Combination drug

Short description: Drug with two or more active ingredients

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A combination drug or drug cocktail 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. One example of a drug cocktail is a drug regiment in antiviral-therapy (ART); PReP, used HIV transmission prophylaxis or HIV/AIDS symptoms, is a combination drug.

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]

## Contents

* 1 History
* 2 Combination legend drugs
* 3 Combination drugs accessible over the counter
* 4 Combination drugs under development
* 5 Combination drugs for veterinary use
* 6 Widely discontinued formulations
* 7 Justification of medical use
* 8 Illicit or informal combinations
* 9 See also
* 10 References
* 11 External links

## 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.

## Combination legend drugs

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The following are generally available as legend drugs, typically availably by prescription.[clarification needed]

For more common combination drugs, see Medicine: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),[6][7][8] and Bangladesh
* amlodipine/benazepril (Lotrel), amlodipine/atorvastatin (Conduet),
* amlodipine/celecoxib (Consensai)
* lisinopril/amlodipine (Lisonorm),
* amlodipine/olmesartan
* amlodipine/valsartan (Exforge)
* amphetamine racemic salt mixture (dextroamphetamine as sulfate and saccharate, levoamphetamine as sulfate and aspartate monohydrate) (Adderall)
* bupropion/naltrexone (Contrave)
* butalbital and caffeine (Butapap); butalbital, caffeine, and either aspirin (Fiorinal) or acetaminophen (Fioricet), Fioricet with Codeine
* calcipotriol/betamethasone dipropionate, Dovobet by LEO Pharma.
* carbidopa/levodopa/entacapone (LCE), Stalevo, Lecigon for infusion therapy in some European countries
* chlordiazepoxide and clidinium bromide[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, ibuprofen/paracetamol (Maxigesic IV[13]
* nirmatrelvir (antiviral) and ritonavir (antiviral), combination drug for treatment and management of COVID-19), Paxlovid[14]
* omeprazole/amoxicillin/rifabutin
* olanzapine/fluoxetine
* oxycodone/acetaminophen (Percocet)
* oxycodone/aspirin (Percodan)
* oxycodone/ibuprofen (Combunol)
* phentermine/topiramate (Qsymia)
* phenylephrine/ketorolac (Omidria)[15]
* pseudoephedrine/carbinoxamine (Rondec) elixir[16]

## Combination drugs accessible over the counter

Combination drugs are sold over the counter in some countries. In the United States, products containing the active ingredient ephedrine, pseudoephedrine, or phenylpropanolamine are stored behind the pharmacy counter and can be purchased without a medical prescription, albeit subject to U.S. Federal drug law recordkeeping requirements as required by the Combat Methamphetamine Epidemic Act of 2005.[17] The following combination drugs are accessible OTC in nearly all locations:

* aspirin/paracetamol (Anacin)[18] and aspirin/paracetamol/caffeine (Excedrin)[19]
* Various cough medicines combine: dextromethorphan, acetaminophen, chlorpheniramine, doxylamine succinate, phenylpropanolamine, pseudoephedrine, guaifenesin, etc. (Robitussin, Coricidin, Altec, Rondec)[20][21][22][23]
* diphenhydramine/dimenhydrinate (Dramamine)[24][25]
* fenproporex/diazepam (Esbelcaps), available in Central America and Paraguay; discontinued in Brazil[26]
* fexofenadine/pseudoephedrine (Allegra-D)
* glucose/fructose/phosphoric acid (Emetrol for Nausea)
* guaifenesin/phenylephrine (Sudafed PE)
* ibuprofen/famotidine (Duexis)[27] and ibuprofen/diphenhydramine (Advil PM); acetaminophen/diphenhydramine (Tylenol PM)
* loratadine/pseudoephedrine (Claritin-D)
* naproxen/diphenhydramine (Aleve PM)[28] and naproxen/pseudoephedrine (Aleve-D)
* oxomemazine/guaifenesin (Toplexil by Aventis), available in France, Algeria, and Morocco[29]

## 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]
* DKT

## Widely discontinued formulations

Several fixed-dose combination drugs marketed in the mid-20th century were later withdrawn due to safety concerns, changing regulatory standards, or abuse potential. Notable examples include:

* Dexamyl – a combination of dextroamphetamine and amobarbital, used as a stimulant-sedative preparation, withdrawn in the early 1980s.

