Chemistry:Oxymorphone

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Short description: Opioid analgesic drug
Oxymorphone
Oxymorphone2DCSD.svg
Oxymorphone3DanJ.gif
Clinical data
Trade namesNumorphan, Numorphone, Opana, others
Other names14-Hydroxydihydromorphinone
AHFS/Drugs.comMonograph
MedlinePlusa610022
License data
Dependence
liability		High
Addiction
liability		High
Routes of
administration		By mouth, buccal, sublingual, intranasal, intravenous, epidural, subcutaneous, intramuscular
Drug classOpioid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityby mouth: 10%
Buccal: 28%
Sublingual: 37.5%
Intranasal: 43%[2]
IV, IM & IT: 100%[3]
Protein binding10%[3]
MetabolismLiver (CYP3A4, glucuronidation)[3]
Elimination half-life7–9 hours[3]
Duration of action: 6–8 hours orally, 4–6 hrs parenteral
ExcretionUrine, feces[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC17H19NO4
Molar mass301.342 g·mol−1
3D model (JSmol)
  (verify)

Oxymorphone (sold under the brand names Numorphan and Opana among others) is a highly potent opioid analgesic indicated for treatment of severe pain. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets.[4] The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally.[5] Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.[6]

It was developed in Germany in 1914. It was patented in 1955 and approved for medical use in 1959.[7] In June 2017 the FDA asked Endo Pharmaceuticals to remove its product from the US market.[8] This was in part due to the opioid epidemic in the US, and the fact that a 2012 reformulation failed to stop illicit injection of the drug. Endo responded by voluntarily removing Opana ER from the market a month later.[9] Generic versions of extended-release oxymorphone, such as those manufactured by Amneal Pharmaceuticals, are still available in the US.[10]

Medical uses

Oxymorphone Immediate Release is indicated for the relief of moderate to severe pain, such as treatment of acute post surgical pain.[11] For any chronic treatment of pain, clinicians should only consider long term use if there is significant clinical benefit to the patient's therapy that outweigh any potential risk. The first line treatment choices for chronic pain are non-pharmacological and non-opioid agents.[12]

Oxymorphone extended-release tablets are indicated for the management of chronic pain and only for people already on a regular schedule of strong opioids for a prolonged period. Immediate-release oxymorphone tablets are recommended for breakthrough pain for people on the extended-release version. Compared to other opioids, oxymorphone has similar pain relieving efficacy.[13]

In the United States it is a Schedule II controlled substance with an ACSCN of 9652.[14]

Oxymorphone ER Tablets should be taken on an empty stomach.[15]

Availability

Brands and forms

Oxymorphone was marketed by Endo Pharmaceuticals, under the brand name(s) Opana and Opana ER. Opana ER was withdrawn by the manufacturer in 2017 due to a FDA request, making it unavailable in the US.[16] However, both IR (immediate release) and ER (extended release) formulations are still available under the generic name Oxymorphone and Oxymorphone ER, provided by a multitude of different manufacturers.

Oxymorphone is also available as an injectable for inpatient use, available for IV (intravenous), IM (intramuscular), and SC (subcutaneous) injection.

An extended release (ER) modified-release dosage form is commonly used, which modifies the pharmacokinetics of the drug.

Oral dosage forms

Oxymorphone comes in a variety of doses.

IR Tablet[17] ER 12 Hour Tablet[17]
5 mg 5 mg
10 mg 7.5 mg
10 mg
15 mg
20 mg
30 mg
40 mg

Special populations

Patients already suffering from debilitation are at a much higher risk of respiratory depression. Nonopioid analgesics should be considered in this population.

Elderly patients are much more sensitive to adverse effects, such as falls, cognitive impairment and constipation, and should be monitored for such. Decreased renal function associated with aging leads to decreased clearance of the drug, resulting in narrow therapeutic windows and increasing the danger of overdose. If oxymorphone is absolutely indicated, smaller initial doses should be started for this population.

