Combination drug

A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form.^[1] Terms like "combination drug" or "combination drug product" can be common shorthand for an FDC product (since most combination drug products are currently FDCs), although the latter is more precise if in fact referring to a mass-produced product having a predetermined combination of drugs and respective dosages (as opposed to customized polypharmacy via compounding^[2]). And it should also be distinguished from the term "combination product" in medical contexts, which without further specification can refer to products that combine different types of medical products—such as device/drug combinations as opposed to drug/drug combinations.^[3] When a combination drug product (whether fixed-dose or not) is a "pill" (i.e., a tablet or capsule), then it may also be a kind of "polypill" or combopill.

Initially, fixed-dose combination drug products were developed to target a single disease (such as with antiretroviral FDCs used against AIDS). However, FDCs may also target multiple diseases/conditions. In cases of FDCs targeting multiple conditions, such conditions might often be related—in order to increase the number of prospective patients who might be likely to use a given FDC product. This is because each FDC product is mass-produced, and thus typically requires having a critical mass of potentially applicable patients in order to justify its manufacture, distribution, stocking, etc.

For sale over the counter to any adult of legal age.

• Dimenhydrinate (8-chlorotheophylline/diphenhydramine) — used to treat motion sickness and nausea, main brand Dramamine
• Glucose/fructose/phosphoric acid — antiemetic taken to relieve nausea and vomiting
• Naproxen/diphenhydramine — relief of mild pain and as a sleep aid.

The Combat Methamphetamine Epidemic Act of 2005 (CMEA) requires any product in the U.S. containing ephedrine or pseudoephedrine be stored behind the pharmacy counter. Of the two, pseudoephedrine is most often combined with other active ingredients, usually an antihistamine, NSAID, and/or expectorant. No prescription is required to purchase [pseudo]ephedrine, but patients are required to verify their identity by having a pharmacy associate scan their ID/license, automatically submitting transaction details into the transaction log, and further requiring the patient to sign a disclaimer agreeing to federal prosecution upon violating CMEA. Logs must be retained for potential audit/review by the Drug Enforcement Administration, which can access the CMEA database to track buyers' purchase history of ephedrine nationwide, and monitor consumer compliance with the monthly purchase limits set by the CMEA. [Pseudo]ephedrine is a sympathomimetic amine, with generally activating effects similar to those of CNS stimulants. Formulations listed are grouped by the types of active ingredients in the product and indications; any FDC with [pseudo]ephedrine is indicated as a decongestant, but some can also treat cough, common cold and flu-like symptoms, aches and pain, and allergy symptoms that present alongside the others.

The fixed-dose combination formulations below are in most jurisdictions only available with a prescription, but accessibility of particular drugs varies by country:

• Adderall – combination of dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.
• Amitriptyline/perphenazine
• Aspirin/paracetamol/caffeine — pain treatment, especially tension headache and migraine
• Aspirin/meprobamate — NSAID pain reliever and minor tranquilizer for pain relief and muscle relaxation, branded Equagesic
• Butalbital/caffeine with acetaminophen (Fioricet), or with aspirin (Fiorinal) — pain treatment, especially tension headache and migraine
• Caffeine/ergotamine — treatment of headaches, such as migraine headache.
• Codeine/paracetamol pairs the opioid analgesic, codeine (which is also a prodrug of morphine), with the antipyretic analgesic, acetaminophen (APAP). Marketed as Tylenol with Codeine No. 3 and Tylenol with Codeine No. 4, distinguished by an increase in dosages between the former and latter.
• Donnatal–Donnatal contains fixed doses of phenobarbital, hyoscyamine sulfate, atropine sulfate and scopolamine hydrobromide — treatment of acid reflux/GERD
• Chlordiazepoxide/clidinium bromide
• Contrave – bupropion/naltrexone indicated for smoking cessation and weight loss
• Esbelcaps – 20mg fenproporex and 6mg diazepam^[4] available in Mexico; never FDA-approved for medical use in the United States
• Qsymia – phentermine/topiramate — indicated for weight management as an anorectic and anti-obesity drug
• Paxlovid – nirmatrelvir/ritonavir — granted emergency use authorization (EUA) by the US Food and Drug Administration for the treatment and management of COVID-19.
• Deanxit by Lundbeck – combination flupentixol/melitracen, a 0.5mg of the first-generation neuroleptic flupentixol combined with 10mg of the [[tricyclic antidepressant|tricyclic antidepressant (TCA), melitracen. Available in India under several generic trade names, this FDC is indicated for depression, dysphoria, anxiety, asthenia, and schizophrenia without hyperactive symptoms.
• Limbitrol – combination amitriptyline/chlordiazepoxide; amitriptyline is a TCA known for its potent anticholinergic and sedative properties, while chlordiazepoxide is relatively mild benzodiazepine, but a CNS depressant nonetheless. Limbitrol is available in India, and used to moderate to severe depression, anxiety, and insomnia. It may also be the current combination drug that most closely resembles the dual-depressant combinations of decades past (e.g. Tuinal, Mandrax (diphenhydramine/methaqualone).

