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Combination drug

Drug with two or more active ingredients From Wikipedia, the free encyclopedia

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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 (sublingual), an [[injection (medicine)|injectable suspension (intramuscular administration or intravenous therapy), or a suppository (rectal). 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 populationand 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 specifically formulated as a pill containing four or more active ingredients,[1][2] frequently requiring custom preparation at a compounding pharmacy in order to meet the personalized specifications deemed necessary by a patient's medical prescription. Such specificities may include uncommon, unconventional, or unavailable dosage, dosage form, a modified release mechanism, and necessity for a particular speed of onset and/or duration of action. Polypills can encompass four or more of any combination of approved prescription drugs and over the counter drugs, and may also include nutritional supplements, amino acids, enzymes, hormones, vitamins and/or essential minerals.[3]

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History

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Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV.[4] 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:[5]

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Combination drugs accessible over the counter

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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.[17] The following combination drugs are accessible OTC in nearly all locations:

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Combination drugs under development

Combination drugs for veterinary use

Combinations no longer available

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Organized according to the pharmaceutical manufacturer..

Abbott

  • Obetrol by Abbott Laboratories was a mixture of methamphetamine and dextroamphetamine salts, discontinued 1973,[32] later re-branded Oby-Rex, swapping methamphetamine for levoamphetamine, the (s) isomer of racemic amphetamine.
  • Tuinal by AbbVie was a capsule containing amobarbital and secobarbital (double barbiturate); voluntarily discontinued by AbbVie in 2008, citing widespread substance abuse as well as declining sales due to a decrease in prescriptions, and thus, demand.[33]

A.H. Robins

AstraZeneca

Behlen Manufacturing (defunct)

Élan Pharmaceuticals of Ireland (previously G.W. Carnrick)

Lemmon (defunct)

Eli Lilly & Company

Jannsen Pharmaceuticals

GSK (previously Smith, Kline & French)

Mallinkcrodt (previously Irwin, Neisler & Co.)

  • Durophet was a racemic mixture of amphetamine salts combining combined 12.5 mg amphetamine and 400 mg methaqualone (sedative-hypnotic), discontinued 1984
  • Durabond, tablet combining 8 mg chlorpheniramine tannate (first-generation antihistamine/FGA), 25 mg pyrilamine tannate (first-generation antihistamine), and "10 mg Tanphetamin (racemic amphetamine tannate)""General Practice American Academy(20)". 1959.
  • Desbutal combined 5 mg methamphetamine and 30 mg pentobarbital, discontinued 1973[32]
  • NalerTan combined 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate (first-generation antihistamine) [41][42]
  • dextroamphetamine, amobarbital, methylcellulose, and nutritional supplements, brandedNexorin
  • Obocell combined 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate (antihistamine); Obocell-TF was identical in composition with the addition of a high-viscosity methylcellulose supplement, also by Neisler and listed as "160 mg Nitrin on the label)[43]
  • OboTan-S: formerly SynaTan-S[44][45][46]) combined 10 mg dextroamphetamine tannate with 35 mg secobarbital[47]
  • Obolip combined dextroamphetamine, phenobarbital, choline, dimethionine, and methylcellulose
  • Euphoramin, 5 mg methamphetamine and 300 mg meprobamate (non-barbiturate, barbiturate-adjacent GABergic minor tranquilizer
  • Dysonil combined methamphetamine, pentobarbital, and salicylamide (analgesic)
  • Direcel combination dextroamphetamine, butabarbital, carboxymethylcellulose
  • DuoDex, combination barbaloin (laxative),[48] dextroamphetamine (stimulant), pentobarbital (barbiturate), thyroid (hormone); The U.S. FDA declared in May 2002 that "aloin-containing laxatives are no longer GRAS [nor] 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.

Parke-Davis

  • Phelantin combined 100 mg phenytoin (anticonvulsant), 32 mg pentobarbital, and 2.5 mg methamphetamine[49]

Polish swlzki Farmc

Pfizer (previously Laderle Laboratories; Roehrig; Wyeth)

Polish swlzki Farmc

Sanofi-Aventis (previously Rorer; Fisons)

  • Biphetamine by R.J. Strausenburgh (1964-66), by Fisons (1966-79) (inscribed RJS) containing equal parts dextroamphetamine and levoamphetamine. Later acquired by Fisons, then R.P. Rorer and rebranded Biphetamine-T[58][59][60][61]

Teva Pharmaceuticals

  • Lamital combined acetaminophen, amobarbital, and methamphetamine

Winston Pharmaceuticals

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Medical use and justification of discontinued combination drugs

