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New Codeine Warnings Prompt Action on Newborns

Kate Traynor

Kate TraynorNews Writer
News Center; AJHP

At Baxter Regional Medical Center, a flurry of activity followed FDA’s April 20 announcement of new warnings and contraindications in the labeling for codeine- and tramadol-containing products to prevent respiratory depression and other adverse events in infants and children.

Angela Powell, a night pharmacist at the 268-bed community hospital in Mountain Home, Arkansas, said that although the overall use of codeine is low in pediatric patients, quick action was needed in 1 particular ward.

“The main thing that we worried about initially was in our labor and delivery area,” Powell said. “Our order sets for that area had Tylenol with Codeine as the preferred analgesic for vaginal deliveries.”

Powell said the change was expedited to be in place before the next scheduled pharmacy and therapeutics committee meeting.

“We preemptively reached out to all of those ob-gyn and family practice docs and got those order sets changed to something else so our breastfeeding mamas weren’t getting codeine products anymore,” she said.

She said there's essentially no pediatric use of tramadol at the hospital.

FDA officials, during an April 20 media briefing, said the labeling changes include a warning to women not to breastfeed while taking codeine or tramadol so as to avoid exposing nursing infants to potentially dangerous amounts of the medications. The labeling for both drugs will also state that they are contraindicated in children younger than 12 years of age.

The officials said the labeling changes represent the agency’s conclusions from data spanning several years and weren’t prompted by a specific incident.

FDA has identified 64 cases worldwide, dating back to 1969, of serious codeine-related breathing problems in children under age 18 years, including 24 deaths. For tramadol, the numbers are 9 cases, including 3 deaths, according to the agency.

FDA has warned of this risk in the past. The agency in 2013 announced a new boxed warning and contraindication for the labeling of codeine-containing products to dissuade clinicians from prescribing the medications to children for pain relief after surgery to remove tonsils or adenoids.

Douglas Throckmorton, deputy director for regulatory programs at FDA’s Center for Drug Evaluation and Research, said during the April 20 briefing that that same contraindication will now be added to the labeling for tramadol-containing products.

New labeling for both drugs will also recommend against their use in adolescents 12-18 years of age who are obese or have obstructive sleep apnea, lung disease, or other conditions that can increase the risk of respiratory depression.

The wording of the labeling changes for the 2 drugs had not been released at presstime.

Throckmorton said FDA is particularly concerned about the effects of the opioids on children whose phenotype for cytochrome P-450 (CYP) 2D6 isozyme metabolism results in ultrarapid metabolism of certain drugs, including codeine.

As codeine is metabolized to morphine, dangerous levels of that opioid may build in the bloodstream, increasing the risks of respiratory depression and serious adverse events, including death.

Of the 10 codeine exposure reports examined by FDA that contained information on CYP2D6 phenotype status, 7 involved patients who were ultrarapid metabolizers and 3 involved extensive metabolizers. All 7 ultrarapid metabolizers and 1 of the extensive metabolizers died after the exposure, according to FDA.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) categorizes ultrarapid metabolizers of codeine as people who carry more than 2 copies of functional alleles of CYP2D6, the gene coding for CYP2D6. The group estimates that 1-2% of patients fall into this category.

Extensive metabolizers, according to CPIC, have 2 CYP2D6 alleles encoding full or reduced isozyme function or 1 fully functioning allele together with a partially functional or nonfunctional allele. About 77-92% of patients are extensive metabolizers, according to CPIC.

Powell said her hospital doesn’t screen for CYP2D6 metabolic phenotype status, and it’s unlikely that clinicians have that phenotype information for their patients.

Throckmorton likewise said that because FDA “can’t easily determine” which users of codeine or tramadol are ultrarapid metabolizers, the labeling changes for the drugs apply broadly to all children and nursing mothers.

Despite FDA’s apparent sense of urgency to restrict pediatric use of codeine and tramadol, the agency has been somewhat imprecise about whether a contraindication constitutes an absolute prohibition of use.

During a December 2015 advisory committee meeting that addressed contraindications for codeine-containing products, FDA Medical Officer Timothy Jiang called a contraindication “a strong recommendation against use of drug in certain patients.”

But FDA told the advisers to consider the regulatory description of contraindication when voting on recommendations. That language reserves that term for clinical situations in which “the risk of use ... clearly outweighs any possible therapeutic benefit.”

Sally Seymour, deputy director for safety at FDA’s Division of Pulmonary, Allergy, and Rheumatology Products, acknowledged to the advisers that although a contraindication is “a very strong statement,” it doesn’t bind clinicians, because the agency doesn’t regulate medical practice.

“Prescribers can choose to make decisions outside of the labeling recommendations,” she said.

An FDA spokesman, when pressed in April to clarify whether the agency considers a contraindication an absolute prohibition to the use of a drug, referred to the same regulatory language provided during the 2015 advisory committee meeting.

The spokesman also stated in an email, without additional clarification, that the agency favors “precise language” in drug labeling, such as “DRUG-X is contraindicated in patients with condition Y” rather than “DRUG-X should not be used in patients with condition Y.”

Powell, at Baxter Regional Medical Center, said it’s sometimes hard to manage contraindications. She said most of her pharmacist colleagues likely view a contraindication as a clear instruction not to give a medication. But the medical staff doesn’t always share that perception, especially for medications they’re accustomed to prescribing without incident.

“When people have been practicing for years, it’s really hard to convince them,” she said.

And she said that although the labor and delivery ward is squared away with respect to codeine use, there remains a low level of pediatric use of the drug elsewhere in the hospital—mostly in the emergency department.

“We haven’t done anything specific to address that yet; our focus was really on the newborns. But I think we'll have to do something to help encourage compliance” with FDA’s new recommendations, Powell said.

[This news story appears in the July 15, 2017, issue of AJHP.]

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