Combination drug

{{about|fixed-dose combination drugs and polypills as treatments|two synergistic drugs chemically linked together|codrug|use of multiple separate and individual drugs for treatment|polypharmacy|drug combined with a separate device or form|[[combination product medical)}}

A combination drug is a preparation of multiple pharmaceuticals or active ingredients in a single dosage form, intended to simplify a patient's treatment regimens, reducing their pill burden, and offering broad potential for treating various conditions among large and diverse patient population experiencing a wide array of symptoms and conditions, and having the major benefit of simplifying a patient's pill burden and simplify their treatment regimen. A fixed-dose combination is the most common sub-type of combination drug; namely, one produced combining at least two active ingredients at standardized, exactified, unchanging dosages with broad potential for treating various conditions among diverse patient populations experiencing a variety of symptoms and conditions, and having the major benefit of simplifying a patient's pill burden and simplify their treatment regimen, despite initially being developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV.^[1]

Another sub-type is the polypill; is any "pill" meant to be taken by mouth (e.g. tablet, capsule) consisting of four or more active ingredients^[2] and often, but not always, in fixed-dose combination. A compounded combination is personally prepared by a compounding pharmacy as instructed by the patient's peronalized medical prescription and their individual needs, contraindications, history, etc.s well the patient;s individual needs. age form]]s, additives such as filler and binders) with specifications catered to an individual patient's needs and their personalized medical prescription. In the case of compounded formulations, a compounding pharmacist may include a range of health products, including prescription drugs, over the counter drugs, sometimes with dietary supplements, amino acids, essential minerals , vitamins, or hormones. An An illicit drug combination refers to any [[street drug synthesized or manufactured in sub-stellar sanitary conditions by an under-qualified amateur chemist, defined as clandestine chemistry. These products likely to contain, across batches, varying ingredients and imprecise doses, inconsistently certain to be free of impure cutting agents, byproducts, inactive ingredients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly purchased and consumed analgesics (pain reliever) in the world, indicated for the temporary relief of minor aches and pain and inflammation. NSAIDs are typically accessible over the counter and may also relieve tension headaches or migraine, while aspirin in particular has anticoagulant (blood-thinning, anti-clotting factors) that can reduce the risk of heart disease, heart failure, or stroke in predisposed patients, and thinning blood, thus lowering one's risk of heart attack or stroke. Paracetamol (International Nonproprietary Name, called acetaminophen in the U.S. has proven efficacy as an antipyretic (fever reducer), and a more debatable analgesic profile as it does not possess antiinflammatory properties. Many patients do find acetaminophen to effectively relieve headache or minor aches joint pain, particularly when resulting from fever, and when acetaminophen is combined with an anti-inflammatory agent and.or caffeine, allowing drug synergy to potentiate the effects of each other. both products may work synergistically and potentiate, or increase/boost/boost the effects of each other.

A fixed-dose combination drug such as Advil Dual Action with Acetaminophen can simplify treatment for a patient experiencing body aches and/or joint pain and inflammation, whereas a patient experiencing inflammatory joint pain and a headache or fatigue/lethargy would benefit the addition of a third active ingredient, such as caffeine, which is commonly combined with pain relievers and fever reducers to provide a slight boost in alertness, mood, and wakefulness, especially when lethargy and fatigue are a result of fever. Caffeine has demonstrated efficacy in reducing reducing tension headaches and migraines in its own right, but also has drug synergy with the other paired ingredients, thus potentiating the effects of each other. Excedrin is a particularly poignant example of a combination able to theoretically treat migraine or tension headache, inflammation, joint pain or arthritis, as well as work as an anticoagulant in patients predisposed to heart disease or stroke per its inclusion of aspirin.^[3]

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:

• Adderall: dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate; indicated for treating attention deficit hyperactivity disorder and narcolepsy.
• Contrave: bupropion (stimulating antidepressant) combined with naltrexone (an opioid antagonist); indicated for aiding smoking cessation and weight loss.
• Qsymia: phentermine hydrochloride (CNS stimulant and anorectic), topiramate (anticonvulsant, appetite suppressant and relieves migraines)indicated for weight management as an anorectic and anti-obesity drug

