Dr. Thomas Hale's Response to FDA
Warning:
Dear Colleagues:
The Food and Drug Administration called yesterday to inform me of their
decision to issue a warning on the use of domperidone in breastfeeding
mothers. They stated that they became concerned after the publication of
several case reports of domperidone toxicity following high dose
"intravenous" domperidone in some patients.
Unfortunately, the correlation of intravenous administration with oral
administration of domperidone is simply ludicrous. Domperidone is only
13-17% bioavailable orally. Peak plasma levels in recipients following
20 mg orally is only 15-18 ng/ml. Peak plasma levels following a 10 mg
intravenous dose is reported to be 1200 ng/ml, almost 80-150 fold more
than oral administration. I don't really see how high doses
intravenously even correlate with the use of low to moderate doses
orally in breastfeeding mothers.
They also stated that the data on the use of domperidone in
breastfeeding mothers was limited, improperly designed, and did not give
a good estimate of the transfer into human milk, or to the infant. While
I agree that the data on domperidone is somewhat limited, these
complaints could be used with virtually every other drug we have on the
US market today, including all the anti-asthma products, analgesics,
antidepressants, and dozens of commonly used drugs. Why hasn't the FDA
issued warning on Advair, morphine, Reglan, Demerol, or Prozac. We
certainly haven't stopped using all these drugs because of limited data
in breastfeeding mothers.
Domperidone has been used world-wide for many years with an excellent
safety record. It is approved for use in all the worlds largest and
finest countries, including England, Australia, Canada, etc. This
warning from the FDA has nothing to do with its safety, its all about
the importation of drugs from Canada and control by this federal agency.
They simply want to stop the importation of all drugs, particularly
those used by the elderly, and now the breastfeeding mother.
The reality is that I still believe domperidone is the safest product we
can use for stimulating milk production in some women. It is still true
that in many mothers it offers the only hope for maintaining a milk
supply for their infants and preventing the untoward effects of formula.
When I asked them if they had consulted with anyone in the field of
human lactation about the consequences of this action, they had not.
When I asked them what breastfeeding mothers were to do, they answered
contact their physician for options, or switch to formula.
I do not propose to advise you as to what you should do, but as for me,
I simply choose to ignore them, and their advice.
Thomas W. Hale, R.Ph., Ph.D.
Professor of Pediatrics
Dr. Christine
Smillie's Response to FDA Warning:
Dear
Sir:
With grave and urgent concern I am writing you, in hopes that you will
read this letter carefully and hear this immediate clinical concern.. I
write as a physician in private practice, specializing in breastfeeding
medicine, board certified by the American Academy of Pediatrics and by
the International Board of Lactation Consultant Examiners. I am a Fellow
of the Academy of Breastfeeding Medicine, and a member of the Section on
Breastfeeding of the American Academy of Pediatrics. I serve actively in
both of those latter organizations, but write today as an individual
physician, on behalf of my own patients.
I write to you with this huge sense of urgency because I am extremely
concerned about the FDA directive issued yesterday about the use of
domperidone in breastfeeding mothers, quite apparently issued without
ever consulting any physicians who are expert in the field. Many of us
have had a long and considerable experience with this drug, not only
each of us in our own individual practices, but also a long and
collective experience among all of us in breastfeeding medicine
worldwide. We in this field are in quite frequent communication with
each other, both via online professional lists, national and
international scientific conferences and symposia, and of course peer
reviewed journals. I can say without hesitation that this is an
extremely safe drug.
Domperidone is well studied, has been used internationally for decades,
and is far safer than metoclopramide because it does not cross the
blood-brain barrier1.
In my first years of practice I used to use oral metoclopramide as a
galactogogue for my patients. However I had an unacceptably high rate of
side effects, most particularly depression, and so many treatment
failures that I abandoned its use altogether, resorting for several
years solely to the use of such herbs as fenugreek. While these herbs
can be quite efficacious, domperidone is clinically superior. Moreover,
there are of course concerns about manufacturers' quality control, lack
of oversight, and the lack of research published about the herbal
agents. Since domperidone has been available via our American
compounding pharmacies (I have never used Canadian pharmacies), I have
had excellent clinical results and a complete lack of side effects in my
patients.
The FDA statement yesterday about domperidone lacks a reasonable
scientific rationale:
For someone at the FDA to extrapolate from case reports and studies of
the intravenous use of this medication, to conclude that the oral route
of this medication is also unsafe is quite odd, since it is so
completely lacking any logical scientific rationale. In fact, many of
the drugs of this class can be found to have cardiac electrical effects,
including for example metoclopramide2, particularly if the
medications are administered intravenously. Many other drugs, for
example, the tricyclic antidepressants, several antibiotics such as the
macrolides and azoles, also can prolong the QT interval, and yet remain
approved by the FDA.
