Domperidone: The Forbidden Fruit

The Food and Drug Administration's Role

Domperidone was submitted to the U.S. Food and Drug Administration (FDA) for approval for use as a gastrointestinal stimulant in 1989, but was not approved. Most recently, the FDA held a meeting of its Pharmacy Compounding Advisory Committee of non-FDA physicians and pharmacists in October 2015. The meeting was held to discuss allowing domperidone to be placed on the list of drugs that can be legally compounded by pharmacies. The vote was 8 to 3 against addition to the list, with all 11 voting members voicing concern about cardiac toxicity. ¹

In 2004, the FDA issued an “FDA Talk Paper” that (1) warned against use of domperidone because of the risk of arrhythmias that had been reported after intravenous use in other countries and (2) warned compounding pharmacies and suppliers of the bulk product used in compounding that they were in violation of federal law and to cease provision of domperidone. Other warnings have been issued to compounding pharmacies and suppliers since 2004.

Compounding pharmacies can range from pharmacies that make specialty products unavailable commercially on a “one-prescription-at-a-time” basis to much larger commercial operations producing large quantities of drugs for what is referred to as the “gray market.” They are typically not federally regulated or inspected, but fall under the regulatory purview of state boards of pharmacy. Most state pharmacy boards do not have the manpower or expertise to provide the same oversight that the FDA provides for conventional drug manufacturers. Some compounding businesses were selling domperidone in 20, 30, and 40 mg strengths, which are greater than the 10 mg dosage forms that are legitimately marketed abroad. Some were also providing injectable domperidone, which had been removed from foreign markets in 1985 because of its toxicity.

The FDA's actions have not put an end to use of domperidone in the United States. A study by the FDA from 2009 to 2015 indicated that between 7,500 and 11,600 prescriptions are dispensed annually in the United States for domperidone, mostly to women. Sixty percent of the prescriptions were written by gastroenterologists, primarily for gastroparesis. Only 6% of prescriptions were written by obstetrician-gynecologists, presumably as a galactagogue. ¹ So, most recent discussion at the level of the FDA has concerned domperidone's use in gastroenterology, not its use as a galactagogue.

Safety

Safety of domperidone encompasses safety for the infant and safety for the mother. With maternal dosages of 10–20 mg three times a day, the concentration in breast milk is <1 mcg/L, which translates into <0.1 mcg/kg daily, or about 0.01% of the mother's weight-adjusted dosage or relative infant dose (RID). Drugs with an RID of <10% are usually considered acceptable during breastfeeding, so the risk of infant toxicity appears negligible.

The primary safety concern is for the mother, because the drug can cause cardiac arrhythmias secondary to a prolonged QTc interval. Other drugs, such as cisapride and terfenadine, have been removed from the U.S. market for the same reason. Population studies in Europe found a higher death rate in older individuals who had received prescriptions of domperidone. Domperidone advocates have argued that young women were not represented in the population; therefore, these studies were irrelevant to nursing mothers. However, more extensive data collected by the European Medicines Agency (EMA) did not confirm an age relationship, but did find that women were more susceptible to sudden cardiac death from domperidone than men. ² Other factors identified by EMA as increasing the risk of arrhythmias are concurrent use of drugs that increase QTc prolongation and drugs that inhibit domperidone's metabolism and increase its serum levels. ¹

A large database study in British Columbia compared new mothers who did and did not receive a prescription for domperidone postpartum. ³ The study found an increased percentage of mothers were hospitalized for cardiac arrhythmias if they had received a prescription for domperidone. A prior history of cardiac arrhythmias and obesity appeared to be predisposing factors for arrhythmias. The absolute frequency of hospitalizations for arrhythmia was low in both groups: 15 of 45,518 domperidone-exposed mothers. This translated to an adjusted hazard ratio of 2.25, but the 95% confidence interval (range 0.84–6.01) included 1.0, so the association cannot be considered definite. However, these results are consistent with those of a meta-analysis that found a 70% increase in the risk of cardiac arrhythmias and sudden death with domperidone. ⁴

If the 2.25 hazard ratio were valid, it would translate into one additional hospitalization for a ventricular arrhythmia for every 12,950 women exposed to domperidone during the first 6 months postpartum. ³ The reaction is sufficiently uncommon that most individual practitioners who prescribe domperidone will never see a case in their career, giving the impression that it does not occur.

