Combination drug

This article is about fixed-dose combination drugs as treatments. For two synergistic drugs chemically linked together, see codrug.

For use of multiple, separate individual drugs for treatment, see polypharmacy.

For use of multiple, separate individual drugs for treatment, see polypharmacy.

For four or more active ingredients combined into one pill, see polypill.

For combiniation of a drug and a medical product or device (e.g. insulin pump), see combination product and transdermal patch.

Combination drug is a general description of any medicine composed of two or more active ingredients combined into a single dosage form (e.g. two drugs in one pill), while fixed-dose combination drug (FDCD) describes a particular type of the former; a mass-manufactured formulated with predetermined, fixed doses of each active substance, which are often well-established generic drugs with consistent peer-reviewed research on, and understanding of, the effects of chronic long-term, abuse potential, safety profile and therapeutic window, knowledge of adverse effects, drug interactions and contraindications, as well as being able to utilize,whether upon an over the counter purchase or upon receiving and filling a prescription.

If multiple symptoms are commonly associated with, or present simultaneously, fixed-dose combination drugs may be an ideal treatment option for certain patients. FDCDs are manufactured to [[USP Pharmaceutical-grade Quality Standards, and sufficient dosing of each active ingredient, within the therapeutic range are often approved for the treatment of various conditions. but sometimes it is only through marketing that FDCDs become mainstream and commonly sed as a one size fits all treatment plan through mass marketing and/or a large number of prescriptions. Another type of combination drug is a polypill, by definition a oral medicine, or "[[tablet (pharmacy)|pill") composed of four or more active ingredients and often, but not always, a fixed-dose combination. While all fixed-dose combination drugs and polypills are "combination drugs" by definition, a "combination drug" can exist without further qualification if, for example, the formulation is a custom-prepared, compounded drug formulation where ingredients and dosing is determined by an individual patient's unique needs and their personalized prescription.

Initial Development and Concept

Fixed-dose combination (FDC) drugs were initially developed to target a single disease, as with antiretroviral FDCs [[indication (medicine)|indicated for treatment of AIDS. FDC drugs may also target multiple disorders or diseases, which may be related to, or comorbid with (occurring alongside) each other.

Combinations of common active ingredients with a variety of uses

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly-used analgesics in the world, and all are indicated for, at minimum, the temporary relief of minor aches and pain caused by, or comborbid to, inflammation; this class of medication includes naproxen, ibuprofen, aspirin, and meloxicam, among others. Aspirin has additional anticoagulant cardioprotective properties, reducing blood clotting and lowering one's risk of heart attack or stroke. Paracetamol is neither an NSAID nor an anti-inflammatory, but may also provide minor pain relief, particularly when used with another analgesic; its primary indication is for reducing fever. A formulation combining a sufficient dose of an anti-inflammatory agent or NSAID with a sufficient dose of a fever-reducing agent is likely to be effective at providing temporary relief from inflammation, minor aches and pain, and fever. Aspirin is the ideal anti-inflammatory compound to include in the formulation supposing the patient has a history of, and/or predisposition to cardiovascular disorders, thus producing combination drug consisting of aspirin and paracetamol. If the patients present with additional symptoms such as lethargy or fatigue and headache stemming from allergy or the common cold, adding a sufficient dose of another active ingredient–caffeine is frequently combined anti-inflammatory agents, or analgesics generally due its ubiquity, ininexpensiveness, and its stimulant-like effects due to its role in blocking adenosine, and has also demonstrated efficacy in treating headache through inducing vasoconstriction in the brain. A formulation encompassing aspirin/paracetamol/caffeine thus has potential as a one size fits all treatment of multiple symptoms with ingestion of one pill.

Contemporary combination drugs

See also: Codrug § Common codrugs, and Synergy § Drug synergy

For more common combination drugs, see WHO Model List of Essential Medicines.

Over-the-counter (OTC)

Fixed-dose combination drugs for sale over the counter include many products indicated for treating motion sickness, nausea, and vomiting, and well as allergy symptoms, including:

• Dramamine (generic dimenhydrinate is itself a combination of 8-chlorotheophylline/diphenhydramine, used to treat motion sickness and nausea.
• Glucose/fructose/phosphoric acid — antiemetic taken to relieve nausea and vomiting

Sleep Aids

• Aleve PM (combination naproxen/diphenhydramine), indicated for mild pain and as a sleep aid
• Advil PM (combination ibuprofen/diphenhydramine)

NSAID and Proton Pump Inhibitor

• ibuprofen/famotidine for acid reflux, indigestion, and general mild pain relief

Cough, Cold, Congestion, Flu, and Allergy

The following medications feature active ingredients with cough suppressant, expectorant, nasal decongestants, antihistamines, and/or fever reducer like acetaminophen:

