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Letter to FDA re Domperidone

Warren Rumble
CDER Ombudsman (HFD-1)
Suite 500
5515 Security Lane
Rockville, MD 20852
Direct telephone line: 301-594-5480
Fax: (301) 827-4312
Re: The FDA's warning about domperidone

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 barrier. (1)

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 metoclopramide, (2) 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 ago. (3), (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 common (5) 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 Hale (7) 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 healthstatus 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.


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

(7) http://neonatal.ama.ttuhsc.edu/lact/html/fda_warning_on_domperidone.html


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