Domperidone Safety Update & the Politics of Prescribing it?

What's the news?

• A European medicines regulatory body (CMDh) has endorsed recommendations from the European Medicines Agency (EMA) to restrict the use of medications containing domperidone. They've agreed it should only be prescribed to relieve symptoms of nausea and vomiting.

• They noted a higher risk was observed in patients older than 60 years, adults taking daily oral doses of more than 30 mg.

• They recommended the dose should be reduced to 10 mg up to three times daily by mouth for adults and adolescents weighing 35 kg or more.

• Domperidone should be taken for a recommended maximum time of 7 days.

• They state evidence confirmed a small increased risk of serious cardiac adverse drug reactions related to the use of domperidone.

• One study that showed up to 80mg per day in healthy individuals did not increase risks - however there are limitations in the study that restrict the conclusions that can be drawn. 

• Of 57 reported cardiovascular fatalities, 27 had other risk factors, while 13 had either an implausible relationship to domperidone administration or an alternative aetiology.

• A significant number of cases have been reported with concomitant or co-suspect medication also linked to cardiac changes.

• As the CMDh position was adopted by majority vote, it will now be sent to the European Commission, who will make an EU-wide legally binding decision.

• Dr Jack Newman & other experts dispute the evidence base for recommendations, given the impact to breastfeeding mothers.  He claims the EMA ignored evidence provided by doctors.

The summary:

Despite official findings, high profile doctors like Jack Newman and Dr Dan Flanders do not feel the studies accurately represent the risk to healthy breastfeeding mothers. Nor that the benefits have been adequately assessed. Dr Newman plans to prescribe as usual. Quotes from both follow below..

The Long Version:

The most obvious flaw would appear to be that guidance for medicines is based on weighing up the risks and benefits. We know the risks of not breastfeeding are significant.

Are lactating mothers comparable to the groups studied?  Do we know what the underlying reasons were that the people within the studies took domperidone in the first place?  Breastfeeding mothers are not typically over 60, and a great many don't have an underlying heart condition. Prescribers could check if any of the medications contraindicated are used - which reduces the risks to what?

We don't know as this isn't covered by this review - because increased lactation is a side effect rather than the primary function of the drug. Instead regarding off license use they simply state:

"Although the scope of the review does not cover use outside the licensed indications (off-label use) the principles behind these recommendations should be considered whenever domperidone is used."

A cynic might wonder if actually the benefits to breastfeeding mums have been considered, and 
perhaps the fact it works and prevents the use of profitable substitutes isn't a popular outcome? 

Or perhaps the EMA didn't want to promote the use of domperidone as safe for lactation when as you will see in a moment, it clearly is against guidance issues by the FDA?

The first person I contacted was Dr Jack Newman. For those that don't know (which I'm sure on this blog aren't many) Dr Newman is internationally recognised as a lactation legend - read all about him here.  Furthermore he has for many years prescribed for his patients, and publicly promoted the use of domperidone for lactation, at doses as high as 80-120mg per day.  Who better to ask about the use of domperidone in breastfeeding mums?  After thousands of cases, has he witnessed any cardiac issues?

Dr Newman, along with Dr Thomas Hale (a clinical pharmacologist, professor at Texas Tech University School of Medicine, and author of Medications and Mothers' Milk - read more about him here) sent extensive information to the EMA when hearing about the review.

Dr Newman said:

"The EMA has done a lot of damage because they did not take into account the very complete information from Dr Thomas Hale and I about the safety of domperidone. This can only be explained because they have an agenda.  It certainly won't change what I do."

The history

It's not the first time health authorities have put the spotlight on domperidone, nor the first time Dr Newman and other leading health professionals have disagreed with them.

2004: the FDA warned breastfeeding mothers about taking domperidone to enhance milk supply because it could conceivably cause an irregular heartbeat.  They went as far as to say:

"FDA is concerned that women may be risking their health if they use domperidone to try to increase milk production."

and

"The bottom line is to advise patients who are breastfeeding not to use domperidone to try to increase their milk supply."

Gosh there must be compelling evidence right?

Except as Dr Jack Newman highlighted when he responded to that warning here - it would seem not.  The politics however sound interesting.

Others shared his opinion.  A study examining the effectiveness of domperidone for mothers expressing for premature babies (which was found to be very successful), also referred to this warning.  Commenting they felt the FDA concern was "grossly overstated", in healthy mothers not on incompatible medication.  They also suggested an ECG could be done prior to starting domperidone in lactating mother (1).