* Tuinal – a combination of two barbiturates, amobarbital and secobarbital, prescribed as a sedative and hypnotic; it became notable both for medical use and recreational abuse. * Ethobral by Wyeth combined secobarbital, butabarbital, and phenobarbital[32][33]

* Anox (Anox Diacels) – a triple barbiturate plus stimulant combination (phenobarbital, butabarbital, secobarbital, with methamphetamine and dextroamphetamine), reflecting the mid-century trend of “upper-lower” formulations.[34]

* Fenfluramine/phentermine (fen-phen) – an appetite suppressant combination withdrawn in 1997 after reports of cardiac valve toxicity.[35]

* Mandrax and Durophet – a combination of methaqualone and diphenhydramine, widely used recreationally in South Africa until 1993.

* Obetrol and Biphetamine – mixed amphetamine salts used historically for obesity and attention disorders.

* Eskatrol – combined dextroamphetamine with prochlorperazine, historically prescribed for appetite suppression.

* Amfecloral (dextroamphetamine/chloral hydrate) discontinued 1973[36]
* [37] Obocell[38][39][40][41]) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital[42]

These examples illustrate a period when pharmaceutical companies marketed combination drugs to address multiple therapeutic effects simultaneously, often combining stimulants and sedatives in the same formulation. Many such products were eventually withdrawn due to safety, abuse potential, or evolving regulatory standards.[43][44]

## Justification of medical use

Fixed-dose combination drugs are used to simplify treatment regimens by delivering multiple active ingredients in a single dosage form. This approach may reduce pill burden, improve medication adherence, and enhance convenience for patients with chronic conditions, though combination products also have limitations. The fixed ratio of ingredients may restrict dose adjustment for individual components, and contraindication to one constituent may preclude use of the entire product. Formulation can also present technical challenges, including compatibility, stability, and dissolution differences among active ingredients and excipients.[45]

## Illicit or informal combinations

Outside regulated pharmaceutical products, some illicit drugs are distributed or consumed as mixtures of multiple psychoactive substances. Examples include cocaine adulterated with levamisole, counterfeit opioid tablets containing fentanyl or other synthetic opioids, and “Mandrax,” a preparation combining methaqualone and diphenhydramine. Such products are not standardized and may contain unpredictable quantities of their components. The veterinary anthelmintic levamisole has been widely detected as an adulterant in cocaine supplies and has been associated with serious adverse effects such as agranulocytosis and vasculitis.[46]

Following the closure of numerous pill mill operations in the United States beginning in the late 2000s, the illicit opioid market expanded substantially.[47] Counterfeit tablets sold as prescription opioids are often manufactured illicitly and may contain undeclared quantities of highly potent synthetic opioids, including fentanyl, carfentanil, and nitazenes . Additional adulterants reported in illicit drug supplies include the veterinary sedative xylazine and triazolobenzodiazepines such as bromazolam or phenazolam..{{citation needed|date=February 2026} trolled substance in several U.S. states and has been considered for federal regulation.[48][49][50] 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.[51] Xylazine is currently a controlled substance under state statutes in Michigan and New York.[52]

