Combination Drugs

A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a ''fixed-dose combination'', with each constituent standardized to specifications of a fixed dose. Fixed-dose combinations are mass-produced and mass marketed, intended to serve as a near universal treatment for a large patient population with diverse medical histories, conditions, predisposition thereof, and treatment requirements.

A '' polypill'' is a pharmacy or capsule containing four or more active ingredients, often needing to be compounded at a specialized pharmacy in order to satisfy the specifications of a patient's personalized prescription and treatment plan, including dosage form, medicinal dosing, and/or mechanism of release. Polypills encompass approved prescription drugs and over the counter drugs, at times including nutritional supplements, amino acids, vitamins, minerals, and hormones.

Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV. Over time, the concept of combination drugs has come to include reducing pill burden for patients, thereby encouraging patient compliance, and generally simplifying treatment plan with one product containing easily accessible (often available over the counter without a prescription requirement), relatively affordable (often generic drugs) ingredients with established therapeutic efficacy and a broad capacity for treating a variety of symptoms and conditions, thus ensuring maximum appeal to a majority of patients amongst a large population with varying needs.

Current prescription combination drugs

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:
* amitriptyline/perphenazine, brand brand Triavil
* amlodipine/benazepril: Lotrel
* amitriptyline/chlordiazepoxide: brandLimbitrol in India, Limbix (Bangladesh)
* amlodipine/atorvastatin brand Conduet
* Amlodipine/celecoxib: brand Consensai
* amlodipine/olmesartan: brand Azor
* amlodipine/valsartan: brand Exforge
* bupropion/naltrexone, 450 mg bupropion hydrochloride and naltrexone, brand Contrave
* butalbital/acetaminophen, brand Butapap
* butalbital and caffeine, branded Fioricet
* butalbital combined with aspirin and caffeine, branded Fiorinal
* butalbital, caffeine, acetaminophen, and codeine: Fioricet with Codeine
* chlordiazepoxide combined with clidinium bromide:
* ephedrine/ethylmorphine: Lephotan
* lisinopril/amlodipine: Lisonorm'
* lisinopril/hydrochlorothiazide: Zestorenic
* Paxlovid: combination of nirmatrelvir and ritonavir for treatment and management of COVID-19.
* hydrocodone/acetaminophen, common brands Norco and Vicodin
* Deanxit by Lundbeck, available in India and Bangladesh: combination of flupentixol and melitracen
* hydrocodone/aspirin: Azdone
* hydrocodone/guaifenesin: Obedron
* hydrocodone/ibuprofen: Ibudone
* omeprazole/amoxicillin/rifabutin, brand Talicia
* olanzapine/fluoxetine, branded Symbyax
* oxycodone/acetaminophen, common brand Percocet
* oxycodone/aspirin: Percodan
* oxycodone/ibuprofen: Combunol
* phentermine/topiramate, under patent as Qsymia: combination of 37.5 mg phentermine hydrochloride and 150 mg topiramate
* phenylephrine/ketorolac brand Omidria
* Amphetamine mixed salts of the racemic: dextroamphetamine sulfate, dextroamphetamine saccharate, levoamphetamine aspartate monohydrate, levoamphetaminee sulfate, commonly Adderall and Mydayis
* pseudoephedrine/carbinoxamine, Rondec syrup

Combination drugs accessible over the counter (OTC)

Fixed-dose 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.

