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Combination drug

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This article is about fixed-dose combination drugs and polypills as treatments. For two synergistic drugs chemically linked together, see codrug. For use of multiple separate and individual drugs for treatment, see polypharmacy.

A combination drug is a combination of two or more pharmaceutical drugs as active ingredients combined into a single dosage form, typically as a fixed-dose combination, with each constituent standardized to specifications of a fixed dose. Fixed-dose combinations are mass-produced and mass-marketed, intended as near universal treatment options for large and diverse patient populations with a multitude adnd variety of medical histories, medical conditions and genetic predisposition, and treatment needs.

A polypill is a pharmacy or capsule containing four or more active ingredients,[1][2] often needing to be compounded at a specialized pharmacy in order to satisfy the specifications of a patient's personalized prescription and treatment plan, including dosage form, medicinal dosing, and/or mechanism of release. Polypills encompass approved prescription drugs and over the counter drugs, at times including nutritional supplements, amino acids, vitamins, minerals, and hormones.[3]

Fixed-dose combination drugs were initially developed to target a single disease, as with antiretroviral FDCs indicated for treating AIDS and HIV.[4] Over time, the concept of combination drugs has come to include reducing pill burden for patients, thereby encouraging patient compliance, and generally simplifying treatment plan with one product containing easily accessible (often available over the counter without a prescription requirement), relatively affordable (often generic drugs) ingredients with established therapeutic efficacy and a broad capacity for treating a variety of symptoms and conditions, thus ensuring maximum appeal to a majority of patients amongst a large population with varying needs.

Current prescription combination drugs

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

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, and include:

Combination drugs accessible over the counter (OTC)

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Fixed-dose 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.[10]

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

Combination drugs in development, yet to be approved for medical use

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Combinations drugs for veterinary use

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Combination drugs no longer widely available

