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Codeine / promethazine Pregnancy and Breastfeeding Warnings

Codeine / promethazine Pregnancy Warnings

Benefit should outweigh risk US FDA pregnancy category: C Comment: Prolonged use of opioids during pregnancy can result in physical dependence in the neonate; women should be advised of the risk of neonatal abstinence syndrome and ensure that appropriate treatment will be available.

Codeine has been shown to be embryolethal and fetotoxic in rats at maternally toxic doses. In rats and rabbits administered doses ranging from 5 to 120 mg/kg during the period of organogenesis, teratogenicity was not observed. Prolonged use of opioids during pregnancy has resulted in babies being born physically dependent. Opioids administered to mothers shortly before delivery may result in some degree of newborn respiratory depression, especially with higher doses. Rat feeding studies with promethazine at doses approximately 2.1 to 4.2 times (6.25 to 12.5 mg/kg) the recommended human daily dose have not shown teratogenicity. Intraperitoneal administration of daily doses of 25 mg/kg have been found to produce fetal mortality in rats. Administration of promethazine within 2 weeks of delivery may inhibit platelet aggregation in the newborn. There are no adequate and well-controlled studies in pregnant women. US FDA pregnancy category C: Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

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Codeine / promethazine Breastfeeding Warnings

Codeine is present in breast milk. For women with normal codeine metabolism (normal CYP450 2D6 activity) the amount of codeine secreted is low and dose-dependent. However, in women who are ultra-rapid metabolizers of codeine (those with a specific CYP450 2D6 genotype) higher-than-expected serum levels of morphine (codeine's active metabolite) may be present in breast milk which may lead to dangerously high serum morphine levels in their breastfed infants. In most cases, a person's specific CYP450 2D6 genotype is unknown. Several small series and 1 small retrospective study suggest that codeine may be causative in episodes of apnea, bradycardia, and cyanosis in the first week of life. A death of a breastfeed infant due to respiratory depression has been reported; the mother was found to be a CYP450 2D6 ultrarapid metabolizer. The anticholinergic effect of promethazine may suppress lactation.

Benefit should outweigh risk Excreted into human milk: Yes (codeine); Unknown (promethazine) Excreted into animal milk: Data not available (codeine); Data not available (promethazine) Comments: -The American Academy of Pediatrics recommends that other agents are preferred over codeine during breastfeeding. -If used, mother-infant pairs should be closely monitored; treating pediatricians should be advised about the use of codeine during breast-feeding.

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References for pregnancy information

  1. "Product Information. Phenergan with Codeine (codeine-promethazine)" Wyeth-Ayerst Laboratories, Philadelphia, PA.

References for breastfeeding information

  1. United States National Library of Medicine "Toxnet. Toxicology Data Network. Available from: URL: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT." ([cited 2013 -]):
  2. Seymour S "Joint Pulmonary-Allergy Drugs and Drug Safety and Risk Management Advisory Committee Meeting, FDA Introductory Remarks. Available from: URL: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/pulmonary-allergydrugsadvisorycom" ([2015, Dec 10]):
  3. "Product Information. Codeine Phosphate-Promethazine HCl (codeine-promethazine)." Par Pharmaceutical Inc (formerly Qualitest Pharmaceuticals Inc), Huntsville, AL.

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