Nalmefene

Source: Wikipedia, the free encyclopedia.

Nalmefene
Clinical data
Trade namesSelincro, Revex, others
Other namesNalmetrene; 6-Desoxy-6-methylenenaltrexone; CPH-101; JF-1; Lu AA36143; NIH-10365; ORF-11676
AHFS/Drugs.comMonograph
MedlinePlusa605043
License data
subcutaneous
Drug classOpioid antagonist
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability40–50% (orally)[6]
Protein binding45%
MetabolismLiver
Elimination half-life10.8 ± 5.2 hours
ExcretionKidney
Identifiers
  • 17-Cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol
JSmol)
  • OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C
  • InChI=1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1 checkY
  • Key:WJBLNOPPDWQMCH-MBPVOVBZSA-N checkY
  (verify)

Nalmefene is a medication that is used in the treatment of

by mouth, administered by injection, or delivered through nasal administration.[7]

In terms of its

dependent on the dosage.[8]

Nalmefene is available as a generic medication.[9]

Medical uses

Opioid overdose

Intravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[3]

Alcohol dependence

Nalmefene is used in the European Union to reduce alcohol dependence[2] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[10]

Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[11] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[11][12] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[12]

Side effects

Very common

The following side effects of nalmefene are very common (≥10% incidence):

  • Insomnia
  • Dizziness
  • Headache
  • Nausea

Common

The following side effects of nalmefene are common (≥1% to <10% incidence):

  • Decreased appetite
  • Sleep disorder
  • Confusional state
  • Restlessness
  • Libido decreased (including loss of libido)
  • Somnolence
  • Tremor
  • Disturbance in attention
  • Paraesthesia
  • Hypoaesthesia
  • Tachycardia
  • Palpitations
  • Vomiting
  • Dry mouth
  • Diarrhea
  • Hyperhidrosis
  • Muscle spasms
  • Fatigue
  • Asthenia
  • Malaise
  • Feeling abnormal
  • Weight decreased

The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.[13]

Pharmacology

Pharmacodynamics

Opioid receptor blockade

Nalmefene at human opioid receptors
Ki
Tooltip Inhibitor constant)		 Ratios Refs
MOR
Tooltip μ-Opioid receptor
KOR
Tooltip κ-Opioid receptor
DOR
Tooltip δ-Opioid receptor		 MOR:KOR:DOR
0.24 nM 0.083 nM 16 nM 3:1:193 [14][15]
0.3 nM 0.3 nM 7.3 nM 1:1:24 [16][17]

Nalmefene acts as an

affinity for the δ-opioid receptor (DOR) (Ki = 16 nM), where it behaves as an antagonist.[14][15][21]

Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the C6 position of naltrexone with a methylene group (CH2). It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison.[14][18]

Nalmefene with a single 1 mg dose by

intravenous injection has been found to produce brain MOR blockade of 99% at 5 minutes, 90% at 2 hours, 33% at 4 hours, and 10% at 8 hours.[22] A lower dose of 1 μg/kg intravenously resulted in brain MOR blockade of 52% at 5 minutes, 33% at 2 hours, 47% at 4 hours, and 26% at 8 hours.[22] With oral administration, peak brain MOR occupancy of 87 to 100% was found after 3 hours with single or repeated dosing of nalmefene.[23][24] At 26 hours (1.1 days) post-administration, brain MOR occupancy was 83 to 100%; at 50 hours (2.1 days), it was 48 to 72%; and at 74 hours (3.1 days), it was 12 to 46%.[23][24] The half-time of nalmefene occupancy of brain MORs is about 29 hours and is much longer than with naloxone.[23][25] Substantial brain MOR occupancy occurs with nalmefene even when blood levels of nalmefene are very low.[23][24] The prolonged brain MOR occupancy of nalmefene may be due to slow dissociation of nalmefene from MORs consequent to its high MOR affinity.[23][24]

Metabolism

Nalmefene is extensively metabolized in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.[citation needed]

Chemistry

Nalmefene is a derivative of naltrexone and was first reported in 1975.[26]

Society and culture

Nalmefene was first reported in a patent in 1974.[27]

United States

In the United States, immediate-release injectable nalmefene was approved in 1995, as an antidote for opioid overdose.[28] It was sold under the brand name Revex.[3] The product was discontinued by its manufacturer around 2008.[29][30][31] A generic version was approved for medical use in the United States in February 2022.[9][32]

In May 2023, the FDA approved a nalmefene hydrochloride nasal spray, under the brand name Opvee, for the emergency treatment of opioid overdose in people twelve years of age and older.[33]

Nalmefene in

pill form, which is used to treat alcohol dependence and other addictive behaviors, is not available in the United States.[8]

European Union

Danish pharmaceutical company Lundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[34] In 2011, they submitted an application for their drug termed Selincro to the European Medicines Agency.[35] The drug was approved for use in the EU in March 2013.[36] and in October 2013, Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[37] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[38] In November 2014, nalmefene was approved as a possible treatment supplied by Britain's National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence.[39]

Research

Oral nalmefene was under development for the treatment of

opioid-related disorders.[41][42]

Nalmefene might be useful to treat

cocaine addiction.[43]