There is a risk of neonatal withdrawal symptom in the newborn if pregnant women take oxymorphone for a prolonged period. Oxymorphone crosses the placenta and holds risk of birth defects, poor fetal growth, stillbirth, and preterm delivery. The children of mothers who are physically dependent on oxymorphone have a higher risk of similar dependence. Due to these severe risks, oxymorphone is highly discouraged among this population. The amount of transfer of oxymorphone into the breast milk is not known and women are cautioned to weigh the risks and benefits before breastfeeding while on this medication.[18]

Side effects

The principal adverse effects of oxymorphone are similar to other opioids with constipation, nausea, vomiting, dizziness, dry mouth and drowsiness being the most common adverse effects. This drug is highly addictive as with other opioids and can lead to chemical dependence and withdrawal.[19]

Overdose

In common with other opioids, oxymorphone overdosage is characterized by respiratory depression, sleepiness progressing to stupor or coma, skeletal muscle weakness, cold and clammy skin, and sometimes slow heart rate and low blood pressure. In a severe case of overdose, apnea, circulatory collapse, cardiac arrest and death can occur.[19]

Pharmacology

Pharmacodynamics

Oxymorphone elicits its effects by binding to and activating the μ-opioid receptor (MOR) and, to a much lesser extent, the δ-opioid receptor (DOR) and κ-opioid receptor (KOR).[3] Its activity at the DOR may augment its action at the MOR.[3] Oxymorphone is 10 times more potent than morphine.[20] The calculation of relative potency indicated that 1 mg of oxymorphone hydrochloride equaled 9.85 mg of morphine sulfate, or 1.02 mg of oxymorphone hydrochloride was equivalent to 10 mg of morphine sulfate.[21]

Oxymorphone at opioid receptors[22]
Affinities (Ki) Ratio
MOR DOR KOR MOR:DOR:KOR
0.78 nM 50 nM 137 nM 1:64:176
Equianalgesic doses[23][24][25]
Compound Route Dose
Codeine PO 200 mg
Hydrocodone PO 20–30 mg
Hydromorphone PO 7.5 mg
Hydromorphone IV 1.5 mg
Morphine PO 30 mg
Oxycodone IV 20 mg
Morphine IV 10 mg
Oxycodone PO 20 mg
Oxymorphone PO 7–10 mg
Oxymorphone IV 1 mg

Pharmacokinetics

Chemistry

Oxymorphone is commercially produced from thebaine, which is a minor constituent of the opium poppy (Papaver somniferum) but thebaine is found in greater abundance (3%) in the roots of the oriental poppy (Papaver orientale).[3][26] German patents from the mid-1930s indicate that oxymorphone as well as hydromorphone, hydrocodone, oxycodone, and acetylmorphone can be prepared—without the need for hydrogen gas—from solutions of codeine, morphine, and dionine by refluxing an acidic aqueous solution, or the precursor drug dissolved in ethanol, in the presence of certain metals, namely palladium and platinum in fine powder or colloidal form or platinum black.

Oxymorphone hydrochloride occurs as odourless white crystals or white to off-white powder. It darkens in colour with prolonged exposure to light. One gram of oxymorphone hydrochloride is soluble in 4 ml of water and it is sparingly soluble in alcohol and ether. It degrades upon contact with light.[19]

Oxymorphone can be acetylated like morphine, hydromorphone, and some other opioids. Mono-, di-, tri-, and tetra- esters of oxymorphone were developed in the 1930s but are not used in medicine at this time. Presumably other esters such as nicotinyl, benzoyl, formyl, cinnimoyl &c.can be produced.[citation needed]

The 2013 US DEA annual manufacturing quotas were 18 375 kilogrammes for conversion (a number of drugs can be made from oxymorphone, both painkillers and opioid antagonists like naloxone) and 6875 kg for direct manufacture of end-products.[27] Oxymorphone is also a minor metabolite of oxycodone, which is formed by CYP2D6-mediated O-demethylation.[3]

History

Oxymorphone was first developed in Germany in 1914,[28] and patented in the US by Endo Pharmaceuticals in 1955.[29] It was introduced in the United States in January 1959 and other countries around the same time.[3]

Society and culture

Brand names

  • Numorphan (suppository and injectable solution)
  • Opana ER (extended-release tablet): June 2017 FDA removal request due to rates of IV abuse.[30]
  • Opana IR (immediate-release tablet)
  • O-Morphon in Bangladesh by Ziska pharmaceutical ltd.