Rather than making this drug completely unavailable to physicians, why
not issue appropriate clinical advice to physicians, so that we can make
appropriate risk/benefit assessments and clinical judgments, e.g.,
screening our patients for renal or cardiac conditions or the
concomitant use of tricyclics, macrolides or azoles?
The rationale for this FDA warning mentioned no new clinical findings.
The case reports about IV use are not new, as the FDA suggests, but are
a from two decades ago3,4. As far as I can tell, this warning
comes not out of any new research data, except perhaps in rodents..
Despite the tens of thousands of breastfeeding women who have taken this
medication over the past decade, I can find no reported cases of torsade,
or even lesser adverse events, in women who take domperidone. In
particular, I think it is rather disingenuous of the FDA to include the
following statement in its warnings: "In several countries where the
oral form of domperidone continues to be marketed, labels for the
product contain specific warnings against use of domperidone by
breastfeeding women and note that the drug is excreted in breast milk
that could expose a breastfeeding infant to unknown risks."
In
fact, such product labels are common5 to almost all the drugs
listed in our own PDR, including many drugs already safely given to
children, drugs with such high molecular weight that they could not
possibly cross
the mammocyte, and drugs with such high protein binding, low oral
bioavailability or such short half-lives as to be virtually unavailable
to the infant. Such PDR product warnings almost uniformly lack any
evidence-based rationale, are vague in their language, and lack
appropriate risk/benefit information, particularly with regard to the
risks of not breastfeeding.
These warnings, apparently written by attorneys rather than
pharmacologists, offer no useful information to the informed clinician,
as they address no real medical risks, but rather the company's own
perceived legal risks, and display a remarkable lack of interest in, or
education about, how drugs are handled by the lactating breast.
For
the FDA to refer to this commercial type of product warning about
domperidone as if this were a reasonable basis for the FDA's action
suggests that the FDA's actual rationale for this action is quite
flawed, or that there is no real rationale at all.
The FDA warning letters to the compounding pharmacies suggest that
domperidone "is not recognized as safe and effective by qualified
experts." In fact, domperidone is used quite commonly by both American
and international experts, i.e. published and esteemed authorities in
breastfeeding medicine, is cited repeatedly in our texts and peer
reviewed journals, and is approved, without qualification, for use in
breastfeeding mothers by the American Academy of Pediatrics Committee on
Drugs.6
I and
my colleagues have many patients who require this medication, and if
domperidone is to suddenly become unavailable to them, there will be a
significant and tragic morbidity for both mothers and babies. I am
horrified that so many mothers of premature infants, and other high risk
children will suddenly have this lifeline taken from them.
When Dr. Thomas Hale7 asked an FDA spokesman what a mother's options
would now be, the spokesman reportedly told him she should contact her
physician. Well, I am that physician, and I am asking, what are my
alternatives? Please ask your colleagues to name me a safe, effective,
FDA approved galactogogue, that will not cause depression, and that I
can trust to work.
I also worry that when physicians stop prescribing domperidone from
their local compounding pharmacies, their patients may take this matter
into their own hands, going offshore for medications without benefit of
their own physician monitoring their health status to determine
appropriate dosing and safe choice of medication.
Mr. Rumble, as ombudsman, I ask you, to whom should we write who will
hear these concerns? Thank you for your time and consideration.
Sincerely,
Christina M. Smillie, MD, FAAP, FABM
1. Barone JA. Domperidone: a peripherally acting dopamine2-receptor
antagonist.
Ann Pharmacother. 1999 Apr;33(4):429-40. Review.
2. Ell dokuz, E. & Kaya, D. (2003) The effect of metoclopramide on QT
dynamicity: double-blind, placebo-controlled, cross-over study in
healthy male volunteers. Alimentary Pharmacology & Therapeutics 18 (1),
151-155.
3. Osborne RJ, Slevin ML, Hunter RW, Hamer J (1985) Cardiac arrhythmias
during cytotoxic chemotherapy: role of domperidone. Hum Toxicol 4:
617-626
4. Joss RA, Goldhirsch A, Brunner KW, Galeazzi RL (1982) Sudden death in
cancer patient on high-dose domperidone. Lancet 1: 1019
5. For example, synthetic oxytocin is a drug identical to the
endogenously ubiquitous human oxytocin, currently marketed as Pitocin
for augmenting labor. Not long ago, it was also available in a nasal
preparation, Syntocin, specifically made and marketed only for aiding
maternal milk ejection.
The PDR included a warning about the use of Syntocin in breastfeeding
mothers, even though those women were the only population for whom the
drug was indicated.
6. AMERICAN ACADEMY OF PEDIATRICS: The Transfer of Drugs and Other
Chemicals Into Human Milk PEDIATRICS Vol. 108 No. 3 September 2001, pp
776-789
http://pediatrics.aappublications.org/cgi/content/full/108/3/776
7.
http://neonatal.ama.ttuhsc.edu/lact/html/fda_warning_on_domperidone.html
