The Scottish Medicines Consortium issued on 8th December, 2008 an advice on the recently approved opioid antagonist methylnaltrexone

ADVICE: following a full submissionMethylnaltrexone  (Relistor)  is  accepted  for  restricted  use  within  NHS  Scotland  for treatment  of  opioid-induced  constipation  in  advanced  illness  patients  who  are  receiving palliative care when response to usual laxative therapy has not been sufficient. It is restricted to use by physicians with expertise in palliative care.

Methylnaltrexone has been shown to be superior to placebo in achieving bowel movement in terminally  ill  patients  with  opioid-induced  constipation  already  receiving  a  stable  laxative regimen.

This is an excerpt of the detailed advice on methylnaltrexone:

Treatment  of  opioid-induced  constipation  in  advanced  illness  patients  who  are  receiving palliative care when response to usual laxative therapy has not been sufficient.

Dosing information
The recommended dose is 8 mg (0.4 ml) by subcutaneous injection (for patients weighing 38-61  kg)  or  12 mg  (0.6  ml)  (for  patients  weighing  62-114  kg).  Patients  whose  weight  falls outside of these ranges should be dosed at 0.15 mg/kg.

The  usual  schedule  is  one  single  dose every  other  day.   Doses may  be  given with  longer intervals, as per clinical need.   Patients may receive  two consecutive doses 24 hours apart, only when there has been no response (bowel movement) to the dose on the preceding day.

Product availability date
08 July 2008

Summary of evidence on comparative efficacy

Methylnaltrexone  bromide  is  a  quaternary  derivative  of  the  non-selective  opioid  antagonist naltrexone.  It  has  lower  lipid  solubility  resulting  in  restricted  access  across  the blood-brain barrier  and  therefore  it  is  effective  in  reversing  the  peripherally  mediated  side  effects  of opioids, without  interfering with  the desired  central analgesic effects.  It selectively binds at the  peripheral  mu-opioid  receptor  with  limited  potency  at  the  kappa  receptor  and  much reduced activity at the delta opioid receptor.

There were  two pivotal phase  lll studies, both  in patients with advanced medical  illness and limited  life  expectancy,  receiving  a  stable  dose  of  opioid  for  at  least  three  days  prior  to randomisation,  on  a  stable  laxative  regimen  for  at  least  three  days prior  to  treatment,  and suffering  from  opioid-induced  constipation  (defined  as  no  clinically  significant  bowel movement within 48 hours).  Efficacy assessments were similar in both studies and included frequency, consistency, difficulty, and time to defaecation.

In  a  double-blind,  single-dose  study  to  evaluate  the  efficacy  of  methylnaltrexone,  154 patients with a  life expectancy of between one and six months were randomised  to a single administration  of  either  subcutaneous  methylnaltrexone  0.15mg/kg  (n=47)  or  0.30mg/kg (n=55)  or  placebo  (n=52),  followed  by  a  4-month  open-label  extension  period.    Treatment with additional  laxatives was permitted during  the study as clinically  indicated, although not permitted within four hours before or after administration of the double-blind dose.

The  primary  outcome  was  the  proportion  of  patients  with  defaecation  (without  a  rescue  intervention) within four hours of the first dose.  In the methylnaltrexone 0.15mg/kg group, 29 patients  (62%  (95% confidence  interval  (CI): 48  to 76)) had a bowel movement within  four hours compared with 32 (58% (95% CI: 45 to 71)) methylnaltrexone 0.30mg/kg patients and seven (13% (95% CI: 4 to 23)) placebo patients.

Secondary  outcomes  included  the  median  time  to  defaecation  and  defaecation  (without rescue  intervention) within  24  hours.  The median  time  to  bowel movement  for  patients  in both  methylnaltrexone  groups  was  significantly  shorter  than  placebo  (1.1  hours  and  0.8 hours  for  the  0.15mg/kg  and  0.3mg/kg  doses  respectively,  compared  with  >24  hours  for placebo).    Significantly  more  patients  had  bowel  movement  within  24  hours  of  receiving methylnaltrexone  compared  with  placebo  patients  (68%  and  64%  for  0.15  and  0.3mg/kg doses respectively versus 27% for placebo).
In  the  other,  multicentre,  double-blind,  placebo-controlled  study,  134  patients  with  a  life expectancy of at least one month were recruited from nursing homes, palliative care sites or hospices.    Patients  were  randomised  to  two  weeks  of  double-blind  treatment  with  either methylnaltrexone  0.15mg/kg  (n=62)  on  alternate  days  (titrating  to  0.3mg/kg  if  required)  or placebo (n=71), followed by a 3-month open-label phase.  Missing values were imputed from the last observation carried forward.