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

* Bayer Anacin: pill available since 1916, constituting 400 mg aspirin and 32 mg caffeine.
* Bayer Coricidin: a product line sold OTC combinations at least 2 mg of an antihistamine ( chlorpheniramine dextromethorphan hydrobromide:
**Coricidin Cold + Cough: antihistamine chlorpheniramine combined with 200 mg guaifenesin ( expectorant) and acetaminophen; and
**Coricidin High Blood Pressure is a combination of chlorpheniramine, guaifenisin or phenylephrine, 325 mg.
* diphenhydramine + 8-chlorotheophylline produces dimenhydrinate, generally branded Dramamine.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."
* fexofenadine/pseudoephedrine by GlaxoSmithKline: combination of 12 mg fexofenadine and 120 mg pseudoephedrine hydrochloride, Allegra-D
* glucose/fructose/phosphoric acid, Emetrol for Nausea: combines glucose with fructose and phosphoric acid
* aspirin/paracetamol/caffeine (primary brand Excedrin) b: product line combining 250 mg aspirin, 400 mg acetaminophen, and 35 mg caffeine
* ibuprofen/famotidine: combination of ibuprofen and famotidine, brand Duexis.
* ibuprofen/diphenhydramine: combination of 400 mg ibuprofen with 25 mg diphenhydramine citrate Advil PM
* loratadine/pseudoephedrine: combination of 10 mg loratadine and pseudoephedrine hydrochloride, Claritin-D
* naproxen/diphenhydramine by Bayer: combination of 220 mg naproxen sodium and 25 mg diphenhydramine hydrochloride
* naproxen/pseudoephedrine (branded Aleve-D): 220 mg naproxen sodium and 120 mg pseudoephedrine hydrochloride
* oxomemazine/guaifenesin (primarily branded Toplexil by Aventis): most frequently taken orally in liquid syrup dosage form, but generically is also available in suppository and pill dosage forms. Aventis' fixed-dose preparation, Toplexil, constitutes oxomemazine exactified to a dose of 1.65 mg/5ml and guaifenesin exactified to 33.3 mg/5ml. Utilized in France, Algeria, Morocco, oxomemazine itself has never been FDA- approved for medical use in the United States.
* Robitussin: a product line of cough medicines containing the antitussive/cough suppressant, dextromethorphan; antipyretic analgesic acetaminophen/paracetamol; either the antihistamine chlorpheniramine maleate, or doxylamine succinate; and the expectorant/mucus thinner, guaifenesin.
* Sudafed PE: combination of 300 mg guaifenesin and 50mg phenylephrine hydrochloride
* Tylenol PM by Johnson & Johnson: combination of 500 mg acetaminophen and 25 mg diphenhydramine
* Vernate by Tutag Pharmaceuticals is an injectable elixir or liquid: 8mg chlorpheniramine maleate and 50 mg phenylpropanolamine per serving.
* Tri-Nefrin for tablet forms; Altec Syrup (primary brand name for liquid tincture formulation) available in Asia
* Vernate Liquid, injectable liquid formulation by Tutag Pharmaceuticals

Combination drugs under development, not yet approved for medical use

* MDMA/citalopram: an empathogen called "Ecstasy" combined with citalopram (SSRI); currently under development in FDA Phase II clinical trials.

Combinations drugs for veterinary use

* Temaril-P: alimemazine and prednisolone; indicated as antitussive and antipruritic in dogs, generic since 2024. The generic alternative to the brand version substitutes alimemazine with trimeprazine, but is otherwise identical in terms of formulation and efficacy.
* Titzeol: combination of tiletamine and zolazepam both major tranquilizers, intended to sedate large animals