• Lephotan: ephedrine (sympathomimetic decongestant) combined with ethylmorphine (antitussive, analgesic agent)
• Librax: chlordiazepoxide (benzodiazepine tranquilizer and muscle relaxant) combined with clidinium bromide^{[clarification needed]}, treating gastrointestinal ulcers
• Paxlovid): granted emergency use authorization by the U.S. Food and Drug Administration for the treatment and management of COVID-19.^[4]
• Coldec, Ceron (pill form): carbinoxamine (anticholinergic antihistamine) combined with pseudoephedrine (sympathomimetic nasal decongestant);
• Rondec Syrup also combines carbinoxamine and pseudoephedrine, albeit in the dosage form of a liquid syrup, and further supplement with 4mg chlorpheniramine maleate (sedating, first generation anthistamine) and 12.5mg phenylephedrine hydrochloride (sympathomimetic); Unavailable in the U.S.^[5]

• Omidria (phenylephrine/ketorolac, preservision of eye tissue during opthalmalogic surgery

• Talicia: Omeprazole (proton pump inhibitor) combined with amoxicillin (anibiotic) and rifabutin

• Zestoric, Prinzide: lisinopril (ACE inhibitor) combined with hydrochlorothiazide (diuretic); treating hypertension
• Lisonorm, Dironorm): lisiniopril combined with amlodipine (calcium channel blocker), hypertension
• Lotrel by Novartis: ratios beginning 5mg amlodipine besilate (calcium channel blocker) combined with 10mg benazepril hydrochloride (ACE inhibitor); consecutive ratios include 5:20 amlodipine:benazpril, 10:20, and 10:40; indicated as a second-line antihypertensive
• Azor: amlodipine besilate combined with olmesartan medoxom (ACE Inhibitor),; second-line treatment of hypertension.
• Conduet, treatment of hypertension with comorbid hypercholesterolemia
• Consensai: amlodipine medoxom combined with celecoxib (COX-2 inhibitor)' indicated for treating hypertension comorbid to hypercholesterolemia and/or osteoarthritis pain.
• Exforge: amlodipine combined with valsartan (Angiotensin II receptor antagonist)

• Triavil, Duo-Vil (amitriptyline/perphenazine): amitriptyline perphenazine
• Deanxit by Lundbeck (flupentixol/melitracen): 0.5mg flupenthixol (typical antipsychotic) and 10mg melitracen (tricyclic antidepressant), available in India, indicated for major depressive disorder and dysphoria
• Limbitrol (amitriptyline/chlordiazepoxide): 12.5mg amitriptyline HCL (sedating TCA, nerve pain relief, 5mg chlordiazepoxide (mild benzodiazepine anxiolytic and muscle relaxant); Limbitrol DS is the double-strength formula: 25mg amitriptyline hydrochloride, 10mg chlordiazepoxide, treating moderate to severe depression]], anxiety, and insomnia.
• Qsymia (phentermine/topiramate): anoretic CNS stimulant and anorectic anticonvulsant, indicated for weight management as an anorectic and anti-obesity drug
• Auvelity: dextromethorphan (antitussive) and bupropion in one tablet, major depressive disorder.
• Symbyax (Olanzapine/fluoxetine): bipolar I disorder
• MDMA/citalopram: an empathogen called "Ecstasy" combined with citalopram (SSRI antidepressant); currently under development in FDA Phase II clinical trials.^[6]

• Percocet: oxycodone and 325mg acetaminophen
• Brontex, Obredon: mild opioid and expectorant to treat chronic pain and looseng phlegm.
• Vicodin, Lortab, Norco combines hydrocodone, 325mg acetaminophen
• Percodan: oxycodone (opioid analgesic, branded Roxicodone in isolation), aspirin (NSAID, anticoagulant, cardioprotective, blood thinner) relieves chronic, severe generalized pain.
• guaifenesin/codeine: guaifenesin (expectorant for chest congestion to thin mucus and phlegm), codeine (a mild opioid analgesic)
• Butapap combines butalbital, acetaminophen, caffeine and codeine
• Combunol: 5mg oxycodone combined with 400 mg ibuprofen
• Azdone): hydrocodone bitartrate combined with aspirin, indicated antitussive
• Ibudone: opioid and anti-inflammatory agent, potentiating analgesics