• Allerest, Chlor-Rest, and Tri-Nefrin are some of the brand names for the oral form of chlorpheniramine (a first-generation antihistamine) combined with phenylpropanolamine ("PPA," a sympathomimetic decongestant); Altec Syrup and Vernate are injectable liquid formulations of this combination, indicated for treating nasal congestion and allergic rhinitis. Altec Syrup remains available over the counter (OTC) in India; Vernate is a discontinued injectable FDCD manufactured by now-defunct Tutag Pharmaceuticals, constituting 8mg chlorpheniramine maleate and 50mg PPA.first-generation antihistamine
• Coricidin is an FDC product line 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.
• Oxomemazine/guaifenesin combines a sedative antihistamine and an expectorant, respectively. Never FDA-approved for use in the U.S.
• Sudafed PE is [guaifenesin/phenylephrine]] and treats cold, flu, and allergy symptoms

Prescription drugs

The combination drugs listed below are generally available by prescription only in most areas of the world; although specifics of product accessibility will vary based upon the laws of certain countries, states, province, counties, and municipal jurisdictions:

CNS Stimulants

• Adderall – combination of dextroamphetamine sulfate, amphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate used for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.

Including tricyclic antidepressants (TCAs)

• Amitriptyline/perphenazine
• Aspirin/meprobamate — NSAID pain reliever and minor tranquilizer for pain relief and muscle relaxation, branded Equagesic

Miscellaneous combinations, antihistamines, sympathomimetic stimulants

• Caffeine/ergotamine — treatment of headaches, such as migraine headache.
• Donnatal, an FDC of phenobarbital, hyoscyamine sulfate, atropine sulfate, and scopolamine hydrobromide — indicated for the treatment of acid reflux and GERD
• Ephedrine/ethylmorphine
• Auvelity combines the cough suppressant dextromethorphan with the stimulant-like antidepressant bupropion in the form of a tablet, for treatment of major depressive disorder (MDD).
• Librax &ndash chlordiazepoxide/clidinium bromide combined, for treating gastrointestinal ulcers
• Contrave – bupropion/naltrexone indicated for smoking cessation and weight loss
• Qsymia – phentermine/topiramate — indicated for weight management as an anorectic and anti-obesity drug
• Paxlovid – nirmatrelvir/ritonavir — granted emergency use authorization (EUA) by the U.S. Food and Drug Administration for the treatment and management of COVID-19.

Analgesics

Non-Opioid and Non-NSAID Analgesics

• Sumatriptan/naproxen combines antidepressant with anti-migraine effects with the NSAID naproxen

NSAIDs combined with other active ingredients

• butalbital/caffeine pairs a relatively mild, slow-release, and long-acting barbiturate salt (butalbital) and a stimulant-like adenosine blocker of methylxanthine class (caffeine), which is the precursor to two common brands of migraine medicines: combined with acetaminophen, the brand name is Fioricet, a prescription drug; combined with aspirin, the brand name is Fiorinal, also RX-only, but is further a controlled substance — pain treatment, especially tension headache and migraine
• Aspirin/paracetamol/caffeine — pain treatment, especially tension headache and migraine
• Propyphenazone/paracetamol/caffeine pairs a quick-release, short-acting fever reducer (propyphenazone) with a longer-acting fever-reducing agent and mild analgesic (paracetamol), with caffeine, capable of relieving fatigue, lethargy, and headache.

Opioids and NSAIDs

• Percocet combines oxycodone and acetaminophen
• Vicodin for Chest Congestion is hydrocodone/guaifenesin
• Vicodin, Lortab, Norco combines hydrocodone and acetaminophen
• Percodan (oxycodone/aspirin) – combines oxycodone and aspirin for relief of severe, chronic pain.
• guaifenesin/codeine
• Advicodone oxycodone/ibuprofen
• Norco Salicylate is hydrocodone/aspirin
• Deanxit by Lundbeck–flupentixol/melitracen combined, 0.5mg flupenthixol (a typical antipsychotic) and 10mg melitracen (tricyclic antidepressant). Available in India, and indicated for depression, dysphoria, anxiety, asthenia, and schizophrenia without hyperactivity.
• Limbitrol–amitriptyline/chlordiazepoxide, a TCA with potent anticholinergic and sedative properties and chlordiazepoxide, respectively, a relatively mild benzodiazepine, but still a CNS depressant, making this combination unique in its combination of depressants. Limbitrol is used in India to treat moderate to severe depression, anxiety, and insomnia.

Limitations of currently-available combination drugs

The above listing also serves as an example of the limitations of combination formulations currently available for treating an all-encompassing far reaching disorder involved multiple co-occurring conditions and symptoms; there is not currently a polypill available indicated for treating tics and at the same time as obsessive-compulsive disorder (OCD) and OCD's resultant behaviors, such as the compulsions to declutter and live minimimally; and/or Attention-Deficit Hyperactivity Disorder; and/or insomnia. As such (see section immediately below), the concept of polypharmacy has in large part filled the role of combination drugs.

