Codeine toxicity in breastfed infants

HSA would like to bring the attention of healthcare professionals to a very rare, but serious health risk in breastfed babies posed by codeine use in nursing mothers who are ultra-rapid metabolisers of codeine.

Background

Codeine is found in many prescription and non-prescription pain relievers and cough syrups. Once ingested, codeine is metabolised by cytochrome P450 2D6 (CYP2D6) to its active metabolite, morphine, which relieves pain or cough. Limited evidence suggests that individuals with a specific CYP2D6 genotype or otherwise known as ultra-rapid metabolisers, may convert codeine to morphine more rapidly and completely than other people. In nursing mothers, this metabolism can result in a higher than expected levels of morphine in serum and breast milk, putting nursing infants at increased risk for morphine overdose.¹

Prevalence of ultra-rapid metabolisers in different ethnic groups

The frequency of CYP2D6 genotype associated ultra-rapid metabolisers varies widely among different racial and ethnic groups. The prevalence is estimated to be 1 per 100 people for those of Chinese, Japanese and Hispanic descent, 3 per 100 for African Americans and 1 to 10 per 100 for Caucasians. North African, Ethiopian and Arab populations have the highest estimated prevalence, from 16 to 28 per 100 people. Regardless of ethnic variation in the prevalence of ultra-rapid metabolisers, it is important to bear in mind that polymorphism of CYP2D6 is clinically important

Case report in the Lancet²

In August 2006, the Lancet published a case report describing a healthy 13-day-old nursing infant who died from morphine overdose. The mother was prescribed 60mg of codeine every 12 hourly after birth for episiotomy pain. This dose was subsequently reduced to 30mg every 12 hourly after she developed side effects of somnolence and constipation. The breastfed infant was found to have poor neonatal feeding around postpartum day ten, noted to have grey skin on day 12 and died on day 13. Postmortem analysis showed no anatomical anomalies but the infant's morphine blood concentration was found to be 70ng/ml. Serum morphine concentrations of breastfed neonates of nursing mothers who are taking codeine typically range from 0 to 2.2ng/ml. A sample of breast milk that was stored on day 10 showed a morphine concentration of 87ng/ml, which was much higher than the typical range of morphine milk concentrations of 1.9 to 20.5ng/ml at repeated codeine doses of 60mg every 6 hours.

Subsequent genotypic analysis of the mother revealed that she was heterozygous for the CYP2D6*2A allele with CYP2D6*2x2 gene duplication which classified her as an ultra-rapid metaboliser. Additionally, genotypic analyses of the maternal grandfather, the father, and the infant showed that they were extensive metabolisers while the maternal grandmother was an ultra-rapid metaboliser.

International regulatory actions

In August 2007, the United States Food and Drug Administration (FDA) issued a public health advisory to warn healthcare professionals and nursing mothers of the increased risk of morphine overdose in breastfed infants of mothers who are taking codeine and are ultra-rapid metabolisers. According to the FDA, nursing mothers have used codeine safely for many years and in medical practice, codeine is generally considered the safest choice among narcotic pain relievers for nursing women and their babies. However, to raise awareness of this potential health risk and to prevent morphine overdose in breastfed infants, FDA is requiring manufacturers of prescription codeine medicines to update their product inserts to include information about codeine ultra-rapid metabolism.^3,4

A similar public advisory was also issued recently by Health Canada in October 2008. Nursing mothers were advised to take precautions to minimise the risk of morphine exposure in breastfed infants and to monitor their infants carefully when they are taking codeine-containing products during breastfeeding. Drug manufacturers of codeine-containing prescription products were also requested to update their product inserts to include information that better identify the risk to breastfed babies whose mothers are ultra-rapid metabolisers of codeine. The labeling guidelines for non-prescription products containing codeine were also being revised to provide more information about this risk.⁵

Local situation

HSA has not received any local reports related to toxic morphine levels in breastfed infants as a result of codeine-containing products ingested by nursing mothers. When prescribing codeine to a nursing mother, physicians should choose the lowest effective dose for the shortest period of time. Healthcare professionals are encouraged to report suspected adverse drug reactions associated with codeine-containing products to the Pharmacovigilance Branch of HSA.

References

1. FDA Alert. Use of codeine products in nursing mothers.  http://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm124889.htm

2. Lancet 2006, Vol 368:704, August 2006

3. FDA Public Health Advisory. Use of codeine by some breastfeeding mothers may lead to life-threatening side effects in nursing babies.
   http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/PublicHealthAdvisories/ucm054717.htm

4. FDA News. FDA warning on codeine use by nursing mothers.  http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108968.htm

5. Health Canada Advisory. Use of Codeine Products by nursing mothers.http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2008/13255a-eng.php