• Anervan: Ergotamine , chlorcyclizine, caffeine anti-migraine medication
• Arthrotec: diclofenac sodium (NSAID) combined with misoprostol (GI Tract Prostaglandin-protectant)
• Cafergot, Migergot: indicated for treatment of headaches, particularly migraine
• Donnatal: phenobarbital, sulfates of hyoscyamine and atropine, and scopolamine hydrobromide (latter two ingredients derive from Atropa bella-donna Belladonna-derived indicated for the treatment of acid reflux , [[GER
• Fiorinal: butalbital ([barbiturate]], sedative, muscle relaxer) combined with aspirin (NSAID, anticoagulant) and caffeine (mild stimlant, anticoagulant)..
• Fioricet: butalbital butalbital (barbiturate) combined with acetaminophen and caffeine; treatment of tension, cluster, and migraine headaches
• Excedrin: aspirin, acetaminophen, and caffeine; indicated as analgesics for tension headache and migraine
• Saridon: caffeine combined with propyphenazone (long-acting antipyretic) and paracetamol (short-acting antipyretic and mild analgesic); indicated for reducing fever and treating minor aches, and relieving fatigue and lethargy.

headache.

• Sybravo: Meloxicam (NSAID) combined with rizatriptan (triptan); indicated as an antimigraine medication; only an FDA-approved drug in January 2025
• Treximit (sumatriptan/naproxen): sumatriptan ([[[triptan]] and antidepressant) combined with naproxen sodium (NSAID)

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

treating motion sickness, nausea, and vomiting, and well as allergy symptoms, including:

• Anacin: 32mg caffeine, 400mg aspirin; 25:262 ratio originally
• Dramamine (dimenhydrinate): 8-chlorotheophylline, diphenhydramine, used to treat motion sickness and nausea.
• Emetrol for Nausea (glucose/fructose/phosphoric acid) — antiemetic taken to relieve nausea and vomiting
• Excedrin: caffeine, acetaminophen, aspirin ; migraine headaches, pain, lethargy due to fever
• Drixoral (dexbrompheniramine/pseudoephedrine): dexbrompheniramine (antihistamine), pseudoephedrine (decongestant), in Canada

• Aleve PM (combination naproxen/diphenhydramine), 220mg naproxen, 12.5mg diphenhydramine hydrochloride, analgesic sleep aid
• Advil PM (ibuprofen/diphenhydramine) 400mg ibuprofen, 25mg diphenhydramine hydrochloride
• Tylenol PM: 500mg acetaminophen, 38mg diphenhydramine hydrochloride

• Duexis (ibuprofen/famotidine) for acid reflux, indigestion, and general mild pain relief and arthritis pain.^[7]

The following medications consist of a variety of active ingredients indicated for cough (cough suppressants), congestion (expectorants and nasal decongestant, antihistamines, and/or an antipyretic (fever-reducing agent). In the United States, any of the products listed below containing ephedrine or pseudoephedrine are not prescription drugs, but they are stored behind the pharmacy counter, and requires additional steps to complete purchase of these products per U.S. federal law, the Combat Methamphetamine Epidemic Act of 2005:^[8]