The brand name Numorphan is derived by analogy to the Nucodan name for an oxycodone product (or vice versa) as well as Paramorphan/Paramorfan for dihydromorphine and Paracodin (dihydrocodeine). The only commercially available salt of oxymorphone in most of the world at this time is the hydrochloride, which has a free base conversion ratio of 0.891, and oxymorphone hydrochloride monohydrate has a factor of 0.85.[19]

Generic pill markings are ATV10/APO; HK10 (10 mgs) oblong white and ATV20/APO; HK20 (20 mgs) oblong white.[citation needed]

Abuse

In 1924, the United States banned the sale and importation of opium for the manufacture of heroin, an opioid pain medication which was being abused. See Anti-Heroin Act of 1924.Template:Relevance

Beginning in the 1990s, prescription opioid drug abuse has been a prevalent public health issue of concern.[31] Since 2013, with greatly increasing morbidity and deaths from overdoses of synthetic opioids, such as oxycodone, tramadol, and fentanyl, this issue has developed into a full-fledged epidemic.[32] This has led to several other public health issues, including the spread of diseases like hepatitis C and human immunodeficiency virus (HIV).[33][34]

In the United States, as of 2013 more than 12 million people abused opioid drugs at least once a year.[35] In 2010, 16,652 deaths were related to opiate overdose, in 2015 this number increased to 33,091.[36][37] In September 2013, new FDA labeling guidelines for long-acting and extended-release opioids required manufacturers to remove moderate pain as use indication, reserving the drug for "pain severe enough to require daily, around-the-clock, long-term opioid treatment"[38] however it did not restrict physicians from prescribing opioids for moderate, "as needed" usage.[35]

In January 2013, the Centers for Disease Control and Prevention (CDC) reported an illness associated with intravenous (IV) abuse of oral Opana ER (oxymorphone) in Tennessee. The syndrome resembled that of thrombotic thrombocytopenic purpura (TTP).[39] Initial therapy included therapeutic plasma exchange, as for TTP. Unlike TTP, no deficient ADAMTS13 activity nor anti-ADAMTS13 antibody was found indicating a thrombotic microangiopathy of different underlying cause. If IV Opana abuse is acknowledged, supportive care, instead of therapeutic plasma exchange could be considered.[40]

In January 2015, the first HIV outbreak linked to abuse of prescription opioid drugs was identified by the Indiana State Department of Health (ISDH), in the small, rural community of Scott County in southeastern Indiana.[41]  ISDH launched an investigation into this HIV outbreak when 11 individuals were confirmed positive for HIV with ties tracing back to the same community. Three months into this investigation, ISDH diagnosed a total of 135 people with HIV, with the numbers still increasing. The cause of this outbreak has been linked to the sharing of needles between opioid abusers, which in some cases, involves sharing needles with up to nine different partners.[34]

In late March 2015, reports indicated Austin, Indiana, was the center of an outbreak of HIV caused by oxymorphone use as an injectable recreational drug. The outbreak required emergency action by state officials.[42][43][44] The NPR podcast "embedded" episode of March 31, 2016 was an in-depth account of a visit to oxymorphone abusers in Austin, Indiana. In 2016, the street price of oxymorphone was reported to be $140.[45]

The common opioid of abuse in this outbreak has been identified as Opana ER, a time-released oxymorphone pain killer formulated to be resistant to crushing, manufactured by Endo Pharmaceuticals. This harder to crush formulation was put into production in 2012 in an effort to reduce the risk of abuse from snorting the crushed up pill. However, opioid abusers circumvented this issue by finding a way to dissolve and inject the drug.[41]

The extent of this outbreak has garnered the attention of both the CDC and FDA. The CDC opened a larger investigation into all disease outbreaks involving Opana ER, focusing on the incidence of thrombotic thrombocytopenic purpura (TTP)-like illness in the 2012 Tennessee outbreak, as well as the 2015 HIV outbreak in Indiana. The FDA launched a post-marketing safety study regarding the reformulation of Opana ER in 2012[46] and the Indiana state government helped fund another study exploring the link between HIV infection and injection use of oxymorphone in Indiana from 2014 to 2015.[47]