Polypharmacy as a substitute for combination pharmaceutical drugs

Current limitation of access to combination drugs capable of simultaneously treating multiple indications necessitates that polypharmacy be used instead, whereby a provider prescribes multiple drugs of multiple classes for multiple indications. The orphan drug pimozide is indicated for treating tics, but benzodiazepines may need to be added to an ever-increasing prescription regimen for social anxiety or OCD; OCD can also be treated with the SSRI fluvoxamine or the TCA clomipramine, but if the primary comorbidity is insomnia, then a sedative-hypnotic and soporific agent, colloquially "sleeping pill" may need to be supplemented to this ever-expanding multi-drug regimen. The limited production and accessibility of fixed-dose combination drugs and polypills is an obstacle and barrier to adequately treating patients with all-encompassing conditions.

Limitations of currently-available combination drugs

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 avilable, and sometimes used in the context of polypharmacy involves various individual medicines for treating tics (often a neuroleptic) and/or generalized or social anxiety (e.g. [[benzodiazepines or SSRIs) and/or obsessive-compulsive disorder (OCD) (nearly always fluvoxamine or clomipramine and anxiety-like compulsions such as 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 9grogginess 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.

Formerly available combination drugs

CNS stimulants or sympathomimetics and CNS depressants

• 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 by Winston Pharmaceuticals: a single, green-colored, fixed-dose polypill capsule combining 7.5mg methamphetamine hydrochloride and 7.5mg dextroamphetamine sulfate with 20mg phenobarbital (long-acting), 20mg butabarbital (intermediate-acting), and 20mg secobarbital (quick-acting), sustained release for 6-10 hours; Winston launched a longer-acting, extended-release formulation in 1965 under the name Diacels
• 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 10by Fisons – 10mg racemic amphetamine (5mg levoamphetamine, 5mg dexamfetamine) and Biphetamine 20step 2, composed pf 20mg racemic amphetamine (10mg levoamphetamine, 10mg dexamphetamine)
• Desbutal–5mg methamphetamine hydrochloride and 30mg pentobarbital sodium, discontinued 1973
• Dexamyl or AmoDex – dextroamphetamine and amobarbital sodium, discontinued 1982
• Durophet M – 13mg racemic amphetamine and 40mg methaqualone hydrochloride
• Esbelcaps – 20mg fenproporex and 6mg diazepam, formerly available in Mexico, Panama, Honduras, Nicaragua, and the Dominican Republic, never FDA-approved for medical use in the U.S.
• Euphoramin – 5mg methamphetamine hydrochloride and 300mg meprobamate
• Obotan-S by Mallinckrodt – Tanfetamin (dextroamphetamine tannate) 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 CNS depressant.
• Seco-Symatan by Irwin, Neisler & Co. – 35mg secobarbital sodium and 17.5 mg dextroamphetamine tannate (an obscure form of d-amphetamine compound marketed as Tanphetamin, Tanphetamine, Tanfetamin and Symatan on its own)

CNS stimulants

• Amphaplex 10–2.5mg methamphetamine saccharate, 2.5mg methamphetamine hydrochloride, and 5mg racemic amphetamine sulfate (2.5mg levoamphetamine sulfate and 2.5mg dextroamphetamine; and Amphaplex 20– 5mg methamphetamine saccharate, 5mg methamphetamine hydrochloride, and 10mg racemic amphetamine sulfate (5mg levoamphetamine sulfate:5mg dextroamphetamine sulfate)

7.5mg butabarbital

• Bontril Timed No. 1 combined 2.5mg dextroamphetamine and 7.5mg butarbartal; No. 2: 5mg dextroamphetamine and 15mg butabarbital; No. 3: 10mg dextroamphetamine and 30mg butabarbital; No. 4: 15mg dextroamphetamine and 60mg butabarbital
• 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

CNS stimulants and first generation antihistamines (FGAs)

• Amplus Now by Pfizer-Roerig Inc.–combined 5mg dextroamphetamine sulfate and 5mg hydroxyzine
• Nalertan–10mg Tanfetamin (dexamphetamine]] tannate), 8mg chlorpheniramine tannate, 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 formual term of a pharmaceutical preparation comprising amphetamine sulfate, pentobarbital sodium, pyrilamine maleate and theobromine

CNS stimulant and typical antipsychotics

• 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

CNS depressants

• 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

CNS depressants and first generation antihistamines

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

Other formulations

• 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

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 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.

Advantages and disadvantages

In general, combination drugs, and particularly fixed-dose combination (FDC) drugs and polypills include many benefits and advantages overpolypharmacy, but perhaps also some disadvantages to consider:

• 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." 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

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

• 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.

External links

• Media related to Combination drugs at Wikimedia Commons