<b>I received this...not sure of the validity but it is worth looking into if you are using pre-mixed vials of Colistin.</b>
Date: 6/11/2007 8:09 AM
Subject: URGENT: Colistin Alert from the Office of Drs. Preston Campbell and Bruce Marshall
Attachments: Attachment A, Colistin MedWatch 053107.pdf; Attachment B, Antimicrobia Journal Stability of Colistin Apr 2003.pdf; Attachment C, Poster 8 Day
Inhalation Toxicology of Polymyxin E1 in Colistin June 2001.pdf
TO: All Cystic Fibrosis Foundation Care Centers
FROM: Preston W. Campbell, III, M.D.
Executive Vice President for Medical Affairs
and
Bruce C. Marshall, M.D., Vice President for
Clinical Affairs
and
Leslie Hazle, M.S., C.P.N., R.N., Director of
Patient Resources
RE: Colistin Alert
We wanted to let you know that the Food and Drug Administration (FDA) is
investigating a recent patient death as possibly being related to
inhaled colistin that was supplied by a compounding pharmacy in premixed
unit dose vials. The purpose of this memo is to inform the prescribing
community of this unfortunate death (Attachment A) and give you
additional details regarding the hydrolysis of the prodrug
colistimethate to more toxic compounds when stored in solution. Our
recommendation is that patients not use premixed unit dose vials of
Colistimethate until the FDA investigation is complete and the safety of
this product is established.
The patient was a 29-year-old woman with cystic fibrosis (CF) with
chronic airway Pseudomonas aeruginosa infection with moderate lung
disease, clinically stable, who was started on maintenance therapy with
75 mg colistimethate sodium delivered by inhalation twice daily by an
electronic vibrating plate nebulizer. The patient started having
increased respiratory symptoms within hours of the first dose. Three
days after initiating treatment, she required urgent hospital admission
with expectoration of large quantities of thin, pink secretions. She
rapidly developed progressive respiratory failure requiring mechanical
ventilation with bilateral ground glass appearance on chest x-ray. A
clinical diagnosis of acute respiratory distress syndrome (ARDS) was
made. Bronchoscopy on admission and 8 days later identified only usual
CF pathogens. The patient died 18 days later from multi-organ failure.
The FDA was informed by a MedWatch submission.
Colistimethate is a prodrug that must be hydrolyzed to the bioactive
form, colistin. The active form, colistin, unfortunately is toxic to
tissues including the airway. The most commonly prescribed form of the
prodrug, colistimethate, is Coly-Mycin. Typically colistimethate is
mixed with sterile water to form a solution prior to nebulization. When
colistimethate is mixed with water, hydrolysis of the prodrug to its
active form, colistin, begins. (Attachment B) Therefore, premixing and
storing colistimethate results in increasing concentrations of the more
active and toxic product, colistin, and adds a variable that may affect
the therapeutic window of the drug and undermine patient safety. This is
illustrated by the fact that the major active ingredient in colistin,
polymyxin E1, was abandoned as a potential pharmaceutical agent after
inhalation toxicity studies showed massive inflammation in both rodents
and dogs at low doses. (Attachment C). Furthermore, the hydrolysis of
colistimethate is complex and as many as 32 products are formed and any
one of these may have toxic effects on the airway.
It is the recommendation of the CF Foundation that patients not use
premixed vials of colistimethate until the FDA investigation is complete
and the safety profile is established. We understand that this may be
an inconvenience for patients using this formulation, but patient safety
is our primary concern. To be clear, we are not advising against the
use of Coly-Mycin when premixed immediately prior to nebulization.
We also ask that, if additional adverse events of compounded
colistimethate into premixed unit dose vials have occurred, you alert us
and submit a MedWatch form by visiting
<a target=_blank class=ftalternatingbarlinklarge href="http://www.fda.gov/medwatch/how.htm.">http://www.fda.gov/medwatch/how.htm.</a>
Date: 6/11/2007 8:09 AM
Subject: URGENT: Colistin Alert from the Office of Drs. Preston Campbell and Bruce Marshall
Attachments: Attachment A, Colistin MedWatch 053107.pdf; Attachment B, Antimicrobia Journal Stability of Colistin Apr 2003.pdf; Attachment C, Poster 8 Day
Inhalation Toxicology of Polymyxin E1 in Colistin June 2001.pdf
TO: All Cystic Fibrosis Foundation Care Centers
FROM: Preston W. Campbell, III, M.D.
Executive Vice President for Medical Affairs
and
Bruce C. Marshall, M.D., Vice President for
Clinical Affairs
and
Leslie Hazle, M.S., C.P.N., R.N., Director of
Patient Resources
RE: Colistin Alert
We wanted to let you know that the Food and Drug Administration (FDA) is
investigating a recent patient death as possibly being related to
inhaled colistin that was supplied by a compounding pharmacy in premixed
unit dose vials. The purpose of this memo is to inform the prescribing
community of this unfortunate death (Attachment A) and give you
additional details regarding the hydrolysis of the prodrug
colistimethate to more toxic compounds when stored in solution. Our
recommendation is that patients not use premixed unit dose vials of
Colistimethate until the FDA investigation is complete and the safety of
this product is established.
The patient was a 29-year-old woman with cystic fibrosis (CF) with
chronic airway Pseudomonas aeruginosa infection with moderate lung
disease, clinically stable, who was started on maintenance therapy with
75 mg colistimethate sodium delivered by inhalation twice daily by an
electronic vibrating plate nebulizer. The patient started having
increased respiratory symptoms within hours of the first dose. Three
days after initiating treatment, she required urgent hospital admission
with expectoration of large quantities of thin, pink secretions. She
rapidly developed progressive respiratory failure requiring mechanical
ventilation with bilateral ground glass appearance on chest x-ray. A
clinical diagnosis of acute respiratory distress syndrome (ARDS) was
made. Bronchoscopy on admission and 8 days later identified only usual
CF pathogens. The patient died 18 days later from multi-organ failure.
The FDA was informed by a MedWatch submission.
Colistimethate is a prodrug that must be hydrolyzed to the bioactive
form, colistin. The active form, colistin, unfortunately is toxic to
tissues including the airway. The most commonly prescribed form of the
prodrug, colistimethate, is Coly-Mycin. Typically colistimethate is
mixed with sterile water to form a solution prior to nebulization. When
colistimethate is mixed with water, hydrolysis of the prodrug to its
active form, colistin, begins. (Attachment B) Therefore, premixing and
storing colistimethate results in increasing concentrations of the more
active and toxic product, colistin, and adds a variable that may affect
the therapeutic window of the drug and undermine patient safety. This is
illustrated by the fact that the major active ingredient in colistin,
polymyxin E1, was abandoned as a potential pharmaceutical agent after
inhalation toxicity studies showed massive inflammation in both rodents
and dogs at low doses. (Attachment C). Furthermore, the hydrolysis of
colistimethate is complex and as many as 32 products are formed and any
one of these may have toxic effects on the airway.
It is the recommendation of the CF Foundation that patients not use
premixed vials of colistimethate until the FDA investigation is complete
and the safety profile is established. We understand that this may be
an inconvenience for patients using this formulation, but patient safety
is our primary concern. To be clear, we are not advising against the
use of Coly-Mycin when premixed immediately prior to nebulization.
We also ask that, if additional adverse events of compounded
colistimethate into premixed unit dose vials have occurred, you alert us
and submit a MedWatch form by visiting
<a target=_blank class=ftalternatingbarlinklarge href="http://www.fda.gov/medwatch/how.htm.">http://www.fda.gov/medwatch/how.htm.</a>