The results of these studies found that the reformulation of Opana to a hard to crush tablet unintentionally increased the risk of transmission of acquired blood borne infections because opioid abusers switched from using the drug through the nasal route to injection. This epidemic caused the risk of acquiring a blood borne infection with the use of injectable opioids to increase in comparison to the risk of acquiring an infection when using injectable heroin or cocaine.[33][46][47]

In June 2017, faced with the public health crisis, the opioid epidemic, the FDA asked Endo Pharmaceuticals to "remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market". In their June 8, 2017 press release they also noted that, this was the first time the FDA had taken steps to "remove a currently marketed opioid pain medication from sale due to public health consequences of abuse."[30] By July 6, 2017, Endo International voluntarily complied with the FDA removal request.[48]

See also

References

  1. ↑ "Drugs@FDA: FDA Approved Drug Products". https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm. 
  2. ↑ "Intranasal absorption of oxymorphone". Journal of Pharmaceutical Sciences 86 (8): 975–6. August 1997. doi:10.1021/js960513x. PMID 9269879. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 Opioids in Cancer Pain (2nd ed.). Oxford, UK: Oxford University Press. 2009. pp. Chapter 17. ISBN 978-0-19-157532-7. https://books.google.com/books?id=aEzg6i2nPMQC&q=978-0-19-157532-7. 
  4. ↑ "Review of oral oxymorphone in the management of pain". Therapeutics and Clinical Risk Management 4 (4): 777–87. August 2008. doi:10.2147/tcrm.s1784. PMID 19209260. 
  5. ↑ "Clinical Pharmacology of Oxymorphone" (in en). Pain Medicine 10 (suppl_1): S3–S10. 2009-04-01. doi:10.1111/j.1526-4637.2009.00594.x. ISSN 1526-2375. 
  6. ↑ "Pharmacodynamic effects of oral oxymorphone: abuse liability, analgesic profile and direct physiologic effects in humans". Addiction Biology 21 (1): 146–58. January 2016. doi:10.1111/adb.12173. PMID 25130052. 
  7. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 52X. ISBN 9783527607495. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA52X. 
  8. ↑ "FDA takes aim at opioid epidemic". Chemical & Engineering News 95 (25): 8. 2017-06-19. https://cen.acs.org/articles/95/i25/FDA-takes-aim-at-opioid-epidemic.html. 
  9. ↑ Office of the Commissioner (2019-09-10). "Press Announcements – FDA requests removal of Opana ER for risks related to abuse" (in en). https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm562401.htm. 
  10. ↑ "Six drug companies subpoenaed in federal opioids probe". The Washington Post. 2019-11-27. https://www.washingtonpost.com/health/six-drug-companies-subpoenaed-in-federal-opioids-probe/2019/11/27/745899e6-112e-11ea-bf62-eadd5d11f559_story.html. 
  11. ↑ "Review of oral oxymorphone in the management of pain". Therapeutics and Clinical Risk Management 4 (4): 777–87. August 2008. doi:10.2147/TCRM.S1784. PMID 19209260. 
  12. ↑ "Guideline for Prescribing Opioids for Chronic Pain". https://www.cdc.gov/drugoverdose/pdf/guidelines_factsheet-a.pdf. 
  13. ↑ "Cancer pain management with opioids: Optimizing analgesia". https://www.uptodate.com/contents/cancer-pain-management-with-opioids-optimizing-analgesia?search=opana&source=search_result&selectedTitle=2~75&usage_type=default&display_rank=1#H12. 
  14. ↑ "Administration Controlled Substance Code Number". DEA. https://www.deadiversion.usdoj.gov/21cfr/cfr/1308/1308_03.htm. 
  15. ↑ "Oxymorphone ER Tablet". https://my.clevelandclinic.org/health/drugs/18265-oxymorphone-er-tablet. 