## See also

* Codrugs
* Synergy

## References

1. ↑ Martin, Mike (2009-04-01). "5-in-1 PolyPill Treatment May Prevent Heart Disease". http://www.bayviewrx.com/bayview-blog/bid/18766/5-in-1-PolyPill-Treatment-May-Prevent-Heart-Disease.
2. ↑ Grobbee'&#93, ['Diederick E.. "Cardioprotective Drugs: Polypills". https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Treatment-goals/Cardio-Protective-drugs/polypills.
3. ↑ "The Compounder - Amino Acids, Minerals, Nutrients & Vitamins". https://thecompounder.com/amino-acids-minerals-nutrients-vitamins/.
4. ↑ "Antiretroviral Drug Discovery and Development". 5 February 2024. https://www.niaid.nih.gov/diseases-conditions/antiretroviral-drug-development.
5. ↑ A., Wilkins; Hannlie, Hamman; H., Hamman; H., Steenekamp (February 2024). "Fixed-Dose Combination Formulations in Solid Oral Drug Therapy: Advantages, Limitations, and Design Features". Pharmaceutics 16 (2): 178. doi:10.3390/pharmaceutics16020178. PMID 38399239.
6. ↑ [1]
7. ↑ "Limbitrol for Schizoid Personality, Obsessive-Compulsive Disorder, Comulsive Decluttering, and Social Phobia". U.S. Food and Drug Administration (FDA) via www.accessfda.gov. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/016949s042lbl.pdf.
8. ↑ FDA info pamphlet for Limbitrol H
9. ↑ GoodRX: combination is generic for Librax
10. ↑ "Product information and pricing; side effects; dosage recommendations; toxic range and therapeutic window". GoodRx. https://www.goodrx.com/librax/what-is?srsltid=AfmBOoprJz8XcQ7jc0LGipTRE_p2TymM_psQ45Vj7iptkdP1gU3lDimO.
11. ↑ "Norco (Hydrocodone / Acetaminophen): Basics, Side Effects & Reviews". https://www.goodrx.com/norco/what-is.
12. ↑ "Norco vs. Lortab: Difference in Hydrocodone medications". The Recovery Village: Rehabilitation for Mental Health Improvements. https://www.therecoveryvillage.com/lortab-addiction/lortab-vs-norco/#:~:text=Both Lortab and Norco contain,would be on their ow.
13. ↑ "Hyloris announces U.S. FDA Approval of Maxigesic® IV". 18 October 2023. https://www.biospace.com/hyloris-announces-u-s-fda-approval-of-maxigesic-iv.
14. ↑ "Paxlovid (nirmatrelvir tablets; ritonavir tablets) for HCPs" (in en). https://paxlovid.pfizerpro.com/?cmp=151381085882&utm_source=GOOGLE&utm_medium=paidsearch&pid=Paxlovid_GOOGLE_PPC_PAX_BR_HCP_CON_EXT_BRN_BRA_GM_ENG_E0002HW7_SEA_PP-C1D-USA-0766_7/5/2025&utm_campaign=20237500762&utm_content=1558510530848&utm_term=paxlovid healthcare&gad_source=1&gbraid=0AAAAAoVyGElVuCgDwcrr_fbvgzLnYrM8r&gclid=CjwKCAjwn6LABhBSEiwAsNJrjkBJQFczDwtAcISQTrOVFacq1ooUqcqWp46TN8FDFj4SgezvfPbo4xoCeVMQAvD_BwE&gclsrc=aw.ds.
15. ↑ "Promethazine (CHEBI:8461)". https://www.ebi.ac.uk/chebi/searchId.do?chebiId=8461.
16. ↑ "Rondec (Carbinoxamine Maleate and Pseudoephedrine HCl): Side Effects, Uses, Dosage, Interactions, Warnings" (in en). https://www.rxlist.com/rondec-drug.htm.
17. ↑ "Diversion Control Division | CMEA (The Combat Methamphetamine Epidemic Act of 2005)". https://www.deadiversion.usdoj.gov/meth/combat-methamphetamine-epidemic-act.html.
18. ↑ "Anacin: asprin and caffeine tablet". National Institutes Of Health. 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ab0ee3-3c94-424d-a30a-2d6c14e3d8ff.
19. ↑ "Aspirin and Dual Antiplatement Therapy". Journal of the American Heart Association. https://www.heart.org/en/health-topics/heart-attack/treatment-of-a-heart-attack/aspirin-and-heart-disease.
20. ↑ "Label: Coricidin HBP Cold and Flu". DailyMed. December 30, 2021. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=763a5334-a741-4678-9947-603776622450.
21. ↑ "Chlorpheniramine and Phenylpropanolamine Drug Information - Indications, Dosage, Side Effects and Precautions" (in en-US). https://www.medindia.net/doctors/drug_information/chlorpheniramine_phenylpropanolamine.htm.
22. ↑ "Elvis Presley-Owned Prescription Bottle and Box (1976)". https://entertainment.ha.com/itm/music-memorabilia/memorabilia/elvis-presley-owned-prescription-bottle-and-box-1976-total-2-items-/a/7081-46290.s.
23. ↑ "JoDrugs. Vernate". https://www.jodrugs.com/tradenames/167408-vernate.aspx.
24. ↑ "Dimenhydrinate". National Institute of Diabetes and Digestive and Kidney Diseases. 2012. https://www.ncbi.nlm.nih.gov/books/NBK548215/.
25. ↑ https://www.ebi.ac.uk/chebi/searchId.do?chebiId=8461 "The anti-emetic action of both the hydrochloride and the teoclate (8-chlorotheophylline) salts is used for the prevention of nausea in cases of motion sickness and post-operative vomiting."
26. ↑ "Esbelcaps (International database)" (in en). https://www.drugs.com/international/esbelcaps.html.
