NALOXEGOL
DR JUMI JACOB
INTRODUCTION
• Pegylated naloxone
• Peripherally selective opiod antagonist
• Trade name-movantik
• Developed by astra zen...
OPIOID RECEPTORS
RECEPTORS SITE ACTION
µ brain
cortex
thalamus
spinal cord
substantia gelatinosa
intestinal tract
µ 1:anal...
Reason for opiod induced constipation
-μ receptors located in the enteric nervous system
- increased nonpropulsive contrac...
Mechanism of action
• pegylated derivative of the μ-opioid receptor
antagonist naloxone
• Peripherally acting μ-opioid rec...
Use of pegylation-compared to
naloxone
(1) Reduced passive permeability across
membranes
(2) P-glycoprotein (P-gp) efflux ...
pharmacokinetics
• Absorption
• Route-oral
• Peak plasma time: <2 hr
• High-fat meal increases extent and rate of absorpti...
Drug interactions
• Coadministration with strong CYP3A4
inducers: Not recommended
• Strong CYP3A4 inhibitors: Contraindica...
Special population
• Pregnancy-category C
• Lactation-unknown
• Mild to moderate Hepatic impairment-no
dose adjustment req...
Contraindications
• Known serious hypersensitivity reaction
• Known or suspected GI obstruction
• Coadministration with st...
Indication and dosing
• For opioid induced constipation
• Oral tablets-25mg OD morning dose
Adverse events
• Abdominal pain
• Diarrhea
• Nausea
• Flatulence
• Vomitting headahe
• Hyperhidrosis
Current treatment options
• methylnaltrexone -need for subcutaneous
administration and a narrow
indication(limitation)
• a...
Study title
• Naloxegol for Opioid-Induced Constipation in
Patients with Noncancer Pain
• N Engl J Med 2014; 370:2387-2396...
Study design
• Randomised
• Double blinded
• Placebo controlled
• Phase 3 trial
• Study period march 2011to september 2012...
Study method
• after intial screening
• randomised(1:1:1)
• Placebo naloxegol(12.5) naloxegol(25)
• N=214 N=213 N=214
Inclusion criteria
• <3 spontaneous bowel movements per week
with one or more of the following
symptoms:
• hard or lumpy s...
Exclusion criteria
1)Cancer within 5 years before enrollment
2)conditions or use of medications associated
with diarrhea o...
Primary end point
• response rate during the 12-week treatment
period.
• response->3 spontaneous bowel movements
per week
...
Secondary end point
• the time to the first postdose spontaneous
bowel movement
• the mean number of days per week with on...
Results-primary end point
Placebo
N=214
Naloxegol12.5
N=213
Naloxegol25
N=214
No of pts (%)
responding
63(29.7) 87(40.8) 9...
Secondary end points
placebo Naloxegol12.5 naloxegol25
No of pts(%) with
post dose SBM
209(97) 211(99) 213(99)
Median time...
Adverse events
placebo Naloxegol(12.5) Naloxegol
25
Pts with any AE
(%)
51 52 63
Abdominal pain 6 10 16
diarrhea 4 6 9
nau...
• THANK YOU
of 24

Naloxegol

drug used for opioid induced constipation
Published on: Mar 3, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Naloxegol