  16. ↑ "Endo to Pull Opana From the Market Following FDA Request.". Pharmacy Times.. 6 July 2017. https://www.pharmacytimes.com/product-news/endo-to-pull-opana-from-the-market-following-fda-request. 
  17. ↑ 17.0 17.1 "Oxymorphone IR Package Insert". Endo Pharmaceuticals. U.S. Food and Drug Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021611s007lbl.pdf. 
  18. ↑ "Login" (in en-US). http://www.crlonline.com/lco/action/doc/retrieve/docid/patch_f/7423#pri. 
  19. ↑ 19.0 19.1 19.2 19.3 "Oxymorphone Hydrochloride". Martindale: The Complete Drug Reference. Pharmaceutical Press. 30 January 2013. http://www.medicinescomplete.com/mc/martindale/current/6249-a.htm. 
  20. ↑ "Oxymorphone: a review". Supportive Care in Cancer 14 (2): 109–115. February 2006. doi:10.1007/s00520-005-0917-1. PMID 16317569. 
  21. ↑ "The analgesic equivalence to morphine and relative side action liability of oxymorphone (14-hydroxydihydro morphinone)". The Journal of Pharmacology and Experimental Therapeutics 125 (2): 116–121. February 1959. PMID 13631610. https://pubmed.ncbi.nlm.nih.gov/13631610/. Retrieved 14 July 2021. 
  22. ↑ "Selectivity of Ligands for Opioid Receptors". Opioids. Handbook of Experimental Pharmacology. 104 / 1. 1993. pp. 645–679. doi:10.1007/978-3-642-77460-7_26. ISBN 978-3-642-77462-1. 
  23. ↑ "Analgesia and Anesthesia". Pharmacology for Women's Health. Jones & Bartlett Publishers. 25 October 2010. pp. 332–. ISBN 978-1-4496-1073-9. https://books.google.com/books?id=o_rHHCsIpckC&pg=PA332. 
  24. ↑ Chestnut's Obstetric Anesthesia: Principles and Practice E-Book. Elsevier Health Sciences. 28 February 2014. pp. 611–. ISBN 978-0-323-11374-8. https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611. 
  25. ↑ Havard's Nursing Guide to Drugs. Elsevier Health Sciences. 1 June 2013. pp. 933–. ISBN 978-0-7295-8162-2. https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933. 
  26. ↑ "The thebaine content of ornamental poppies belonging to the papaver section oxytona". Planta Medica 42 (1): 45–9. May 1981. doi:10.1055/s-2007-971544. PMID 17401879. 
  27. ↑ "2013 – Proposed Adjustments to the Aggregate Production Quotas for Schedule I and II Controlled Substances and Assessment of Annual Needs for the List I Chemicals Ephedrine, Pseudoephedrine, and Phenylpropanolamine for 2013" (in en-US). http://www.deadiversion.usdoj.gov/fed_regs/quotas/2013/fr0620.htm. 
  28. ↑ The Essence of Analgesia and Analgesics. MA, USA: Cambridge University Press; 1 edition. 2010. p. 123. ISBN 978-0521144506. https://books.google.com/books?id=ZwPIjKg0XukC&q=oxymorphone+1914+germany&pg=PA123. 
  29. ↑ Leweustein MJ, "Morphine derivative", US patent 2806033, published 1955-03-08, issued 1957-10-09
  30. ↑ 30.0 30.1 "FDA requests removal of Opana ER for risks related to abuse" (Press release). Silver Spring, Maryland. U.S. Food and Drug Administration. June 8, 2017. Retrieved 26 October 2017. Today, the U.S. Food and Drug Administration requested that Endo Pharmaceuticals remove its opioid pain medication, reformulated Opana ER (oxymorphone hydrochloride), from the market... This is the first time the agency has taken steps to remove a currently marketed opioid pain medication from sale due to the public health consequences of abuse...[FDA Commissioner Scott Gottlieb, M.D.]: "We are facing an opioid epidemic – a public health crisis, and we must take all necessary steps to reduce the scope of opioid misuse and abuse.
  31. ↑ "Vital Signs: Overdoses of Prescription Opioid Pain Relievers --- United States, 1999--2008". 2011-11-04. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm. 
  32. ↑ Centers for Disease Control and Prevention (2022-06-01). "Understanding the Opioid Overdose Epidemic". https://www.cdc.gov/opioids/basics/epidemic.html. 