References

  1. ^ "Prescription medicines: registration of new chemical entities in Australia, 2015". Therapeutic Goods Administration (TGA). 21 June 2022. Archived from the original on 10 April 2023. Retrieved 10 April 2023.
  2. ^ a b c "Selincro 18mg film-coated tablets". UK Electronic Medicines Compendium. September 2016. Archived from the original on 27 April 2021. Retrieved 13 June 2017.
  3. ^ a b c d "Revex- nalmefene hydrochloride injection, solution". DailyMed. Archived from the original on 21 January 2022. Retrieved 11 February 2022.
  4. ^ "Opvee- nalmefene hydrochloride spray". DailyMed. 19 June 2023. Retrieved 25 June 2023.
  5. ^ "Selincro EPAR". European Medicines Agency. 17 September 2018. Archived from the original on 11 February 2022. Retrieved 11 February 2022.
  6. PMID 26483076
    .
  7. ^ "FDA Approves Prescription Nasal Spray to Reverse Opioid Overdose". U.S. Food and Drug Administration (FDA) (Press release). 23 May 2023. Retrieved 1 June 2023.
  8. ^
    PMID 31643618. Bookshelf ID: NBK548295. Archived
    from the original on 13 November 2021. Retrieved 12 February 2022.
  9. ^ a b "Competitive Generic Therapy Approvals". U.S. Food and Drug Administration (FDA). 11 February 2022. Archived from the original on 12 February 2022. Retrieved 11 February 2022.
  10. ^ "Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence". NICE. 26 November 2014. Archived from the original on 27 March 2021. Retrieved 13 June 2017.
  11. ^
    PMID 26694529
    .
  12. ^
    PMID 25187751
    .
  13. ^ "Selincro". European Medicines Agency. Archived from the original on 24 October 2015. Retrieved 3 November 2015.
  14. ^
    PMID 15988468
    .
  15. ^
    ISBN 978-0-12-420177-4. Archived
    from the original on 10 January 2023. Retrieved 31 October 2016.
  16. ^
    PMID 9686407
    .
  17. ^
    S2CID 162168648
    .
  18. ^
    PMID 23881605
    .
  19. PMID 25121147. Archived
    from the original on 28 October 2021. Retrieved 28 April 2016. (subscription required)
  20. ISBN 978-1-139-95300-9. Archived
    from the original on 10 January 2023. Retrieved 31 October 2016.
  21. PMID 25647453
    .
  22. ^
    ISBN 9780123983350
    .
  23. ^
    S2CID 9227860
    .
  24. ^
    S2CID 2453226
    .
  25. PMID 9374341
    .
  26. ISBN 9781118889572. Archived
    from the original on 10 January 2023. Retrieved 13 June 2017.
  27. ^ U.S. patent 3,814,768
  28. ^ "Nalmefene label" (PDF). U.S. Food and Drug Administration. Archived (PDF) from the original on 12 February 2022. Retrieved 12 February 2022.
  29. ^ "Baxter discontinues Revex injection". Monthly Prescribing Reference website. Haymarket Media, Inc. 9 July 2008. Archived from the original on 11 October 2016. Retrieved 10 October 2016.
  30. ^ "Drug Shortages". U.S. Food and Drug Administration (FDA). Archived from the original on 26 December 2008.
  31. ^ "Determination That Revex (Nalmefene Hydrochloride Injection), 0.1 Milligram Base/Milliliter and 1.0 Milligram Base/Milliliter, Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness". Federal Register. 3 November 2017. Archived from the original on 28 January 2022. Retrieved 11 February 2022.
  32. ^ "Nalmefene hydrochloride: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Archived from the original on 12 February 2022. Retrieved 11 February 2022.
  33. ^ "FDA Approves Prescription Nasal Spray to Reverse Opioid Overdose". U.S. Food and Drug Administration (FDA) (Press release). 23 May 2023. Retrieved 1 June 2023.
  34. ^ Clinical trial number NCT00811720 for "Efficacy of nalmefene in patients with alcohol dependence (ESENSE1" at ClinicalTrials.gov
  35. ^ "Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan". The Pharma Letter. 22 December 2011. Archived from the original on 23 June 2012. Retrieved 5 March 2012.
  36. ^ "Selincro". European Medicines Agency. 13 March 2013. Archived from the original on 4 September 2018. Retrieved 4 October 2014.
  37. ^ "Alcohol cravings drug nalmefene granted approval in Scotland". BBC News. 7 October 2013. Archived from the original on 28 April 2021. Retrieved 21 June 2018.
  38. ^ "Nalmefene granted approval in England". The Independent. 3 October 2014. Archived from the original on 18 June 2022.
  39. ^ "Alcohol dependence treatment accepted for NHS use". MIMS. 26 November 2014. Archived from the original on 28 April 2021. Retrieved 13 June 2017.
  40. ^ "Nalmefene oral - Acorda Therapeutics/Lundbeck A/S". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 1 November 2021. Retrieved 1 November 2021.
  41. ^ "Nalmefene hydrochloride injection - Purdue Pharma". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 7 November 2021. Retrieved 1 November 2021.
  42. ^ "Intranasal nalmefene - Opiant Pharmaceuticals". AdisInsight. Springer Nature Switzerland AG. Archived from the original on 2 November 2021. Retrieved 1 November 2021.
  43. PMID 24484983
    .
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