordiazepoxide (Limbitrol-H), available in the United States, India, ^{[6] [7] [8]} and Bangladesh
• amlodipine/benazepril (Lotrel)
• amlodipine/atorvastatin (Conduet)
• amlodipine/celecoxib (Consensai)
• amlodipine/lisinopril (Lisonorm)
• amlodipine/olmesartan (Azor)
• amlodipine/valsartan (Exforge)
• amphetamine racemic salts (combining dextroamphetamine sulfate and saccharate with levoamphetamine sulfate and aspartate monohydrate), branded Adderall by Shire Pharmaceuticals, among others such as Mydayis and Adzenys ODT
• bupropion/naltrexone (Contrave)
• butalbital and caffeine (Butapap)
• butalbital, caffeine, and either aspirin (Fiorinal), or acetaminophen (Fioricet]]), also available with codeine as Fioricet with Codeine
• calcipotriol/betamethasone dipropionate, Dovobet by LEO Pharma.
• carbidopa/levodopa/entacapone (LCE), Stalevo, Lecigon for infusion therapy in some European countries
• chlordiazepoxide (benzodiazepine) and clidinium bromide (anticholinergic), Librax ^{[9] [10]}
• ephedrine/ethylmorphine
• flupentixol/melitracen, available in Bangladesh as Deanxit by Lundbeck
• hydrocodone/acetaminophen ^[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/amoxicillin/rifabutin (Talicia)
• olanzapine/fluoxetine (Symbyax)
• oxycodone (opioid) and acetaminophen, Percocet
• oxycodone and aspirin, Percodan
• oxycodone and ibuprofen (nonsteroidal anti-flammatory), Combunol
• phentermine/topiramate (Qsymia by Vivus)
• phenylephrine/ketorolac (Omidria) ^[15]
• pseudoephedrine/carbinoxamine (Rondec) elixir ^[16]
• tramadol/paracetamol ^{[ citation needed ]}

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 and caffeine) tablet, widely available since 1916 ^[18]
• chlorpheniramine (first-generation antihistamine and decongestant) and phenylpropanolamine, 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: cough medicine combining chlorpheniramine and dextromethorphan, with select formulas supplementing guaifenesin and acetaminophen is Coricidin Cold + Cough and 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 America and South America, including Paraguay and Uruguay ^[26]
• fexofenadine/pseudoephedrine (Allegra-D)
• glucose/fructose/phosphoric acid (Emetrol for Nausea)
• guaifenesin and phenylephrine (Sudafed PE by Merck)
• ibuprofen/famotidine (Duexis) ^[27]
• ibuprofen/diphenhydramine (Advil PM)
• loratadine/pseudoephedrine (Claritin-D by AstraZeneca)
• naproxen sodium and diphenhydramine hydrochloride, Aleve PM by Bayer ^[28]
• naproxen and pseudoephedrine, Aleve-D
• oxomemazine/guaifenesin (Toplexil by Aventis), 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

Combination drugs under development

• MDMA/citalopram, entactogen and SSRI antidepressant in Phase II clinical trials for treating 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]
• Tuinal by AbbVie: amobarbital/secobarbital double barbiturate combo, discontinued by manufacturer AbbVie in 2008 per widespread substance abuse and decrease in prescriptions. ^[33]
• Phenephen by A.H. Robins: hyoscyamine sulfate, phenacetin, and aspirin; also available in a separate formulation as Phenephen with Codeine
• Pondimin or "fenfluramine/phentermine", informally called "fen-phen", 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 dextroamphetamine/chloral hydrate molecular compound) by G.W. Carnrick Laboratories, ^[38] discontinued 1973 ^[32]
• Bontril Timed numbers 1, 2, 3, and 4: four different dosage combinations of dextroamphetamine and butabarbital. ^{[ citation needed ] [39]}
• Delcobese, racemic amphetamine molecule with each enantiomer bonded to sulfate and adipate, "withdrawn voluntarily in 1984, unrelated to safety or legal concerns" ^[40]
• 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 ][ clarification needed ]}
• Eskatrol by Smith, Kline & French combined dextroamphetamine and prochlorperazine, discontinued 1981
• Daprisal tablet combined dextroamphetamine, amobarbital, and aspirin^{[ citation needed ]}
• 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) ^{[41] [42]}
• 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) ^[43]
• OboTan-S: formerly SynaTan-S ^{[44] [45] [46]} ) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital ^[47]
• DuoDex, combination barbaloin (laxative), ^[48] 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 ^[49]
• Reladorm combined 100 mg cyclobarbitol and 10 mg diazepam, previously available in Russia, discontinued 2019 ^[50]
• 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. ^[51]
• Amplus Now by Roehrig combined 5 mg dextroamphetamine sulfate with 5 mg hydroxyzine (first-generation antihistamine) ^{[52] [53]}
• Amvicel combined 10 mg dextroamphetamine, 40 mg amobarbital, 15 mg phenobarbital, 30 mg nicotinamide, plus vitamins and essential minerals ^[54]
• Edrisal combined 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine sulfate and Edrisal with Codeine added 160 mg codeine ^{[ citation needed ]}
• EthobralTriple-Barbiturate Tablets by Wyeth combined secobarbital, butabarbital, and phenobarbital ^{[55] [56]}
• Biphetamine, Obetrol, Oby-Rex: varying formulations by different manufacturers of mixed amphetamine salts. Biphetamine-T was timed ^{[57] [58] [59] [60]}
• ANOX (extended-release formulation marketed as ANOX Diacels) capsules combined 20 mg each phenobarbital, butabarbital, and secobarbital with 7.5 mg each methamphetamine hydrochloride and dextroamphetamine sulfate ^[61]

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." ^[62]

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. ^[63] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed. ^{[64] [65]}

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. ^[66] , and the typical antipsychotic, pimozide, is specifically approved (as an orphan drug) for this indication. ^[67] 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." ^[68]

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. ^[69] 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. ^{[70] [71]}

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and synthetic triazolobenzodiazepines, bromazolam, clobromazolam, phenazolam, and flualprazolam. ^[72] 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. ^[73] Xylazine is currently a controlled substance under state statutes in Michigan and New York. ^[74] "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. ^[75] "Mandrax" is now synthesized via clandestine chemistry as a free base preparation, which is smoked for an intense, short-lived "high". ^[76]

See also

• Codrugs
• Synergy#Drug synergy

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External links

• Media related to Combination drugs at Wikimedia Commons