Combination drug

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 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

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:

• amitriptyline/perphenazine, common brand Triavil
• amlodipine/benazepril: Lotrel
• bupropion/naltrexone: combination of 450 mg bupropion hydrochloride and naltrexone, branded Contrave
• butalbital/acetaminophen, branded Butapap
• butalbital and caffeine, branded Fioricet
• butalbital combined with aspirin and caffeine, branded Fiorinal
• butalbital, caffeine, acetaminophen, and [[codeine: Fioricet with Codeine
• amitriptyline/chlordiazepoxide: branded Limbitrol and Limbix in India
• amlodipine/atorvastatin brand Conduet
• Amlodipine/celecoxib: brand Consensai
• amlodipine/olmesartan: brand Azor
• amlodipine/valsartan: brand Exforge
• 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:

• Anacin by Bayer: OTC pill available since 1916, currently composed of 400 mg aspirin and 32 mg caffeine per serving (directions allow for not more than two tablets simultaneously).
• Coricidin by Bayer: a pharmaceutical product line of OTC combinations comprising a minimum of 2 mg chlorpheniramine maleate and dextromethorphan hydrobromide; Coricidin Cold & Cough further comprises two additional ingredients, 200 mg guaifenisin and acetaminophen; and Coricidin High Blood Pressure HBP is Coricidin plus 325 mg.
• Dramamine by Merck: a combination of 8-chlorotheophylline and diphenhydramine, yielding the chemical compound, dimenhydrinate, which is listed as a single active ingredient on the medicine's leaflet.
• fexofenadine/pseudoephedrine (Allegra-D) by GlaxoSmithKline): combination of 12 mg fexofenadine and 120 mg pseudoephedrine hydrochloride
• glucose/fructose/phosphoric acid, branded Emetrol for Nausea: combines glucose with fructose and phosphoric acid
• aspirin/paracetamol/caffeine (product line branded as 'Excedrin) by Bayer: product line combining 250 mg aspirin, 400 mg acetaminophen, and 35 mg caffeine
• ibuprofen/famotidine: combination of ibuprofen and famotidine, brand Duexis.
• ibuprofen/diphenhydramine (Advil PM): combination of 400 mg ibuprofen with 25 mg diphenhydramine citrate
• loratadine/pseudoephedrine, (Claritin-D): combination of 10 mg loratadine and pseudoephedrine hydrochloride
• naproxen/diphenhydramine (Aleve PM) by Bayer: combination of 220 mg naproxen 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 [[|tincture|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 pharmaceutical product line of cough medicines containing mixtures of dextromethorphan, acetaminophen, chlorpheniramine, 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 Pharma is an injectable liquid: 8mg chlorpheniramine maleate and 50 mg phenylpropanolamine per serving.
• Tri-Nefrin (among other trade names for tablet forms; Altec Syrup (primary brand name for liquid tincture formulation) available in Asia

Vernate Liquid, injectable liquid formulation by

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
• AutoMeprol-Fauziopolis by ?: combination appoved only for canines weighing over 100 lbs combining 7.5 mg phenobarbital sodium, 75mg carprofen, 11mg CBD exxtract, and clomipramine

Combination drugs no longer widely available

• Acutran by 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, Inc.: 10 mg dextroamphetamine sulfate, 30 mg nicotinamide, 40 mg amobarbital, 15 mg phenobarbital sodium, and essential vitamins and minerals
• Artogesic or artigesic 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, capsule polypill combining 7.5 mg each of two amphetamine salts: methamphetamine hydrochloride and dextroamphetamine sulfate, alongside 20 mg each of three barbiturate salts: phenobarbital, butabarbital, and secobarbital.
• Anxine by Behlen Manufacturing: combination of 120 mg mephenesin, 35 mg cyclobarbital sodium, and 2.5 mg dextroamphetamine sulfate, and
• BamaDex by Behlen Manufacturing: 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 (12.5 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
    • Tanphetamin by Neisler Laboratories: levoamphetamine and dextroamphetamine, both bonded to a tannic acid molecule.

• Bontril Timed product line by G.W. Carnrick Laboratories: 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: combination 5 mg methamphetamine hydrochloride and 30 mg pentobarbital sodium, discontinued 1973
• Dexamyl by Smith, French & Kline and Dexytal by Lilly & Co. (liquid elixir): 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: combination of 500 mg acetaminophen, 15 mg amobarbital sodium, and 2.5 mg methamphetamine hydrochloride
• Esbelcaps: combination of 20 mg fenproporex with 6 mg diazepam; never available in the U.S., but available OTC and by prescription in several Central American and South American countries until 2020
• Eskatrol by Smith, Kline & French: 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 : methaqualone hydrochloride and diphenhydramine, formerly commercially available in South Africa
• Mediatric by : 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 Laboratories: 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 [with Codeine]: by A.H. Robins: combination of hyoscamine sulfate, phenacetin, and aspirin, [option of additional 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: formerly SynaTan-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: combination of 100 mg cyclobarbital sodium and 10 mg diazepam, available in Russia until 2019
• Tuinal by Abbott Laboratories: 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 combination drugs are often formulated as a 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, 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 powder, ephedrine or pseudoephedrine; and in recent years, the flesh-eating veterinary antibiotic levamisole

Illicit depressants and opiates

Due to the crackdown of pill mills between 2007-2012, 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 freebase form of methaqualone, which is smoked for a quick high.

The proportion of cutting agents as part of a product's overall composition has increased greatly since 2013. Powder sold as "heroin" is often found to be "cut" or "adulterated" with central nervous system depressants as diverse as major tranquilizers and antipsychotics (e.g. quetiapine), first-generation antihistamines (e.g. diphenhydramine, meclizine, promethazine, pyrilamene, doxylamine, hydroxyzine), or benzodiazepine, barbiturate, or opiate derivative and analogs, often research chemicals, including clobromazolam and etizolam. Since 2020, there has been a noticeable rise amongst active ingredients in opioid combinations containing fentanyl.

Since 2023, worldwide samples of illicit combinations featuring opioids have contained substances classified as nitazene. have been found in these opioid samples– all of which mimic the muscle relaxant, anxiolytic, and analgesic properties of pharmaceutical-grade opioid medications. U.S. Attorney General has indicated interested in federally regulating the relative mild veterinary sedative xylazine, which is currently available by prescription only, as a federally-controlled Schedule III controlled substance per the Controlled Substances Act, a direct response to its implication in overdose deaths featured in products alongside fentanyl and other power central nervous system depressants; xylazine is currently a controlled substance at the state level in Michigan and New York.

See also

• Codrugs
• Synergy#Drug synergy

External links

• Media related to Combination drugs at Wikimedia Commons