Combination drugs no longer widely available

* Acutran by G.W. Carnrick Laboratories: amfecloral, a chemical compound constituting dextroamphetamine sulfate and chloral hydrate, discontinued 1973
* Ambar by Wyeth: combination of methamphetamine hydrochloride and phenobarbital sodium; Ambar Extentab is the extended-release formulation
* Amphaplex 10 and Amphaplex 20 by Laderle Laboratories: combination of 2.5 mg methamphetamine saccharate, 2.5 mg methamphetamine hydrochloride, 2.5 mg levoamphetamine sulfate, and 2.5 mg dextroamphetamine sulfate; the latter comprised 20 mg in aggregate: combining 5 mg methamphetamine saccharate, 5 mg methamphetamine hydrochloride, 5 mg levoamphetamine sulfate, and 5 mg dextroamphetamine sulfate.
* Amplus Now by Roehrig Laboratories, Inc.–combined 5 mg dextroamphetamine sulfate and 5 mg hydroxyzine
* Amvicel by Roehrig Laboratories: 10 mg dextroamphetamine sulfate, 30 mg nicotinamide, 40 mg amobarbital, 15 mg phenobarbital sodium, and essential vitamins and minerals
* Artogesic by Cole Pharmaceuticals: combination of dextroamphetamine, mephobarbital, phenacetin, and salicylamide. Name since recycled by Glenmark of India for a brand of ibuprofen.
* Apamead by Lederle Laboratories: combination of dextroamphetamine sulfate, amobarbital sodium, aspirin, and phenacetin
* Anox by Winston-Salem Pharmaceuticals were encapsulated polypills containing a fixed dose combination of three barbiturate salts (each measured at 20 mg for a total of 60 mg barbiturates) combined with two amphetamine salts, each measured at 7.5 mg, for a total quantity of 15 mg amphetamines. Anox encompassed phenobarbital, butabarbital, secobarbital, methamphetamine hydrochloride, dextroamphetamine sulfate, respectively measured at 7.5 mg, 7.5 mg,.
**Diacels is the extended release version of this.
**Ethobral was Wyeth's combination.
* Anxine by Behlen Manufacturing: combination of 120 mg mephenesin, 35 mg cyclobarbital sodium, and 2.5 mg dextroamphetamine sulfate, and
* BamaDex by Behlen: combination of 5 mg dextroamphetamine and 400 mg meprobamate
* Biphetamine T-12.5 and Biphetamine T-20 by Fisons: combination of 6.25 mg levoamphetamine and 6.25 mg dextroamphetamine (1/2.5 mg racemic amphetamine; 10 mg levoamphetamine and 10 mg dextroamphetamine (20 mg racemic amphetamine)
* Delcobese by the Lemmon Drug Company: combination of mixed salts of amphetamine sulfate and adipate: 50% levoamphetamine sulfate and adipate combined with 50% dextroamphetamine sulfate and adipate, voluntarily withdrawn from production by the Lemmon Company in 1984
* Bontril Timed product line by Carnrick: Bontril Timed No. 1 combined 2.5 mg dextroamphetamine and 7.5 mg butabarbital sodium; Bontril Timed No. 2 5 mg dexamphetamine and 15 mg butabarbital; Bontril Timed No. 3 10 mg dexamphetamine with 30 mg butabarbital; and Bontril Timed No. 4 15 mg dexamphetamine with 60 mg butabarbital.
* Desbutal Neisler Laboratories: combination 5 mg methamphetamine hydrochloride and 30 mg pentobarbital sodium, discontinued 1973
* Dexytal by Eli Lilly & Co., as a liquid elixir: dextroamphetamine and amobarbital sodium
* Dexamyl by Smith, Kline & French, as tablets: and dextroamphetamine and amobarbital sodium, discontinued 1982
* Durophet M by/ Neisler Labs: combination of 6.5 mg levoamphetamine and 6.5 mg dextroamphetamine (13 mg racemic amphetamine) with 400 mg methaqualone hydrochloride; available in the United Kingdom until 1984, amidst international crackdown on methaqualone
* Durabond by Neisler Laboratories:
* Daprisal by GlaxoSmithKline: dextroamphetamine sulfate, 32.5 mg amobarbital sodium, and 162.5 mg aspirin
* Direcel: combined dextroamphetamine, butabarbital, and carboxymethylcellulose; Direcel-T added thyroid hormone
* Duodex: combination of 16.25 mg aloin, 15 mg amphetamine sulfate, 16.25 mg pentobarbital, and thyroid hormone
* Dysonil: combination of methamphetamine hydrochloride, pentobarbital sodium, and salicylamide
* Edrisal: combination 160 mg aspirin and 160 mg phenacetin with 2.5 mg amphetamine sulfate; a formulation containing 16 mg codeine as an additional active ingredient was branded Edrisal with Codeine
* Elpanal Lamital by Teva Pharmaceuticals: combination of 500 mg acetaminophen, 15 mg amobarbital sodium, and 2.5 mg methamphetamine hydrochloride
* Esbelcap ( fenproporex/ diazepam): combination of 20 mg fenproporex with 6 mg diazepam; never approved foruse in the JU.S., but is available over the counter in Central and South American countries until 2020
* Eskatrol by Smith, French & Kline: combination of dextroamphetamine and prochlorperazine; discontinued 1981
* Euphoramin: 5 mg methamphetamine hydrochloride and 300 mg meprobamate
* NalerTan by Neisler: combination of 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate
* Mandrax by Lemmon Company: methaqualone hydrochloride and diphenhydramine, commercially available in South Africa until 1990s
* Mediatric by Janssen: combination of two hormones, 0.25 mg Premarin (Conjugated Estrogens USP) and 2.5 mg methyltestosterone, along with 100 mg vitamin c, b vitamins, and 1 mg methamphetamine hydrochloride
* Nexorin: combination of dextroamphetamine sulfate, amobarbital sodium, methylcellulose, and supplements
* Obocell by Neisler: combination of 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate; Obocell-TF was nearly identical but with an additional 160 mg high-viscosity methylcellulose
* Obetrol by Abbott Laboratories: combination of various mixed salts of the substances, methamphetamine and dextroamphetamine; discontinued in 1973
* Obolip: dextroamphetamine and phenobarbital, with choline bitartrate, di-methionine, and methylcellulose
* Phelantin by Parke-Davis: combination of 100 mg phenytoin sodium, 32 mg pentobarbital sodium, and 2.5 mg methamphetamine hydrochloride.
* Phenephen: by A.H. Robins: combination of hyoscamine sulfate, phenacetin, and aspirin,
* Phenephen with Codeine by A.H. Robins: combination of hyoscamine sulfate, phenacetin, aspirin, codeine
* Pondimin ( Fen-Phen): combination of fenfluramine and phentermine, discontinued 1997
* SynaTan-S by Neisler Laboratories: combined 10 mg dextroamphetamine tannate with 35 mg secobarbital sodium, since 1955
* OboTan-S by Mallinckrodt: combination 10 mg dexamphetamine tannate and secobarbital sodium
* Pre M.T. by Behlen Manufacturing, a polypill and tablet containing: levoamphetamine sulfate, dextroamphetamine sulfate, pentobarbital sodium, pyrilamine maleate, and a micro-dose of theobromine.
* Reladorm by unknown domestic Russian manufacturer: combination of 100 mg cyclobarbital sodium and 10 mg diazepam, available in Russia until 2019
* Tuinal by Abott: combination of two barbiturate salts, amobarbital and secobarbital, discontinued 1999