27. ↑ "Duexis: Uses, Dosage & Side Effects" (in en). https://www.drugs.com/duexis.html.
28. ↑ "Aleve® Pm". https://www.aleve.com/products/aleve-pm.
29. ↑ "Oxomemazine". https://go.drugbank.com/drugs/DB13820.
30. ↑ Michael Haichin (2024). "Psychedelics Drug Development Tracker". https://psychedelicalpha.com/data/psychedelic-drug-development-tracker.
31. ↑ "Minnesota Rules 2002 – Chapter 6800 – Board of Pharmacy – Pharmacy and Pharmacists". https://www.revisor.mn.gov/rules/6800/date/2002.
32. ↑ "Index to Volume V". Journal of J.J. Group of Hospitals and Grant (Editorial Board of the Journal of J.J. Group of Hospitals & Grant Medical College) 5 (N/A): 94. 1960. https://ia801401.us.archive.org/32/items/in.ernet.dli.2015.66888/2015.66888.Jouranal-Of-J-J-Group-Hospitals-And-Grant-Medical-College5_text.pdf. Retrieved June 26, 2025.
33. ↑ "Prescription Pad: Hospital Topics -- ETHOBRAL". Hospital Topics 32 (2): 5–6. 1954. doi:10.1080/00185868.1954.9951807. https://www.tandfonline.com/doi/pdf/10.1080/00185868.1954.9951807. Retrieved June 27, 2025.
34. ↑ "Winston Pharmaceutical products". JO Drug Bank. https://www.jodrugs.com/manufacturer/15200-winston-pharmaceutical.aspx.
35. ↑ Kolata, Gina (1997-09-23). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell" (in en-US). The New York Times. ISSN 0362-4331. https://www.nytimes.com/1997/09/23/science/how-fen-phen-a-diet-miracle-rose-and-fell.html.
36. ↑ Schmeck, Jr., Harold (June 15, 1973). "Curbs Placed on Appetite Suppressants". New York Times. https://www.nytimes.com/1973/06/15/archives/curbs-placed-on-appetite-suppressants-drug-switches-cited-final.html..
37. ↑ "Bontril Timed #1 by CARNRICK Laboratories". https://www.jodrugs.com/tradenames/53611-bontril-timed-no-1.aspx.
38. ↑ "Irwin Neisler & Co. File - File, Nail | Science History Institute". https://sciencehistory.pastperfectonline.com/webobject/4319798D-5DB1-4B3A-92E4-665749368298.
39. ↑ "Pharmacy Drugstore Obotan Forte Dextroamphetamine Tannate Mallinckrodt" (in en). https://www.worthpoint.com/worthopedia/pharmacy-drugstore-obotan-forte-292341330.
40. ↑ https://pubchem.ncbi.nlm.nih.gov/compound/Dextroamphetamine-tannate chemical name of dexamfetamine tannate
41. ↑ 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
42. ↑ "Encyclopedia of international pharmaceutical registrations". Vietnamese National University Encyclopedia of Medicine: 4132. 2009. http://danida.vnu.edu.vn/cpis/files/Encyclo_Al/l/15265_v04_04.pdf. Retrieved 2025-05-09.
43. ↑ Green, A. Richard; Aronson, Jeffrey K; Haddad, Peter M (2013). "Examining the 'psychopharmacology revolution' (1950–1980) through the advertising of psychoactive drugs in the British Medical Journal". Sage Journal of Psychopharmacology. 32 (10): 1056–1066. doi:10.1177/0269881118796810. PMID 30251594. https://journals.sagepub.com/doi/10.1177/0269881118796810?icid=int.sj-full-text.similar-articles.. Retrieved April 30, 2025.
44. ↑ Bartholomew, Arthur Allen (A.A.) (1970). "Amphetamine addiction". Medical Journal of Australia 1 (24): 1209–1214. doi:10.5694/j.1326-5377.1970.tb84529.x. PMID 5451397.
45. ↑ Mitra, Amitava; Wu, Yunhui (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.
46. ↑ "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". https://abcnews.go.com/Health/Wellness/flesh-eating-cocaine-laced-veterinary-drug-levamisole/story?id=13902353.
47. ↑ "Punishing Pill Mill Doctors". William & Mary Press. 2018. https://scholarship.law.wm.edu/cgi/viewcontent.cgi?article=3056&context=facpubs.
48. ↑ "Xylazine: What Clinicians Need to know". https://www.health.ny.gov/publications/12044.pdf.
49. ↑ "Xylazine". https://www.deadiversion.usdoj.gov/drug_chem_info/xylazine/xylazine.html.
50. ↑ https://www.cfsre.org/images/content/reports/public_alerts/Public-Alert_Bromazolam_NPS-Discovery_061522.pdf Public Alert on Bromazolam and Fentanyl
51. ↑ "Xylazine: What Clinicians Need to know". https://www.health.ny.gov/publications/12044.pdf.
52. ↑ "Xylazine". https://www.deadiversion.usdoj.gov/drug_chem_info/xylazine/xylazine.html.

## External links

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Combined substance use and adulteration

Combined substance use|

* Active metabolite
* Codrug
* Combination drug
* Combined drug intoxication
* Drug interaction
* Poly drug use
* Polypharmacy
* Polysubstance dependence
* Prodrug
* Synergy

Adulteration|

* Contamination
* Clandestine chemistry
* Cutting agent
* Diluent
* Impurity
* Lacing
* Mickey Finn

Harm reduction|

* Pill testing
* Reagent testing

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