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  • Acutran by G.W. Carnrick Laboratories is composed of amfecloral, a compound molecule pairing dextroamphetamine sulfate and chloral hydrate,[25] discontinued 1973[26]
  • Ambar by Wyeth combined methamphetamine hydrochloride and phenobarbital; Ambar Extentab was the extended-release formulation
  • Amphaplex 10 and Amphaplex 20 by Laderle Laboratories combined 2.5 mg methamphetamine saccharate, 2.5 mg methamphetamine hydrochloride, and 5 mg racemic amphetamine sulfate; latter combined 5 mg methamphetamine saccharate, 5 mg methamphetamine hydrochloride, and 10 mg amphetamine sulfate.[27]
  • Amplus Now by Roehrig Laboratories combined 5 mg dextroamphetamine sulfate with 5 mg hydroxyzine[28] [29]
  • Amvicel by Roehrig combined 10 mg dextroamphetamine sulfate, 40 mg amobarbital, and 15 mg phenobarbital with 30 mg nicotinamide with vitamins and minerals[30]
  • Apamead by Lederle combined dextroamphetamine sulfate and amobarbital sodium with aspirin and phenacetin
  • Anox by Winston Pharmaceuticals[citation needed] was a brand of encapsulated polypills combining a fixed dose of three barbiturate salts (20 mg each of phenobarbital, butabarbital, and secobarbital) and two amphetamine salts (7.5 mg each of methamphetamine hydrochloride and dextroamphetamine sulfate)[31]
  • Anxine by Behlen[citation needed] combined 120 mg mephenesin, 35 mg cyclobarbital, and 2.5 mg dextroamphetamine sulfate, and [32][33]
  • Bama-Dex by Behlen combined 5 mg dextroamphetamine and 400 mg meprobamate[34]
  • Biphetamine T-12.5 and Biphetamine T-20 by Fisons combined both enantiomers of racemic amphetamine (dextroamphetamine and levoamphetamine) at doses of 6.25 mg each, for a total of 12.5 mg; the latter contained in aggregate 20 mg of racemic amphetamine.
  • Bontril Timed No. 1 combined 2.5 mg dextroamphetamine and 7.5 mg butabarbital; Bontril Timed No. 2 5 mg dexamphetamine and 15 mg butabarbital; Bontril Timed No. 3 10 mg dexamphetamine and 30 mg butabarbital; Bontril Timed No. 4 15 mg dexamphetamine with 60 mg butabarbital, all manufactured and marketed by G.W. Carnrick Laboratories.[35]
  • Delcobese by Lemmon Drug combined racemic amphetamine sulfate and racemic amphetamine adipate and was "withdrawn voluntarily in 1984, unrelated to safety or legal concerns"[36]
  • Desbutal by Neisler Laboratories combined 5 mg methamphetamine hydrochloride and 30 mg pentobarbital, discontinued 1973[26]
  • Dexytal by Eli Lilly & Co. was an elixir combining dextroamphetamine sulfate and amobarbital
  • Dexamyl by Smith, Kline & French was a tablet comprising dextroamphetamine sulfate and amobarbital, discontinued 1982
  • Durophet-M by Neisler combined 12.5 mg racemic amphetamine and 400mg methaqualone, discontinued 1984
  • Durabond by Neisler was a tablet composed of "chlorpheniramine tannate, 8 mg.; Pyrilamine tannate, 25 mg.; Tanphetamin (rf-amphetamine tannate), 10 mg""General Practice American Academy(20)". 1959.</ref>
  • Daprisal by GlaxoSmithKline combined dextroamphetamine, 32.5 mg amobarbital, and 162.5 mg aspirin
  • Direcel combined dextroamphetamine, butabarbital, carboxymethylcellulose and became Direcel-T with the addition of thyroid hormone
  • DuoDex combined 16.25 mg aloin, 15 mg dextroamphetamine, 16.25 mg pentobarbital, and thyroid hormone
  • Dysonil combined methamphetamine hydrochloride, pentobarbital, and salicylamide
  • Edrisal combined 160 mg aspirin, 160 mg phenacetin, 2.5 mg amphetamine sulfate, and Edrisal with Codeine contained an additional 16 mg codeine[37]
  • Ethobral by Wyeth was an encapsulated polypill combining fixed doses of the barbiturates phenobarbital, butabarbital, and secobarbital with fixed doses of methamphetamine hydrochloride and dextroamphetamine sulfate
  • Eskatrol by Smith, French & Kline: combination of dextroamphetamine and prochlorperazine; discontinued 1981
  • Euphoramin: 5 mg methamphetamine hydrochloride and 300 mg meprobamate
  • Lamital by Teva Pharmaceuticals: combination of 500 mg acetaminophen, 15 mg amobarbital sodium, and 2.5 mg methamphetamine hydrochloride
  • Mandrax by Lemmon: methaqualone hydrochloride and diphenhydramine, commercially available in South Africa until 1990s
  • Mediatric by Janssen Pharmaceuticals combined two hormones (0.25 mg Premarin and 2.5 mg methyltestosterone) with 100 mg vitamin c, b vitamins, and 1 mg methamphetamine hydrochloride
  • NalerTan by Neisler: combination of 12.5 mg dextroamphetamine tannate, 8 mg chlorpheniramine tannate, and 25 mg pyrilamine tannate[38][39]
  • Nexorinombination of dextroamphetamine sulfate, amobarbital, methylcellulose, and supplements
  • Obocell by Neisler: combination of 5 mg dextroamphetamine phosphate and 25 mg methapyrilene phosphate; with the addition of 160 mg Nitrin (Neisler's brand of high-viscosity methylcellulose), it was sold as Obocell-TF.[40]
  • Obetrol by Abbott Laboratories encompassed a variety of methamphetamine and dextroamphetamine salts, discontinued 1973[26] and later re-branded Oby-Rex by replacing methamphetamine with levoamphetamine, the (s) isomer of single-entity racemic amphetamine.
  • Obolip combined dextroamphetamine, phenobarbital, choline bitartrate, di-methionine, and methylcellulose
  • Phelantin by Parke-Davis combined 100 mg phenytoin sodium, 32 mg pentobarbital sodium, and 2.5 mg methamphetamine hydrochloride.[41]
  • Phenephen by A.H. Robins combined hyoscyamine sulfate, phenacetin, and aspirin, while Phenephen with Codeine had additional codeine
  • Pondimin (casually known as "fen-phen" combined fenfluramine and phentermine, discontinued 1997[42]
  • SynaTan-S by Neisler combined 10 mg dextroamphetamine tannate with 35 mg secobarbital sodium[43]
  • OboTan-S by Mallinckrodt combined 10 mg dexamphetamine tannate and secobarbital[44][45][46]
  • Pre M.T.[citation needed] by Behlen combined racemic amphetamine sulfate, pentobarbital, and pyrilamine maleate with a microdose of theobromine
  • Reladorm by combined 100 mg cyclobarbital and 10 mg diazepam available in Russia until 2019, discontinued[47]
  • Tuinal by AbbVie was a dual-barbiturate combination of sodiums amobarbital and secobarbital. In 1999, AbbVie voluntarily discontinued both Tuinal and Placidyl, citing declining prescriptions and sales.