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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. Substituted amphetamines (stimulants) simultaneously functioned as appetite suppressant, antidepressant, and eugeroic agents, also increasing mental alertness and concentration and physical stamina, while a GABAergic depressant (e.g. a barbiturate, benzodiazepine, antipsychotic, or quinazolone) offered tranquilizing, muscle relaxant, sedative properties to ease overstimulation, paranoia, anxiety without eliminating the stimulant's therapeutic benefits. Patients are empowered with the capability of alleviating symptoms of multiple medical conditions with the ingestion of a single dosage form, reducing the patient's pill burden and consistently showing improved medication compliance scores. The American Association of Orthodontists asserts that fixed-dose combinations "limit clinicians' ability to customize dosing regimens."[63]

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.[64] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[65][66]

Limitations of polypharmacy for multi-faceted disorders

Example with Tourette Syndrome (tics and excessive motor activity, anxieties, ADHD, autism, etc.)

The limitations of combination formulations currently available for treating the large number of overlapping neurological symptoms inherent to most neurological conditions is a hindrance to properly treating disruptive, concurrent symptoms. Tourette's is a stellar example of this dilemma, because the minimum diagnostic criteria is habitual, repeated physical movements, muscle spasms, the compulsive need to repeat motions and succumb to the premonitory urge to release perform needless, disruptive central nervous system] motor activity ("motor tics").

Obsessive-compulsive disorder, social anxiety, and anxiety are all commonly likely to comorbidity with tics; as such, polypharmacy necessitates secondary or even tertiary solutions to treat these aspects of the umbrella term: OCD alone is often resolved clomipramine (a tricyclic antidepressant) anxietys 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's Syndrome is a neurological disorder, generally diagnosed and treated by a neurologist or psychiatrist familiar with tic disorders. Tourette's most often involves chronic motor and vocal tics (described by NIH as "semi-voluntary" actions performed in response to a premonitory urge, an internal sensory phenomenon akin to a buildup of tension, only able to be alleviated upon releasing a tic.[67], and the typical antipsychotic, pimozide, is specifically approved (as an orphan drug) for this indication.[68] Tourette's, however, is an all-encompassing umbrella term that presents not just as chronic motor/physical and vocal/phonic tics; tics are nearly always comorbid to symptoms of obsessive-compulsive anxiety and/or social anxiety, avoidant personality or schizoid personality, ADHD, as well as insomnia, depression, and Asperger syndrome. clonidine and guanfacine are approved for ADHD, which often comorbid to Tourette's, but not necessarily guaranteed to reduce tics.

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Illicit drug combinations

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Products sold as "powder cocaine" or "crack cocaine" are often found to contain very little, if any, coca alkaloids. ABC News has conducted several investigative journalism analyses and metanalyses and have reported that the greatest concern with any illicit stimulant is that they include undetermined amounts of designer drugs and/or research chemicals; instead of cocaine or pharmaceutical stimulants (e.g. amphetamines, cocaine) products are likely to contain MDMA, crystal meth, and caffeine. Increasingly, the flesh-eating veterinary antibiotic levamisole has been found in "powder cocaine."[69]

Since the forced closure of so many pill mills in the U.S. beginning in 2007, a black market for opioids has flourished and continuously expanded.[70] As demand increases for relatively mild opioid "pain pills" ranging from codeine, hydrocodone, oxycodone, morphine, diacetylmorphine (Heroin) items being deceptively sold as such are adulterated by undeclared amounts of highly potent synthetic opioids of questionable purity. The death of Prince resulted from him unknowingly ingesting fentanyl in the form of counterfeit pills designed to resemble Percocet (oxycodone/acetaminophen) tablets. These "pressed" pills are synthesized via clandestine chemistry by untrained chemists and often cut with agents including fentanyl, carfentanil, and as of September 2024, nitazenes.[71][72]

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and synthetic triazolobenzodiazepines, bromazolam, clobromazolam, phenazolam, and flualprazolam.[73] In April 2025, U.S. Attorney General Pam Bondi stated a desire to regulate xylazine under U.S. federal drug law) as a Schedule III controlled substance.[74] Xylazine is currently a controlled substance under state statutes in Michigan and New York.[75] "Mandrax" is a genericized trademark and street name for the illicit combination of methaqualone and diphenhydramine, named after the pharmaceutical brand that was available by prescription in South Africa until 1993.[76] "Mandrax" is now synthesized via clandestine chemistry as a free base preparation, which is smoked for an intense, short-lived "high".[77]

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References

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