New FDA approval granted for Naltrexone

[Guest guest]

I just got off the phone with Jaquiline, Dr. Bihari's companion. She

told me that Progenics had just gotten FDA approval for a new usage of

Naltrexone. Relieving bowl constipation caused by opiate use. Because

it involves a new delivery system, injection, they actually got a

patent.

I went to their site and found the following:

colectomy may accelerate bowel recovery and hospital discharge without

affecting opioid

analgesia

E Viscusi, J Rathmell, A Fichera, S Binderow, TJ Gan, N Stambler, F

Galasso,

D Penenberg, R Israel

Jefferson Medical College, Philadelphia, PA; Fletcher Health Care,

Burlington, VT;

University of Chicago, Chicago, IL; Absolute Research Solutions, Powder

Springs, GA; Duke

University, Durham, NC; Progenics Pharmaceuticals, Inc., Tarrytown, NY

Background: Postoperative ileus (POI) occurs in patients who undergo

bowel resection, and can

lead to prolonged hospitalization. Methylnaltrexone, a quaternary

derivative of naltrexone, blocks

peripheral effects of opioids while sparing central analgesic effects.

In this double-blind,

randomized and placebo-controlled study, it was hypothesized that

methylnaltrexone would

shorten the duration of, or prevent POI without affecting opioid

analgesia.

Methodology: Following IRB approval and informed patient consent, 65

patients undergoing

segmental colectomies were randomized to receive within 90 minutes

post-surgery either IV

methylnaltrexone 0.3 mg/kg every 6 hours or placebo, until 24 hours

after GI recovery, discharged

from the hospital, or for a maximum of 7 days. Postoperative analgesic

therapy included fentanyl,

morphine or hydromorphone. Vital signs and adverse events (AEs) were

monitored during the

study.

Results: Methylnaltrexone-treated subjects had a more favorable response

than placebo subjects

in the " time to " measures of efficacy (Table).

Time To (mean ± SD) Methylnaltrexone

(hrs) n=33

Placebo (hrs) n=32 p Value (log-rank *)

Toleration of Full Liquids 68.1 ± 9.0 97.3 ± 18.7 0.119

Toleration of Solid Food 97.4 ± 11.6 123.9 ± 17.1 0.205

First Bowel Movement 98.0 ± 5.7 118.1 ± 10.3 0.038

GI Recovery 114.8 ± 9.4 136.8 ± 15.9 0.263

Discharge Eligibility 116.1 ± 6.9 148.7 ± 17.2 0.049

Actual Discharge 138.3 ± 6.7 164.5 ± 16.1 0.159

*2-sided

Analgesic requirements and pain scores were similar between the two

groups. AEs

occurred more often in the placebo group compared with the

methylnaltrexone group

including nausea (63% vs. 30%), vomiting (25% vs. 12%), and abdominal

pain (13% vs.

0%), respectively. POI, reported as an AE, occurred in 5 (16%) subjects

in the placebo

group and in 2 (6%) of subjects in the methylnaltrexone -treated group.

No serious AEs

related to study drug were reported.

Conclusion: Methylnaltrexone following segmental colectomy appears to

accelerate

bowel recovery and hospital discharge without affecting opioid

analgesia.

Methylnaltrexone was safe and well tolerated

As well as:

American Society of Clinical Oncology

Annual Gastrointestinal Cancers Symposium

January 19 - 21, 2007

Orlando World Center Marriott

Orlando, FL

Session E: Sun., January 21, 7:00 - 8:00 am

301 and 302 studies

Phase III Results from Two Multi-center Randomized Double-Blind Placebo-

Controlled Trials of Methylnaltrexone for Opioid-Induced Constipation

(OIC) in

Patients with Advanced Illness (AI)

Jay 1, MD, Sloan Karver2, MD, Gail Austin Cooney3, MD, Bruce

H.Chamberlain4, MD, Watt5, DO

1San Diego Hospice, San Diego, CA; 2Gulfside Regional Hospice, New Port

Richey, FL;

3Hospice of Palm Beach County, Inc. West Palm Beach, FL; 4Harmony Home

Health,

Murray, UT; 5Research Center of the Ozarks, LLC, Everton, MO

Background: Constipation is a common and distressing side effect of

opioid treatment.

Patients (pts) with AI often experience severe OIC, which is

debilitating and significantly

complicates pain management. Methylnaltrexone, a quaternary derivative

of the opioid

antagonist naltrexone, antagonizes the peripheral effects of opioids

without effecting

analgesia and does not cross the blood brain barrier. These two studies

investigated the

safety and efficacy of subcutaneous (SC) methylnaltrexone to treat OIC

in AI patients.

Methods: Study 301 enrolled 154 pts who were given a single dose of

methylnaltrexone

0.15 or 0.30mg/kg, or placebo. In the 302 study, 133 pts received either

placebo or

methylnaltrexone 0.15mg/kg SC QOD for 2 weeks. Pts had a life expectancy

of <6

months, no laxation for 48 hours, and were on opioids and stable doses

of laxatives for >=3

days. The primary efficacy endpoint was laxation within 4 hours after a

first dose of

study drug. Additional endpoints were laxation within 24 hours, laxation

occurring

within 4 hours of at least 2 of first 4 doses (302 study), adverse

events (AE), pain scores,

and opioid withdrawal symptoms.

Results: Methylnaltrexone-treated patients had significantly improved

laxation (62% in

301 study and 48.4% in 302 study) within the first 4 hours of study drug

administration

(Table). No significant changes in pain scores were noted. There were no

reports of

systemic opioid withdrawal due to study medication. In both studies,

Methylnaltrexone

was well tolerated with transient abdominal cramping and flatulence

being the most

common AEs.

American Society of Clinical Oncology

Annual Gastrointestinal Cancers Symposium

January 19 - 21, 2007

Orlando World Center Marriott

Orlando, FL

Comparison of Time to Laxation: Placebo vs Methylnaltrexone values in

301 and 302 Studies

Time to values Placebo Methylnaltrexo

ne

(0.15 mg/kg)

p-Value Methylnaltrexo

ne

(0.30 mg/kg)

p-Value

Laxation within 4 hrs

of one dose (301

study)

13%

(n = 52)

62%

(n = 47)

<0.0001** 58%

(n =55)

<0.0001**

Laxation within 4 hrs

(302 study)

15.5%

(n = 71)

48.4%

(n = 62)

<0.0001*

Laxation within 24

hours (301 study)

33%

(n = 52)

68%

(n = 47)

=0.0004* 64%

(n =55)

=0.0014*

At least 2 laxations

within 4 hours over the

first 4 doses (302

study)

8.5%

(n = 71)

51.6%

(n = 62)

<0.0001*

Median time to

laxation (301 study)

>24 hrs 70 min <0.0001*** 45 min <0.0001***

* Chi-Square, ** Cochran-Mantel-Haenszel, *** log rank

Conclusion: SC methylnaltrexone effectively induces laxation in AI pts

with OIC upon

single and QOD dosing. The drug acts quickly, and is generally well

tolerated