2011: the risk of sudden death was flagged up by the French Medicines Agency.  They released the following :

"Off-label use of domperidone in stimulating lactation: Caution - Information Point

Galactorrhea (milk production by the mammary glands) is one of the side effects of domperidone. This undesirable effect is due to its antagonistic action of the neurotransmitter dopamine, which inhibits, at the pituitary level, the secretion of prolactin hormone triggering lactation. Domperidone has no authorization in stimulating lactation. This indication is not recognized by any health authority, either in Europe or the United States.'s Summary of Product Characteristics in force specifying that domperidone should not be used during breastfeeding."

and

"These risks are taken into account in lactating women and potentially in the breast-fed infant. No cases of cardiac adverse events have nevertheless been reported to date in pharmacovigilance in infants breastfed by women treated with domperidone.  The benefit / risk ratio of domperidone in stimulating lactation has not been evaluated." (here)"

Rather unusual that a statement released purely to address stimulating lactation would refer to it as an "undesirable effect", however what it does highlight is that agencies like the FDA and ANSM are so aware mothers are using domperidone they have both released specific statements.  They also acknowledge that the drug has not been evaluated for breastfeeding mothers.

What's even more confusing is despite all this - the CMDh when reviewing policies for the whole of Europe didn't acknowledge mums using it for lactation at all?  Nor did the EMA.  They weighed up the risks/benefits purely based on symptoms like "nausea".

March 2012: Health Canada endorsed an advisory statement indicating that health practitioners should exercise caution when prescribing domperidone at doses greater than 30 mg/day 10.   They referenced two studies as evidence for the guidance, one Dutch and one Canadian.

The Fight Back - Leading Lactation Experts Respond....

May 2012: in response to the Health Canada endorsement,  the International Lactation Consultants Association (ILCA) released  "A Consensus Statement on the Use of Domperidone To Support Lactation".

The authors were high profile international experts including; Dr Daniel Flanders (MD FRCPC Lecturer, Paediatrics), Dr Aviva Lowe (MD FRCPC), Dr Michael Kramer (MD. Professor, Departments of Pediatrics, and of Epidemiology, Biostatistics and Occupational Health), Dr Orlando da Silva (MD MSc FRCPC. Associate Professor, Department of Paediatrics),  Dr Jack Newman (MD FRCPC. Assistant Professor, Department of Pediatrics) and several nurse/lactation consultants.

The paper was also endorsed by a further 14 similar professionals. 

They state:

"The justification for this advisory, especially in young breastfeeding women, is not supported by the scientific literature."

and

"Of the thousands of mothers the authors of this statement have collectively treated with domperidone for the purposes of breastfeeding support, no one is aware of a single case of maternal death from ventricular arrhythmia. In fact, Health Canada’s Canada Vigilance Program has confirmed that between  1965 and 2011, there were no cardiac-related deaths reported among women taking Domperidone 35"

They also highlighted the very important point that in the studies referenced, one had an average patient age of 72.5 years, and the other 79.4!  Additionally many of the patients in the studies had pre-existing health problems.

Furthermore the risk quoted in younger patients was almost the same as that outcome occurring by chance alone, and that the risk in females was significantly lower than in males.

Hmmmmmmm

They concluded:

"There is strong consensus among the experts in this group that the advisory does not present valid arguments to justify changing the long established domperidone prescribing practices among lactation physicians across Canada."

Read the full statement here

May 2012: the MHRA, an executive agency of the UK Department of Health, published a drug safety update basically echoing that released by Canada Health.  They referenced the same two studies quoted, plus a further two older studies.  Both which have an average patient age of 60 plus.

September 2012: "Canadian Family Physician" (the official journal of the college of family physicians in Canada) published an article entitled "Health Canada advisory on domperidone, Should I avoid prescribing domperidone to women to increase milk production?"

They concluded:

"Owing to the demographic characteristics of the populations in both studies,11,12 the risks reported in these papers would not directly apply to healthy women of childbearing age. Nonetheless, caution is advised when prescribing domperidone with other drugs that prolong the QT interval or with those that interfere with domperidone metabolism, or for women who have underlying cardiac diseases.1"

March 2013: The review of domperidone was initiated at the request of the Belgian medicines
authority.

Minutes from  EMA meeting states:

"Before any review is started, BE should gather further data on the legal status of domperidone-containing medications as well as the indications, posology or off label use in the EU"

February 2014: "Prescrire (Prescribe), an independent journal called for the European Medicines Agency (EMA) to "Stop the use of domperidone once and for all".

