Combination drug
A combination drug 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, an injectable suspension, or a suppository. 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. 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, 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.
History
Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV. 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.Current prescription combination drugs
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:- amitriptyline/perphenazine
- amitriptyline/chlordiazepoxide, available in the United States, India, and Bangladesh
- amlodipine/benazepril
- amlodipine/atorvastatin
- amlodipine/celecoxib
- amlodipine/lisinopril
- amlodipine/olmesartan
- amlodipine/valsartan
- amphetamine racemic salts, branded Adderall by Shire Pharmaceuticals, among others such as Mydayis and Adzenys ODT
- bupropion/naltrexone
- butalbital and caffeine
- butalbital, caffeine, and either aspirin, or acetaminophen, also available with codeine as Fioricet with Codeine
- calcipotriol/betamethasone dipropionate, Dovobet by LEO Pharma.
- carbidopa/levodopa/entacapone, Stalevo, Lecigon for infusion therapy in some European countries
- chlordiazepoxide and clidinium bromide, Librax
- ephedrine/ethylmorphine
- flupentixol/melitracen, available in Bangladesh as Deanxit by Lundbeck
- hydrocodone/acetaminophen LorTab by UCB is now solely available as a syrup in the U.S.
- hydrocodone and aspirin, Azdone
- hydrocodone and guaifenesin, Obedron, Flowtuss
- hydrocodone and ibuprofen, Ibudone
- ibuprofen and acetaminophen intravenous solution, ibuprofen/paracetamol and ritonavir, Paxlovid'''
- omeprazole/amoxicillin/rifabutin
- olanzapine/fluoxetine
- oxycodone and acetaminophen, oxycodone/acetaminophen
- oxycodone/aspirin
- oxycodone and ibuprofen, oxycodone/ibuprofen
- phentermine/topiramate
- phenylephrine/ketorolac
- pseudoephedrine/carbinoxamine elixir
- Ephedrine/ethylmorphine
- Propyphenazone/paracetamol/caffeine
- tramadol/paracetamol
Combination drugs accessible over the counter
- aspirin/paracetamol and aspirin/paracetamol/caffeine
- Various cough medicines combine: dextromethorphan, acetaminophen, chlorpheniramine, doxylamine succinate, phenylpropanolamine, pseudoephedrine, guaifenesin, etc.
- diphenhydramine/dimenhydrinate
- fenproporex/diazepam, available in Central America and Paraguay; discontinued in Brazil
- fexofenadine/pseudoephedrine
- glucose/fructose/phosphoric acid
- guaifenesin/phenylephrine
- ibuprofen/famotidine and ibuprofen/diphenhydramine ; acetaminophen/diphenhydramine
- loratadine/pseudoephedrine
- naproxen/diphenhydramine and naproxen/pseudoephedrine
- oxomemazine/guaifenesin, available in France, Algeria, and Morocco
Combination drugs under development
- MDMA/citalopram, entactogen and SSRI antidepressant in Phase II clinical trials for treating post-traumatic stress disorder.
Combination drugs for veterinary use
- Temaril-P combines alimemazine and prednisolone, 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
Widely discontinued formulations
- Obetrol contained methamphetamine and dextroamphetamine salts, discontinued 1973.
- Tuinal contained amobarbital/secobarbital
- Phenephen by A.H. Robins: hyoscyamine sulfate, phenacetin, and aspirin; also available in a separate formulation as Phenephen with Codeine
- "fenfluramine/phentermine" or "fen-phen", discontinued 1997
- Anxine 120 mg mephenesin, 35 mg cyclobarbital, and 2.5 mg dextroamphetamine
- Bama-Dex combined 5 mg dextroamphetamine and 400 mg meprobamate
- Acutran dextroamphetamine/chloral hydrate molecular compound) by G.W. Carnrick Laboratories, discontinued 1973
- Bontril Timed numbers 1, 2, 3, and 4: four different dosage combinations of dextroamphetamine and butabarbital.
- Delcobese, racemic amphetamine molecule with each enantiomer bonded to sulfate and adipate, "withdrawn voluntarily in 1984, unrelated to safety or legal concerns"
- Mandrax, a tablet combining methaqualone and diphenhydramine, only available in South Africa until 1993, "Lemmon " was a street name for diverted methaqualone
- Dexytal by Eli Lilly, combination dextroamphetamine and amobarbital elixir
- Eskatrol by Smith, Kline & French combined dextroamphetamine and prochlorperazine, discontinued 1981
- Daprisal tablet combined dextroamphetamine, amobarbital, and aspirin
- Dexamyl tablet combined dextroamphetamine and amobarbital, discontinued 1982
- Durophet was a racemic mixture of amphetamine salts combining combined 12.5 mg amphetamine and 400 mg methaqualone, discontinued 1984
- Durabond, tablet combining 8 mg chlorpheniramine tannate, 25 mg pyrilamine tannate, and "10 mg Tanphetamin "
- Desbutal combined 5 mg methamphetamine and 30 mg pentobarbital, discontinued 1973
- NalerTan combined 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate
- Obocell combined 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate
- OboTan-S: formerly SynaTan-S) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital
- DuoDex, combination barbaloin, dextroamphetamine, pentobarbital, thyroid ; The U.S. FDA declared in May 2002 that "aloin-containing laxatives are no longer GRAS effective for OTC use" upon the IARC classifying whole-leaf herbal extracts of aloe vera as "possibly carcinogenic to humans" due to presence of latex.
- Phelantin combined 100 mg phenytoin, 32 mg pentobarbital, and 2.5 mg methamphetamine
- Reladorm combined 100 mg cyclobarbitol and 10 mg diazepam, previously available in Russia, discontinued 2019
- Amphaplex 10 by Laderle combined 2.5 mg methamphetamine saccharate, 2.5 mg methamphetamine hydrochloride, and 5 mg racemic amphetamine sulfate; Amphaplex 20 combined 5 mg methamphetamine saccharate, 5 mg methamphetamine hydrochloride, and 10 mg racemic amphetamine sulfate.
- Amplus Now by Roehrig combined 5 mg dextroamphetamine sulfate with 5 mg hydroxyzine
- Amvicel combined 10 mg dextroamphetamine, 40 mg amobarbital, 15 mg phenobarbital, 30 mg nicotinamide, plus vitamins and essential minerals
- Edrisal combined 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine sulfate and Edrisal with Codeine added 160 mg codeine
- Ethobral Triple-Barbiturate Tablets by Wyeth combined secobarbital, butabarbital, and phenobarbital
- Biphetamine, Obetrol, Oby-Rex: varying formulations by different manufacturers of mixed amphetamine salts. Biphetamine-T was timed
- ANOX capsules combined 20 mg each phenobarbital, butabarbital, and secobarbital with 7.5 mg each methamphetamine hydrochloride and dextroamphetamine sulfate
Justification of medical use
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.