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. Central nervous system stimulants were versatile as anorectic, antidepressant, and eugeroic (wakefulness-promoting) agents, boosting mental alertness and physical stamina, as well as the ability to maintain focus and motivation. Theoretically, when combined with a CNS depressant, a stimulant's adverse effects (primarily overstimulation , paranoia, and/or anxiety) could be mitigated or reduced/balanced without eliminating the stimulant's therapeutic benefits. The stimulating component was almost always of the substituted amphetamine chemical class or an amphetamine derivative or analog; the tranquilizing component was either one or more barbiturate salts, or non-barbiturate GABAergic drugs (e.g. meprobamate, methaqualone) with a similar mechanism of action, with tranquilizing, muscle relaxant, and sedating effects.

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,"[48] despite conceding that these combinations were often capable of replacing Monoamine Oxidase Inhibitors (MAOIs) in patients with treatment-resistant depression where MAOI treatment is appropriate, but where the MAOI-related dietary restrictions would otherwise hinder patient compliance.

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[49] For prescribers, if one constituent of the combination is contraindicated for a patient, the product cannot be prescribed.[50][51]

Limitations of currently-available combinations

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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 for which treatment options are currently limited; only the typical antipsychotics, pimozide and haloperidol are specifically approved for treating the tic component of Tourette's[52]; clonidine and guanfacine are approved for ADHD, which often comorbid to Tourette's, but not necessarily guaranteed to reduce tics. Typically identified by 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.[53] 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 traits of high-functioning autism (formerly "Asperger syndrome").

Illicit "street" drug combinations

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So-called "powder cocaine" often contains stimulants meant to mimic cocaine's effects; many batches analyzed did not contain any cocaine or coca alkaloids at all; most frequently, "powder cocaine" is found to contain designer drugs and/or research chemicals including synthetic cathinones, MDMA, methamphetamine, caffeine, and increasingly the flesh-eating veterinary antibiotic levamisole have been found in "powder cocaine."[54]

Since the forced closure of so many pill mills in the U.S. beginning around 2007, a black market for opioids has flourished and continuously expanded.[55] 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. Prince died in April 2016 from taking pills he thought were "Percocet;" in actuality, the "Percocet" was not relatively mild oxycodone, but fake "presses" ("pressed pills") that resulted in Prince's gradual ingestion of unknown, but lethal, quantities of fentanyl. "Presses" are synthesized via clandestine chemistry by untrained chemists and often cut with agents including fentanyl, carfentanil, and as of September 2024, nitazenes.[56][57]

Other cutting agents increasingly found in illicit supplies include the veterinary drug xylazine and the designer drugs (synthetic triazolobenzodiazepines) bromazolam, clobromazolam, phenazolam, and flualprazolam.[58] 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.[59] Xylazine is currently a controlled substance under state statutes in Michigan and New York.[60]

Mandrax is the trade name of a pharmaceutical combination drug consisting of methaqualone and diphenhydramine.[61], once prescribed in South Africa, but banned in 1993. "Mandrax" is now synthesized via clandestine chemistry as a free base preparation, which is smoked for an intense, short-lived "high".[62]