• Allegra-D – fexofenadine/pseudoephedrine, a second-generation antihistamine and a sympathomimetic decongestant
• Claritin-D – loratadine/pseudoephedrine, a second-generation antihistamine and an activating decongestant
• Zyrtec-D – cetirizine/pseudoephedrine, 5mg ceterizine (second-generation antihistamine), sympathomimetic decongestant
• Aleve-D pairs the NSAID analgesic Aleve with the activating decongestant pseudoephedrine
• Robitussin: cough medicines comprising dextromethorphan, acetaminophen, chlorpheniramine,
• Allerest, Chlor-Rest, Tri-Nefrin (all pills for oral administration); Altec Syrup (syrup taken orally): chlorpheniramine (sedating first-generation antihistamine) and phenylpropanolamine (PPA) (activating sympathomimetic nasal decongestant) of varying fixed doses. Vernate by Tutag Pharmaceuticals: 8mg chlorpheniramine maleate, 50mg PPA per serving.^[9][10][11]
• Coricidin by Bayer: a product line of fixed-dose combination drugs indicated for cough, cold- and flu-like symptoms, allergic rhinitis, and nasal and chest congestion. At basic, ingredients include dextromethorphan (a cough suppressant), chlorpheniramine maleate, (a first-generation antihistamine), and the expectorant guaifenesin, with certain Coriciden also including 500mg acetaminophen.^[12]
• Oxomemazine/guaifenesin combines a sedative antihistamine and an expectorant, respectively. Never FDA-approved for use in the U.S.
• Sudafed PE): guaifenesin, phenylephrine (expectorant and nasal decongestant).

• 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^[13]

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.

• Acutran (amfecloral): dextroamphetamine sulfate and chloral hydrate), discontinued 1973
• Ambar (standard release): unknown doses of methamphetamine hydrochloride and phenobarbital; Ambar Extentab (XR) formulation
• Amvicel: 10mg dextroamphetamine sulfate, 40mg amobarbital, 15mg phenobarbital; Amvicel-X: supplemented with multivitamins (A, B, and C), minerals (calcium, iron, manganese, zinc), and 30mg nicotinamide
• Anox polypill capsule by Winston Biotech: sustained-release 7.5mg methamphetamine hydrochloride, 7.5mg dextroamphetamine sulfate with 20mg phenobarbital, 20mg butabarbital, 20mg secobarbital; Diacelx: extended-release formulation launched 1965^{[citation needed]}
• Anxine: 2.5mg dextroamphetamine sulfate, 35mg cyclobarbital, and 120mg mephenesin (a muscle relaxant)
• Appetrol: 5mg dextroamphetamine, 400mg meprobamate (tranquilizer and anxiolytic)
• BamaDex: 6mg dextroamphetamine, 400mg meprobamate (minor tranquilizer and anxiolytic)
• Biphetamine T-12.5by Fisons:12.5mg racemic amphetamine (1:1 mixture 6.25mg levoamphetamine:6.25mg dextroamphetamine)
• Biphetamine T-2020 by Fisons: 20mg [[racemic [[amphetamine (1:1 mixture 10mg levoamphetamine:10mg dextroamphetamine)
• Desbutal: 5mg methamphetamine hydrochloride and 30mg pentobarbital, discontinued 1973
• Dexamyl: dextroamphetamine and amobarbital, discontinued 1982
• Durophet M: 13mg racemic amphetamine (1:1 6.25mg levoamphetamine:6.5mg dextroamphetamine, 40mg methaqualone hydrochloride
• Esbelcaps: 20mg fenproporex,6mg diazepam, Mexico, Panama, Honduras, Nicaragua, Dominican Republic^[14]
• Euphoramin: 5mg methamphetamine hydrochloride, 300mg meprobamate
• SynaTan-S, later ObaTan-S by Neisler Laboratories: Tanphetamin is the a generic trademark referring to the compound Tanphetamin, which was introduced by Neisler Labs in 1954 following the bonding of d-amphetamine to a tannate molecule. In 1957, Neisler chemists combined 10mg Tanphetamin and 35mg secobarbital to create an FDC marketed as SynaTan-S. Upon being acquired by Mallinckrodt in 1976, SynaTan was rebranded OboTan: formerly SynaTan, by Mallinckrodt, and likewise, SynaTan-S was renamed OboTan-S: formerly SynaTan-S, by Mallinckrodt. each continued distribution with the same formulation of active ingredients, merely renamed, until production ceaased in 2000.^[15]
• Phelantin (capsule) by Parke-Davis: 100mg phenytoin (anticonvulsant), 30mg pentobarbital (depressant, antiepileptic), and 2.5mg methamphetamine hydrochloride (mild counteraction of sedation)

^[16][17][18] Dextroamphetamine tannate was still listed as an activeely imported product according to this tariff list from 2008, albeit very rarely.