Domperidone is metabolized by CYP3A4, which is inhibited by a number of substances, such as grapefruit juice, fluconazole, erythromycin, clarithromycin, and others. These agents increase maternal serum domperidone concentrations from three- to fivefold. Drugs that cause QTc prolongation, such as histamine H₂-blockers, can also add to the risk. ⁵ Even without excessive dosages or interacting substances, abdominal cramping, nausea, diarrhea, dry mouth, headache, and dizziness have been reported in domperidone galactagogue studies. Another problem occurs with rapid discontinuation after high-dose and long-term use, which can result in insomnia, anxiety, and tachycardia. Symptoms can persist for weeks until domperidone is restarted and tapered more slowly. ⁶

Internationally, no country has approved the use of domperidone as a galactagogue, but concern about its safety has grown. Several European countries changed the drug from over-the-counter to prescription status and lowered the maximum recommended dosage. An analysis by French pharmacovigilance professionals concluded, “The use of domperidone as a galactagogue is worrisome as drug-induced long QT syndrome occurred mostly in women.” ⁷ A recent review from The Netherlands recommended that an electrocardiogram be obtained to exclude QTc prolongation with domperidone dosages higher than 30 mg daily or administration for longer than 2 weeks. ⁸ A survey of neonatal units in Australia found that many units had modified their guidelines for domperidone use over the past 2 to 3 years with 80% of respondents lowering their maximum dosage to 30 mg per day, and one limiting treatment duration to 7 days. ⁹ Canadian investigators felt that the several warnings from Health Canada about the cardiac risks of domperidone hampered their efforts to recruit patients. ¹⁰

Efficacy

Although numerous published articles on the use of domperidone as a galactagogue are reported in LactMed, only a few of them are scientifically rigorous. A meta-analysis by the Cochrane collaboration on medications to enhance milk production in mothers of preterm infants found only two studies worthy of inclusion, both using domperidone. ¹¹ Another meta-analysis that also included studies on term infants found three valid domperidone studies, two of which were included in the Cochrane analysis. ¹² A third systematic review discounted one of the studies in the previous review, but added one newer trial that was not included in the other reviews. ⁷ Although all of the systematic reviews found domperidone to be effective, the magnitude of milk enhancement was small. The four studies have a combined total of 60 subjects who received domperidone. For reference, a new drug in the United States is typically studied in 500 to 3,000 subjects before FDA approval.

Recently, the long-awaited results of the Canadian multicenter EMPOWER study were published. ¹⁰ It was a well-designed study to evaluate the use of domperidone as a galactagogue in the mothers of preterm infants (≤29 weeks of gestation). The endpoint was a 50% increase in milk supply at the end of the course of domperidone. Mothers received either 4 weeks of domperidone or 2 weeks of placebo followed by 2 weeks of domperidone. The original intention was to enroll 560 mothers, but the study was closed after enrolling only 90 mothers. Although a greater percentage of mothers experienced a 50% or more increase in milk volume with 4 weeks of domperidone, the difference between the two groups was not statistically significant and the absolute increase in milk volume was modest. Another interesting finding was that even after 2 weeks of placebo, mothers who received domperidone essentially matched the breast milk output of those who received 4 weeks of therapy by the end of the 4 weeks. This indicates that 2 weeks of therapy is probably sufficient.

Findings of EMPOWER are consistent with other galactagogue studies. A study of metoclopramide use in the mothers of preterm infants found no difference between the metoclopramide and placebo in the amount of milk produced or the duration of breastfeeding. ¹³ In this study, all mothers of preterm infants were allowed entry into the study. In the EMPOWER study, only mothers with milk production of <150 mL/kg of infant weight daily were enrolled initially. However, because of slow enrollment, that value was increased to 250 mL/kg per day, which would include almost all mothers of preterm infants. It seems that including mothers who are able to produce sufficient milk without a galactagogue tends to dilute differences between the drug and placebo. Importantly, galactagogue studies employing good hospital practices, maternal breastfeeding instruction, and follow-up, as in EMPOWER, usually show the least difference in outcome between the galactagogue and placebo. ¹⁴ Studies that show dramatic rises in milk output have generally used only a galactagogue instead of good practices.

Although “inadequate milk supply” is frequently given as the reason that mothers stop breastfeeding, first-time mothers (at least) may have difficulty in distinguishing between an adequate and inadequate milk supply. If the infant's weight is satisfactory, reassurance may be all that is required. ¹⁵

In summary, domperidone is a mildly effective galactagogue with rare but serious adverse reaction risks for the mother. As tempting as it might seem as a solution to breastfeeding problems, focusing on best practices and maternal reassurance appear to be more fruitful ways of ensuring an adequate maternal milk supply.