Medical use and justification of discontinued combination drugs

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 (colloquially called "uppers") were used as appetite suppressants, antidepressants, and wakefulness-promoting agents, and further effects include increased mental alertness and concentration/focus, as well as physical energy and motivation. The addition of a central nervous system depressant mitigated the stimulant's adverse effects without eliminating therapeutic benefits. In most cases, the "upper" component of these combination drugs was a salt, or mixed salts, of racemic amphetamine, dextroamphetamine, or methamphetamine, while the "downer" was typically one or more barbiturates (most commonly amobarbital, phenobarbital, pentobarbital, and/or secobarbital) or similar GABAergic, non-barbiturate tranquilizers or sedatives, frequently meprobamate or methaqualone, respectively, which provided anxiolytic, muscle relaxant, and hypnotic effects. Upper and downer combination drugs were often capable of substituting for Monoamine Oxidase Inhibitors (MAOIs) in patients with treatment-resistant depression where MAOIs are indicated, but where MAOI-related dietary restrictions would impact patient's life.

Combination drugs offer the advantage over polypharmacy by decreasing patients' pill burden. Overall, giving patients the ability to take control and alleviate symptoms, and potentially treat or cure multiple conditions by consuming all of their medical treatments efficacious treatment options by the ingestion of a single pill, which consistently improves patient medication compliance by reducing their pill burden. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."

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 For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.

Limitations of currently-available combinations

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 whose only FDA-approved treatment is the neuroleptic pimozide, a drug only used for tics due Tourette's disorder; every other treatment is an off-label use. While Tourette's is typically identified by chronic motor and vocal tics–"semi-voluntary" movements and noises made in response to a " premonitory urge," an internal buildup of compulsive tension that can only be temporarily upon performing/making the motion/sound demanded by compulsion. Tourette's, however, is an all-encompassing umbrella term that includes not just chronic physical and phonic tics, but also presents with such comorbid symptoms as anxiety (often OCD, social anxiety, schizoid personality, avoidant personality disorder, or generalized anxiety), ADHD, insomnia, depression, and traits of high-functioning autism formerly called Asperger syndrome.

Illicit streets as de facto drug combinations

Illicit stimulants

Illicit drugs are formulated as powder, paste, or counterfeit "pressed" pills intended to resemble their pharmaceutical-grade counterparts. Since 2018, ABC News of Houston reports that product described as "powder cocaine" originating from a clandestine laboratory are increasingly analyzed and found to contain other stimulants, which may provide similar excitement in order to mimic cocaine's effects in a cost-effective, deceptive manner; many of the batches analyzed did not contain any cocaine or coca alkaloids whatsoever; instead, they were blends of various designer drugs and research chemicals, typically synthetic cathinones, MDMA, methamphetamine, caffeine, ephedrine or pseudoephedrine; and in recent years, the flesh-eating veterinary antibiotic levamisole

Illicit depressants (opiates, sedative, tranquilizers)

Due to the crackdown of pill mills between 2007 and 2012, the opioid epidemic frequently includes drug deals whereby a substance may often be sold as "heroin" or legitimate pharmaceutical pills ("pressed," counterfeit, often adulterated pills).
Mandrax in South Africa is now produced via clandestine chemistry as a free base form of methaqualone, which is smoked for a quick, intense, short-lived "high". Proportionate to an illicit substance's active ingredient or alkaloid, cutting agents have risen in quantities present. In the United States, analyzed samples of products declared upon sale/drug transacting to be "heroin" 97% contained, at minimum, trace amounts of adulerating "cutting agents", generally a synthetic opioid such as fentanyl, carfentanil, nitazene.

Mislabeled products containing non-opioid ingredients will likely comprise clobromazolam, etizolam, or another benzodiazepine. Several other central nervous system depressants have been identified in samples of products sold as "heroin," intended to mimic sedative and analgesic properties of opioids, including major tranquilizers such as drowsiness-inducing typical, first generation antipsychotics (e.g. haloperidol, e.g. chlorpromazine) or the atypical antipsychotics quetiapine or olanzapine, as both are "neuroleptics") or a particularly sedating first-generation antihistamines such as diphenhydramine, and increasingly xylazine–which is only approved forveterinary use via prescription. In April 2025, U.S. Attorney General Pam Bondi stated a goal of making xylazine a federally-controlled Schedule III controlled substance per the Controlled Substances Act, xylazine is currently a controlled substance at the state level in Michigan and New York.

See also

* Codrugs
* Synergy#Drug synergy

References

External links

*

{{Combined substance use and adulteration

Dosage forms