• Amphaplex 10:2.5mg methamphetamine saccharate, 2.5mg methamphetamine hydrochloride, and 5mg racemic amphetamine sulfate (2.5mg levoamphetamine sulfate:2.5mg dextroamphetamine;^[19] and Amphaplex 20– 5mg methamphetamine saccharate, 5mg methamphetamine hydrochloride, and 10mg racemic amphetamine sulfate (5mg levoamphetamine sulfate: 5mg dextroamphetamine sulfate)
• Bontril Timed No. 1: 2.5mg dextroamphetamine and 7.5mg butarbartal; Bontril Timed No. 2: 5mg dextroamphetamine, 15mg butabarbital; Bontril No. 3: 10mg dextroamphetamine, 30mg butabarbital; Bontril Timed No. 4: 15mg dextroamphetamine, 60mg butabarbital ^[a][20]
• Delcobese was 4 components of single-entity racemic amphetamine: 1/4 racemic amphetamine (l- and d- isomers) adipate and 1/4 racemic (l- and d- isomers) amphetamine sulfatedextroamphetamine adipate, and dextroamphetamine sulfate.
• Obetrol by Abbott Laboratories was a combination of various mixed salts of methamphetamine and dextroamphetamine salts; discontinued in 1973 following a crackdown by the DEA on combination drugs composed of controlled substances of the DEA and a subsequent crackdown on combination medicines. Obetrol was reformulated as Oby-Rex and replaced the methamphetamine salts with salts from the other half of racemic amphetamine, which is technically a single entity, hence obyRex.hetamine.
• Pondimin ("Fen-Phen") – fenfluramine/phentermine, anti-obesity medication discontinued 1998^[21]

• Amplus Now^[22] by Pfizer-Roerig Inc.^[23]–combined 5mg dextroamphetamine sulfate and 5mg hydroxyzine
• NalerTan and Durabond: 10mg dextroamphetamine tannate, 8mg chlorpheniramine tannate, and 25mg pyrilamine tannate^[24][25]
• Obocell' by Irwin, Neisler and Co.: 5mg dextroamphetamine phosphate 25mg methapyrilene phosphate; Obocell-TF: Obocells formula with an added "160mg per tablet" (methylcellulose)^[26]
• Pre-M-T, FDC polypill tablet by Behlen Laboratories: microdose of theobromine syngerstically potentiates racemic amphetamine sulfate–by definition, an equal 1:1 ratio of levoamphetamine to dextroamphetamine– the two depressants are the highly-potent barbiturate sodium pentobarbital, combined with the mildy sedating first-generation antihistamine pyrilamine maleate. Additionally, a microdose of theobromine which a very mild "stimulant" related to caffeine and found in cacao and chocolate. The low dose simply provides drug synergy between the other four compounds.

• Eskatrol by Smith, Kline & French (now GlaxoSmith Kline) – Among the top 200 prescription drugs indicated for weight loss in the U.S. in 1980 dextroamphetamine and prochlorperazine, discontinued 1981

• Reladorm – 100mg cyclobarbital and 10mg diazepam, insomnia treatment (soporific) in Russia, discontinued 2019
• Tuinal– Tuinal combined two barbiturate salts, namely sodium amobarbital and secobarbital, discontinued late 1990s

• Mandrax – methaqualone and diphenhydramine, formerly available in South Africa, now limited to clandestine chemistry