  33. ↑ 33.0 33.1 "Injecting Opana: Indiana's HIV Outbreak and America's Opioid Epidemic". 2015-03-02. https://medium.com/addiction-unscripted/injecting-opana-indiana-s-hiv-outbreak-and-america-s-opioid-epidemic-65501f9aa6c8. 
  34. ↑ 34.0 34.1 "Dangers Of Opana Opioid Painkiller Outweigh Benefits, FDA Panel Says" (in en). NPR.org. 16 March 2017. https://www.npr.org/sections/health-shots/2017/03/16/520291362/dangers-of-opana-opioid-painkiller-outweigh-benefits-fda-panel-says. 
  35. ↑ 35.0 35.1 "FDA to require stricter labeling for pain drugs". Los Angeles Times: pp. A1 and A9. 11 September 2013. 
  36. ↑ "Drug Overdose in the United States: Fact Sheet". Centers for Disease Control. https://www.cdc.gov/homeandrecreationalsafety/overdose/facts.html. 
  37. ↑ "Increases in Drug and Opioid-Involved Overdose Deaths - United States, 2010-2015". MMWR. Morbidity and Mortality Weekly Report 65 (50–51): 1445–1452. December 2016. doi:10.15585/mmwr.mm655051e1. PMID 28033313. 
  38. ↑ "ER/LA Opioid Class Labeling Changes and Postmarket Requirements". FDA. https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM367697.pdf. 
  39. ↑ "Thrombotic thrombocytopenic purpura (TTP)-like illness associated with intravenous Opana ER abuse--Tennessee, 2012". MMWR. Morbidity and Mortality Weekly Report 62 (1): 1–4. January 2013. PMID 23302815. PMC 4604918. https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6201a1.htm. 
  40. ↑ "Successful treatment of intravenously abused oral Opana ER-induced thrombotic microangiopathy without plasma exchange". American Journal of Hematology 89 (7): 695–7. July 2014. doi:10.1002/ajh.23720. PMID 24668845. 
  41. ↑ 41.0 41.1 "Community Outbreak of HIV Infection Linked to Injection Drug Use of Oxymorphone — Indiana, 2015" (in en). https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6416a4.htm. 
  42. ↑ "How an HIV outbreak hit rural Indiana — and why we should be paying attention". Washington Post. 30 March 2015. https://www.washingtonpost.com/blogs/wonkblog/wp/2015/03/30/how-an-hiv-outbreak-hit-rural-indiana-and-why-we-should-be-paying-attention/. 
  43. ↑ "Community Outbreak of HIV Infection Linked to Injection Drug Use of Oxymorphone--Indiana, 2015". MMWR. Morbidity and Mortality Weekly Report 64 (16): 443–4. May 2015. PMID 25928470. 
  44. ↑ "Threading the Needle--How to Stop the HIV Outbreak in Rural Indiana". The New England Journal of Medicine 373 (5): 397–9. July 2015. doi:10.1056/NEJMp1507252. PMID 26106947. 
  45. ↑ "Embedded" (in en). NPR.org. 2016-03-31. https://www.npr.org/podcasts/510311/embedded. 
  46. ↑ 46.0 46.1 "Postmarketing Safety Issues Related to Reformulated Opana ER". Joint Meeting of the Drug Safety and Risk Management (DSaRM) Advisory Committee and the Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) Meeting. United States: US Food and Drug Administration, Surveillance and Epidemiology. 13 March 2017. https://www.fda.gov/files/advisory%20committees/published/FDA-Briefing-Information-for-the-March-13-14--2017-Joint-Meeting-of-the-Drug-Safety-and-Risk-Management-Advisory-Committee-and-the-Anesthetic-and-Analgesic-Drug-Products-Advisory-Committee.pdf. 
  47. ↑ 47.0 47.1 "HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014-2015" (in EN). The New England Journal of Medicine 375 (3): 229–39. July 2016. doi:10.1056/nejmoa1515195. PMID 27468059. 
  48. ↑ "Endo caves to FDA pressure, will pull Opana ER from the market". Fierce Pharma. July 6, 2017. http://www.fiercepharma.com/regulatory/endo-caves-to-fda-pressure-to-pull-opana-er-from-market. 



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