There  were  two  co-primary  endpoints  during  the  double-blind  phase:  the  proportion  of patients who  had  defaecation  (without  a  rescue  intervention) within  four  hours  of  the  first dose and the proportion of patients who had defaecation within four hours after two or more of  the  first  four  doses  (the  first week  of  double-blind  treatment).    In  the methylnaltrexone group, 30 patients (48% (95%CI: 36 to 61)) had bowel movement within four hours compared with  11  placebo  patients  (16%  (95%CI:  7  to  24)).    For  the  second  primary  endpoint,  32 methylnaltrexone patients (52% (95% CI: 39 to 64)) compared with six placebo patients (8% (95%CI:  2  to  15))  had  bowel  movement  after  two  or  more  doses  in  the  first  week  of treatment.

Secondary and  tertiary outcomes  included  the proportion of patients with defaecation within four hours after four or more of the seven doses,  the proportion of patients with defaecation within four to 24 hours after each dose, the time to bowel movement, overall pain scores and symptoms  of  opioid  withdrawal.    These  endpoints  in  general  supported  the  results  of  the primary  outcomes. There were  no  differences  between  the  groups  in pain  scores over  the study  period,  indicating  that  methylnaltrexone  did  not  cause  clinically  relevant  opioid withdrawal symptoms.

There were no defined primary outcomes for the open-label extension and it mainly provided information on the long-term safety of methylnaltrexone.  However it did show that the time to defaecation remained fairly constant over time.  In an additional analysis, when the outcomes of  the  first  dose  of  the  two  studies  was  combined,  age  and  gender  were  found  not  to influence the outcome.

Summary of evidence on comparative safety

The overall  rate of adverse events was  similar  in  the methylnaltrexone  (81%) and placebo groups  (80%).    In  the  methylnaltrexone  group,  the  most  commonly  reported  treatment-emergent  adverse  events  were  abdominal  pain  (17%),  flatulence  (13%),  vomiting  (13%), nausea  (11%),  and  malignant  neoplasm  progression  (11%).    Most  treatment-emergent adverse  events were  rated  as mild  or moderate  by  the  investigators.    In  a majority  of  the patients  in both  treatment groups,  the  treatment-emergent adverse events were not  related or were unlikely to be related to study drug.

Serious adverse events occurred  in 18% of methylnaltrexone patients and 28% of placebo patients,  none  were  deemed  by  the  investigators  to  be  related  to  study  drug.
Discontinuations  due  to  adverse  events  occurred  in  6%  and  7%  of  patients  in  the methylnaltrexone and placebo groups, respectively.
Summary of clinical effectiveness issues

Methylnaltrexone  has  been  shown  to  be  superior  to  placebo  in  achieving  defaecation (without  the  need  foe  rescue  intervention)  in  terminally  ill  patients  with  opioid-induced constipation, who were already being treated with a stable laxative regimen.  A re-analysis of responders  requested  by  the  Committee  for  Medicinal  Products  for  Human  Use  (CHMP) found that the more severe the constipation, the higher the response with methylnaltrexone.
The side effect profile was as expected. However the studies had small patient numbers and the double-blind assessment period was of short duration.

Just over half of patients achieved bowel movement within four hours of the initial dose and this may  be  due  to  a  number  of  confounding  factors  including  use  of  other  concomitant medications,  the  disease  process,  diet,  immobility  and  lack  of  fluid  intake.    In  addition, opioids cause decreased gastric emptying and prolonged oral-caecal  transit  time  through a centrally mediated action.   These effects would not be  inhibited by  the peripheral action of methylnaltrexone.

The  European Public  Assessment Report  (EPAR)  noted  that  a  reduction  in  overall  ‘usual laxative medication’ was  not  convincingly  shown. There was  a  significant  difference  in  the proportion of patients who achieved a ‘satisfactory’ weekly bowel movement frequency in the first week but  there was no significant difference  in  this outcome  in  the second week which might suggest  that methylnaltrexone has a similar efficacy  to standard and  rescue  laxative treatment combined.

The primary outcome in the clinical studies investigated methylnaltrexone used as an add-on treatment  to  already  stable  laxative  therapy,  so  more  of  a  rescue  treatment  rather  than continuous treatment of constipation aimed at normalisation of bowel movement.  Therefore, the  single-dose  study  followed  by  as  needed  administration may  better  reflect  the  use  of methylnaltrexone  in  clinical  practice.   For  the  patients  in whom  the  drug  shows  efficacy  it offers an alternative to the discomfort of an enema or the indignity of a manual evacuation.

Subcutaneous administration rather than an oral formulation and a requirement to rotate the injection  site may  be  potential  disadvantages,  especially  in  patients  who may  already  be receiving a number of  injections.   At present no  compatibility  studies have been done and therefore methynaltrexone should not be mixed with other drugs.  Most of the patients in the studies  were WHO  performance  status  3  or  4,  therefore  should  represent  the  patients  in whom  this will  be  used  in  practice.   However  in  the  two-week  double-blind  study,  all  the recruited  patients  were  in  care  and  therefore  may  not  represent  the  situation  for  those patients wishing to self-administer.

The European Medicines Agency (EMEA) has emphasised that methylnaltrexone should not be used in indications outwith its marketing authorisation.

Source: Scottish Medicines Consortium. Drug Advice: methylnaltrexone bromide (Relistor)

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