• Acutran or amfecloral – dextroamphetamine sulfate and chloral hydrate), discontinued 1973
• Ambar – methamphetamine hydrochloride and phenobarbital and Ambar Extentab (extended-release formulation)
• Amvicel-X – 10mg dextroamphetamine sulfate, 40mg amobarbital, 15mg phenobarbital, vitamins A, B vitamins, and C, 30mg nicotinamide, calcium, iron, manganese, and zinc
• Anox Diacels by Winston Pharmaceuticals – a polypill in capsule form composed of: 7.5mg methamphetamine hydrochloride, 7.5mg dextroamphetamine sulfate, 20mg phenobarbital, 20mg butabarbital, and 20mg secobarbital^[5]
• Anxine – 2.5mg dextroamphetamine sulfate, 35mg cyclobarbital, and 120mg mephenesin (a muscle relaxer)
• Appetrol – 5mg dextroamphetamine and 400mg meprobamate and BamaDex – 6mg dextroamphetamine and 400mg meprobamate
• Biphetamine 10 by Fisons – 10 mg racemic amphetamine; Biphetamine 20–20 mg racemic amphetamine
• Desbutal – 5mg methamphetamine hydrochloride and 30mg pentobarbital sodium, discontinued 1973
• Dexamyl – dextroamphetamine and amobarbital sodium, discontinued 1982
• Durophet M – 13mg racemic amphetamine (6.25mg levoamphetamine:6.25 dextroamphetamine) and 40mg methaqualone
• Euphoramin – 5mg methamphetamine hydrochloride and 300mg meprobamate
• Obotan-S by Mallinckrodt – dextroamphetamine and secobarbital sodium
• Phelantin by Parke-Davis – yellow capsule containing 100mg phenytoin, 30mg pentobarbital sodium, and 2.5mg methamphetamine hydrochloride; effects were primarily anti-epileptic and depressive of the CNS.
• Seco-Symatan by Irwin, Neisler & Co. – 35mg secobarbital and 17.5 mg dextroamphetamine tannate (Tanphetamin)

• Amphaplex 10 – 2.5mg methamphetamine saccharate, 2.5mg methamphetamine hydrochloride, and 5mg racemic amphetamine sulfate (2.5mg levoamphetamine sulfate and 2.5mg dextroamphetamine^[6]
• 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 butabarbital, timed-release formulation
• Bontril Timed No. 2 – 5mg dextroamphetamine and 15mg butabarbital, timed-release formulation
• Bontril Timed No. 3 – 10mg dextroamphetamine and 30mg butabarbital, sustained-release formulation
• Bontril Timed No. 4 – 15mg dextroamphetamine and 60mg butabarbital, extended-release
  • Note:not to be confused with Bontril or Bontril PDM, a trade name of phendimetrazine.
• Delcobese–combination of amphetamine adipate, amphetamine sulfate, dextroamphetamine adipate, and dextroamphetamine sulfate.
• Obetrol–Obetrol included various mixed methamphetamine and dextroamphetamine salts; discontinued in 1973 and reformulated as Oby-Rex, replacing methamphetamine with levoamphetamine, the other half of single entity racemic amphetamine.
• Pondimin ("Fen-Phen") – fenfluramine/phentermine, anti-obesity medication discontinued 1998^[7]

• Amplus-Improved by Roerig Laboratories – 5mg dextroamphetamine sulfate, 5mg hydroxyzine, and supplements^[8]
• Nalertan – 10mg dextroamphetamine tannate, 8mg chlorpheniramine tannate, and 25mg pyrilamine tannate
• Obocell by Irwin, Neisler & Co. – Obocell's formula was 5mg dextroamphetamine phosphate and 25mg methapyrilene
• Obocell-TF – identical formulation to Obocell with the addition of 160mg Nitrin (high-viscosity methylcellulose)
• Pre-M-T was the informal term of a pharmaceutical preparation comprising amphetamine sulfate, pentobarbital sodium, pyrilamine maleate and theobromine
• Vernate by Tutag Pharma – 8mg chlorpheniramine maleate and 50mg phenylpropanolamine, discontinued 2001^[9]

• Eskatrol by Smith, Kline & French (now GlaxoSmith Kline) – Eskatrol was commonly prescribed in the U.S. as a diet pill comprising 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, once available in South Africa

• 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 also included 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 sodium amobarbital, and 2.5mg methamphetamine hydrochloride
• Lamital by Teva Pharmaceuticals – 500mg acetaminophen, 15mg sodium amobarbital, 2.5mg methamaphetamine hydrochloride
• 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 and 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 patients were unlikely to comply with dietary restrictions on tyramine necessary the MAOI class of medications.

Fixed-dose combination (FDC) drug products, or combination drugs and polypills generally, include such advantages and disadvantages as:

• Improved medication compliance by reducing the pill burden of patients.

• Combination drugs are reviewed by regulatory agencies, such as the U.S. Food and Drug Administration (FDA) before receiving approval to be marketed, thus reducing the probability of adverse drug interactions among a combination product's individual ingredients.

• FDC drug products may be developed by a pharmaceutical company as a way to effectively extend proprietary rights, if not exclusivity or a monopoly, on producing a specific formulation or product, even if individual active ingredients may be off-patent.

• There may not be an FDC available with the appropriate drug strengths/dosages for a given patient, which risks some patients getting too much of an ingredient and others getting too little. As noted by the American Association of Orthodontists (AAO), fixed-dose combinations "limit clinicians' ability to customize dosing regimens."^[10] A potential solution to this includes custom-compounded FDC drugs and/or polypills prepared via pharmaceutical compounding, allowing a compounding pharmacist to prepare and dispense drug products specifically tailored for individual patients, assisting polypharmacy.

• If an FDC results in an adverse drug reaction, it may be difficult to identify the active ingredient responsible for causing the reaction. This can be avoided by starting each medication individually and monitoring for reactions, prior to transitioning to an FDC.

• 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^[11]

• For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.^[12]

• 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.^[13]

• Media related to Combination drugs at Wikimedia Commons