They said:

"The European Medicines Agency (EMA) is due to issue an opinion on domperidone in March 2014, but there is a chance it will simply recommend lower dosages or shorter treatment durations. These measures are insufficient to fully protect patients"

Yikes wow they really want it totally off the market.

They go on to say:

"According to this data, domperidone was dispensed at least once to about 7% of French adults in 2012, i.e. about 3 million adults. Based on these data and the incidence of sudden death in France, using conservative assumptions, it is likely that about 25 to 120 sudden deaths were attributable to domperidone in France in 2012."

I dug out said analysis.  Interestingly they found that over 20% of said "approximate deaths" could potentially be prevented by ensuring other drugs given were not contraindicated.  They also noted the majority deaths occurred within the first week of use and concluded that domperidone's effectiveness is "too modest to justify the exposure to premature deaths."

But again this isn't examining the effectiveness for sustaining lactation is it?  Despite the Medicines Association in the same country releasing a specific warning to breastfeeding mothers just a few years prior?

March 2014: PRAC (EMA) completes the review and recommends restricting use of domperidone.

April 2014: The CMDh reviewed the PRAC findings and endorsed them:

"These recommendations are based on careful consideration of data on the safety and efficacy of domperidone from various sources. This comprised non-clinical and clinical data, both published and unpublished, including a thorough QT study, cumulative review of case reports of cardiac disorders and vascular investigations from the safety databases for domperidone products, pharmacoepidemiological studies, and published and unpublished efficacy studies."

So domperidone is definitely not suitable for those with an underlying heart issue, or those who are taking certain medications. There is a list of drugs that prolong QT interval here (courtesy of Wendy Jones, BSc, MSc, PhD, MRPharmS.) and so it is important to check whether something you're taking is compatible.

Dr Jack Newman has shared the email he has sent the EMA/CMDh in response to the new guidance:

"I am afraid the EMA has done a great disservice to the mothers and babies of the EU.  Your group obviously ignored the information sent to you by Dr Thomas Hale and yet you used the old FDA warning of 2004 to frighten everyone out of using a very useful drug, the benefits of which far exceed any risk.  The statement you sent out gives the impression that these 60 deaths were new and that  is how the press is reporting it as if this were new data.  You might remember that the patients that died and on whose history the FDA warning was based, were getting huge doses of domperidone intravenously.  On top of that these patients were very sick and were getting other drugs of great potency and toxicity.
 It concerns me that there are, every year, deaths in the EU, associated with the use of the birth control pill and yet the EMA has not developed restrictions on these hormones.  And yet you restrict the use of domperidone.  To be honest, the statement by the EMA on domperidone is shameful and likely to harm many mothers and their babies.  I left the attachments I sent you earlier on the risks of artificial feeding."

And to conclude Dr Dan Flanders, a Toronto paediatrician - kindly agreed to share his thoughts too:

"1. The studies quoted have one or more of the following issues:
a. Domperidone given was massive dose given IV
b. Patients in the studies were much older than child-bearing women
c. Patients in the studies were much sicker than typical child-bearing women d. Many patients in the studies were already on medications known to cause significant QT prolongation. It makes no sense to extrapolate data from these studies and apply recommendations to young, likely healthy lactating women. 

2. In a breastfeeding mother-baby dyad paradigm, firm recommendations against the use of a medication like domperidone undermines a women’s right to choose how she wishes to feed her baby. When I offer domperidone to breastfeeding moms, I am always careful to convey very explicitly the cardiac risks associated with using domperidone. I also discuss the potential benefits of using domperidone to support breastfeeding. Having been informed, it is then up to mother (and family) to decide whether or not the risk(s) outweigh(s) the potential benefits. Doctors and health care organization must not paternalistically impose these decisions on the mother-baby dyad. It is as much a personal decision as it is a medical one. In my opinion, promoting informed choice - not publishing blanket warnings of harm - is the more appropriate way to go."

As a lactation consultant I have to wonder how easily mothers will be able to obtain domperidone in the future - and how many breastfeeding relationships will suffer as a result.  At the moment pharmacies appear to be restricting over the counter sales to sickness only, after the European Comission rule it could become prescription only - relying on the discretion of a doctor and whether he is willing to prescribe off-label...

References:

1. Elise W-X. Wan, Kaye Davey, Madhu Page-Sharp1, Peter E. Hartmann, Karen Simmer and Kenneth F. Ilett1: Dose-effect study of domperidone as a galactagogue in preterm mothers with insufficient milk supply, and its transfer into milk, British journal of clinical pharmacology, DOI: 10.1111/j.1365-2125.2008.03207.x