• Artogesic: – dextroamphetamine and mephobarbital with phenacetin and salicylamide
• Apamead – dextroamphetamine sulfate and amobarbital with aspirin and phenacetin
• Dysonil – methamphetamine hydrochloride, pentobarbital sodium, and salicylamide)
• Edrisal–160mg aspirin, 160mg phenacetin, and 2.5mg amphetamine sulfate; Edrisal with Codeine was an identical formulation that included the addition of 16mg codeine
• Daprisal by GlaxoSmith Kline – dextroamphetamine sulfate, 32.5mg amobarbital, and 162.5mg aspirin
• Decobese – 15mg dextroamphetamine and 16mg amobarbital, with 75mg betaine anhydrous and 194mg bile salts
• Direcel: dextroamphetamine, butabarbital, and carboxymethylcellulose; Direcel-T was identical with the inclusion of thyroid hormone
• Duodex – capsule containing 16.25 mg aloin, 15mg amphetamine sulfate, 16.25mg pentobarbital, and thyroid hormone
• Elpanal by Teva Pharmaceuticals: 500mg acetaminophen, 15mg amobarbital, and 2.5mg methamphetamine hydrochloride; Lamital by Teva was merely the sustained-release formulation.
• Mediatric – 0.25mg Premarin (Conjugated Estrogens USP), 2.5mg methyltestosterone, 100mg ascorbic acid, B vitamins, and 1mg methamphetamine hydrochloride
• Nexorin: dextroamphetamine sulfate, amobarbital, methylcellulose, and supplements
• Obolip: dextroamphetamine, phenobarbital, plus choline bitartrate, di-methionine, and methylcellulose

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 CNS 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.

There are advantages and disadvantages of combination drug therapy, including using fixed-dose combination drugs and/or polypills, as opposed to partaking in polypharmacy and increasing one's pill burden by keeping track of an organized schedule or any FDCD with 2, 3, or 4 active ingredients, relative to the concept of polypharmacy. 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. Polypharmacy, however, is the recommended starting practice, as taking individual forms (pills, capsules, tincture, etc.) of distinct medication allows the patient to see what the specific direct results and adverse effects from a single active ingredient may be. After the titration period of at least 4 weeks, the patient is likely safe to begin taking a fixed-dose combination pill or a polypill; it's worth nothing that even patient who have used a specific for months, years, or even decades can theoretically develop an adverse drug reaction at any time, at which point the situation is further complicated because the patient may not recall the difference life before and after consistent dosing of the combo, and if they attempt to discontinue use abruptly, there is the risk of withdrawal symptoms.

The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."^[27] AAO states their organizational position is that custom-compounded fixed-dose combination drugs, as well as compounded polypills are superior to mass-marketed, mass-manufactured, one size fits all style treatment.

• 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^[28] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.^[29]

A patient's drug and dosage counts may vary depending on whether the patient or clinician counts a combination product as a single drug, or if a formulation's individual active ingredient are accounted. A patient ingesting numerous active ingredients might not be considered to be engaged in polypharmacy if they use a combination product consisting of multiple ingredients, but counted as one drug.^[30]

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, including synthetic cathinone; methamphetamine and varying mixtures of racemic amphetamine, its components, derivatives and analogues; MDMA, caffeine powder, ephedrine or pseudoephedrine, fenproporex; levamisole, a flesh-eating veterinary antibiotic^[31] sibutramine, yohimbe; a minority of samples products contained over 5% of genuine cocaine, or coca leaf extract.

Due to the crackdown of pill mills between 2007-2012, the opioid epidemic now includes preparations declared to be "heroin" or "pressed" replica pills of hydrocodone (sold Norco or LorTab); oxycodone (sold as Percocet), yet are rarely pure in their ingredient compositions. Cutting agents have grown in proportion to the overall composition of these products, such that "heroin" has been cut and mixed with CNS Depressants including major tranquilizers such as quetiapine; muscle relaxants like carisoprodol or cyclobenzaprine; first-generation antihistamines like diphenhydramine or hydroxyzine); and benzodiazepine derivative and analogue research chemicals, including gidazepam, pinazepam, clobromazolam, etizolam). Since 2020, there has been a noticeable rise amongst active ingredients in opioid combinations containing fentanyl (more potent than heroin), and increasingly, carfentanil (an elephant and rhinoceros tranquilizer more potent than fentanyl).

Since 2023, worldwide samples of illicit combinations featuring opioids have contained the most lethal known substance to date: those belong to the nitazene chemical class.^[32] 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,^[33] a direct response to its implication in overdose deaths featured in products alongside fentanyl and other power CNS depressants; xylazine is currently a controlled substance at the state level in Michigan and New York.^[34]

• Codrugs
• Synergy#Drug synergy

• Media related to Combination drugs at Wikimedia Commons