See also

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References

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  1. ^ Martin, Mike (2009-04-01). "5-in-1 PolyPill Treatment May Prevent Heart Disease". www.bayviewrx.com. Archived from the original on 2014-02-27.
  2. ^ https://www.escardio.org/Education/ESC-Prevention-of-CVD-Programme/Treatment-goals/Cardio-Protective-drugs/polypills
  3. ^ "The Compounder - Amino Acids, Minerals, Nutrients & Vitamins".
  4. ^ "Antiretroviral Drug Discovery and Development". National Institutes of Health. 5 February 2024. Retrieved 2025-04-25.
  5. ^ https://www.goodrx.com/librax/what-is?srsltid=AfmBOoprJz8XcQ7jc0LGipTRE_p2TymM_psQ45Vj7iptkdP1gU3lDimO Per GoodRX, the combination is generic for Librax
  6. ^ https://www.biospace.com/hyloris-announces-u-s-fda-approval-of-maxigesic-iv
  7. ^ "Paxlovid (nirmatrelvir tablets; ritonavir tablets) for HCPs". paxlovid.pfizerpro.com. Retrieved 2025-04-24.
  8. ^ "Promethazine (CHEBI:8461)".
  9. ^ "Rondec (Carbinoxamine Maleate and Pseudoephedrine HCl): Side Effects, Uses, Dosage, Interactions, Warnings". RxList. Retrieved 2025-04-24.
  10. ^ "Diversion Control Division | CMEA (The Combat Methamphetamine Epidemic Act of 2005)". www.deadiversion.usdoj.gov. Retrieved 2025-04-24.
  11. ^ https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=51ab0ee3-3c94-424d-a30a-2d6c14e3d8ff National Institute of Health FDA overview
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  15. ^ https://www.ebi.ac.uk/chebi/searchId.do?chebiId=8461 "The anti-emetic action of both the hydrochloride and the teoclate (8-chlorotheophylline) salts is used for the prevention of nausea in cases of motion sickness and post-operative vomiting."
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  27. ^ "Amphaplex 10 methamphetamine amphetamine Palmedics Bottle narcotic empty | #1825423307". Worthpoint. Retrieved 2025-04-24.
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  36. ^ Cite error: The named reference curbs on UD was invoked but never defined (see the help page).
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  39. ^ "Irwin Neisler & Co. File - File, Nail | Science History Institute". sciencehistory.pastperfectonline.com. Retrieved 2025-04-24.
  40. ^ https://www.neurores.org/index.php/neurores/article/viewFile/356/345 precursor to Dilantin, sans barbiturate salt component
  41. ^ Kolata, Gina (1997-09-23). "How Fen-Phen, A Diet 'Miracle,' Rose and Fell". The New York Times. ISSN 0362-4331. Retrieved 2025-04-24.
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  44. ^ https://pubchem.ncbi.nlm.nih.gov/compound/Dextroamphetamine-tannate chemical name of dexamfetamine tannate
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  46. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Nar/cotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  47. ^ "Glaucoma Medical Therapy-Principles and Management" (PDF). www.oculist.net.
  48. ^ Mitra, Amitava; Wu, Yunhui (September 2012). "Challenges and Opportunities in Achieving Bioequivalence for Fixed-Dose Combination Products". The AAPS Journal. 14 (3): 646–655. doi:10.1208/s12248-012-9378-x. ISSN 1550-7416. PMC 3385830. PMID 22684403.
  49. ^ Kennedy Seele, 2020 November 12
  50. ^ Lee, GB; Hosking, SM; Etherton-Beer, C; Pasco, JA; Williams, LJ; Holloway-Kew, K; Page, AT (February 2025). "Defining polypharmacy in older adults: a cross-sectional comparison of prevalence estimates calculated according to active ingredient and unique product counts". International Journal of Clinical Pharmacy. doi:10.1007/s11096-025-01882-7. PMC 12125127. PMID 39954222.
  51. ^ https://www.mayoclinic.org/drugs-supplements/pimozide-oral-route/description/drg-20065529
  52. ^ https://pmc.ncbi.nlm.nih.gov/articles/PMC7289498/ National Institutes of Health -- Premonitory Urge phenomenon as a related to the compulsion to tic in obsessive-compulsive anxiety stemming from Tourette's
  53. ^ "Cocaine Laced With Veterinary Drug Levamisole Eats Away at Flesh". ABC News. Retrieved 2025-04-24.
  54. ^ "Punishing Pill Mill Doctors". William & Mary Press. 2018. Retrieved 2025-05-10.
  55. ^ "News: February 2025 – UNODC EWA: Increasing availability of nitazenes calls for global response". www.unodc.org. Retrieved 2025-04-24.
  56. ^ https://www.oas.org/ext/DesktopModules/MVC/OASDnnModules/Views/Item/Download.aspx?type=1&id=1045&lang=1 Sep 2024 Nitazenes in the Supply of Pressed Counterfeit Pills
  57. ^ https://www.cfsre.org/images/content/reports/public_alerts/Public-Alert_Bromazolam_NPS-Discovery_061522.pdf Public Alert on Bromazolam and Fentanyl
  58. ^ "Xylazine: What Clinicians Need to know" (PDF). New York State Department of Health.
  59. ^ "Xylazine". Diversion Control Division. Retrieved 2025-04-24.
  60. ^ https://www.ojp.gov/pdffiles1/Digitization/117274NCJRS.pdf Page 79 describes Mandrax and its Schedule I status in the U.S. also including a photograph of the pharmaceutical-grade tablet
  61. ^ South Africa - a Profile of the Drug Trade (PDF). United Nations. pp. 1–3. Retrieved 2025-05-10.
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