  • 1. NALOXEGOL DR JUMI JACOB
  • 2. INTRODUCTION • Pegylated naloxone • Peripherally selective opiod antagonist • Trade name-movantik • Developed by astra zeneca • FDA approval -2014 • Use-opioid induced constipation
  • 3. OPIOID RECEPTORS RECEPTORS SITE ACTION µ brain cortex thalamus spinal cord substantia gelatinosa intestinal tract µ 1:analgesia physical dependence μ2: respiratory depression miosis euphoria reduced GI motility physical dependence μ3: possible vasodilation K Brain,spinal cord Analgesia,convulsant action,antidepressant,miosis, dysphoria δ Brain,peripheral neurons analgesia,physical dependence
  • 4. Reason for opiod induced constipation -μ receptors located in the enteric nervous system - increased nonpropulsive contractions - inhibition of water and electrolyte secretion. - inhibition of gastric emptying, -an increase in pyloric tone,resting anal sphincter tone -delay of transit throughout the small and large intestine
  • 5. Mechanism of action • pegylated derivative of the μ-opioid receptor antagonist naloxone • Peripherally acting μ-opioid receptor antagonist(PAMORA)
  • 6. Use of pegylation-compared to naloxone (1) Reduced passive permeability across membranes (2) P-glycoprotein (P-gp) efflux transporter substrate (3) Allows for oral bioavailability.
  • 7. pharmacokinetics • Absorption • Route-oral • Peak plasma time: <2 hr • High-fat meal increases extent and rate of absorption • Distribution • Protein bound: Low (~4.2%) • Vd: 968-2140 L • Metabolism • Substrate of CYP3A and P-gp • Elimination • Excretion: 68% feces (~16% unchanged); 16% urine (<6% unchanged) •
  • 8. Drug interactions • Coadministration with strong CYP3A4 inducers: Not recommended • Strong CYP3A4 inhibitors: Contraindicated • Moderate CYP3A4 inhibitors: Avoid coadministration; if unavoidable, reduce dose to 12.5 mg qDay
  • 9. Special population • Pregnancy-category C • Lactation-unknown • Mild to moderate Hepatic impairment-no dose adjustment required • Severe hepatic impairment-avoid • Mild renal impairment-no dose adjustment
  • 10. Contraindications • Known serious hypersensitivity reaction • Known or suspected GI obstruction • Coadministration with strong CYP3A4 inhibitors
  • 11. Indication and dosing • For opioid induced constipation • Oral tablets-25mg OD morning dose
  • 12. Adverse events • Abdominal pain • Diarrhea • Nausea • Flatulence • Vomitting headahe • Hyperhidrosis
  • 13. Current treatment options • methylnaltrexone -need for subcutaneous administration and a narrow indication(limitation) • alvimopan -approved only for shortening the course of postoperative ileus.
  • 14. Study title • Naloxegol for Opioid-Induced Constipation in Patients with Noncancer Pain • N Engl J Med 2014; 370:2387-2396June 19, 2014
  • 15. Study design • Randomised • Double blinded • Placebo controlled • Phase 3 trial • Study period march 2011to september 2012 • 115 centres
  • 16. Study method • after intial screening • randomised(1:1:1) • Placebo naloxegol(12.5) naloxegol(25) • N=214 N=213 N=214
  • 17. Inclusion criteria • <3 spontaneous bowel movements per week with one or more of the following symptoms: • hard or lumpy stools, • Straining • sensation of incomplete evacuation
  • 18. Exclusion criteria 1)Cancer within 5 years before enrollment 2)conditions or use of medications associated with diarrhea or constipation (other than opioid-induced constipation) 3) evidence of gastrointestinal obstruction, and conditions that confer an increased risk of bowel perforation.
  • 19. Primary end point • response rate during the 12-week treatment period. • response->3 spontaneous bowel movements per week • an increase of one or more spontaneous bowel movements over baseline for at least 9 of 12 treatment weeks • > 3 of the final 4 treatment weeks.
  • 20. Secondary end point • the time to the first postdose spontaneous bowel movement • the mean number of days per week with one or more spontaneous bowel movements.
  • 21. Results-primary end point Placebo N=214 Naloxegol12.5 N=213 Naloxegol25 N=214 No of pts (%) responding 63(29.7) 87(40.8) 95(44.4) P value 0.015 0.001
  • 22. Secondary end points placebo Naloxegol12.5 naloxegol25 No of pts(%) with post dose SBM 209(97) 211(99) 213(99) Median time(H) to first SBM 35.8 20.4 5.9 P value <.001 <.001
  • 23. Adverse events placebo Naloxegol(12.5) Naloxegol 25 Pts with any AE (%) 51 52 63 Abdominal pain 6 10 16 diarrhea 4 6 9 nausea 5 7 8 flatulence 3 3 6 vomitting 3 2 5 headache 3 2 5
  • 24. • THANK YOU

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