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Label Changes for:

Codeine Sulfate Tablets

May 2013

Changes have been made to the BOXED WARNING, CONTRAINDICATIONS, WARNINGS and PRECAUTIONS sections of the safety label.

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)

 

May 2013

  • Codiene Sulfate Solution
  • Codeine Sulfate Tablets, 15mg, 30 mg, and 60 mg.
  • Fioricet with Codeine (butalbital, acetaminophen, caffeine, and codeine phosphate) Capsules
  • Fiorinal with Codeine (butalbital, aspirin, caffeine, and codeine phosphate, USP) Capsules
  • Promethazine and Codeine Syrup
  • Promethazine, Phenylephrine and Codeine Syrup
  • Soma Compound with Codeine (carisoprodol, aspirin, and codeine phosphate) Tablets
  • SynalgosDC (dihydrocodeine bitartrate, aspirin and caffeine) Capsules

 

This information pertains to the risk of respiratory depression and death in children related to ultra-rapid metabolism of codeine to morphine.

BOXED WARNING

  • WARNING: Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine due to a CYP2D6 polymorphism (see WARNINGS – Codeine Phosphate - Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).

CONTRAINDICATIONS

  • Codeine sulfate is contraindicated for postoperative pain management in children who have undergone tonsillectomy and/or adenoidectomy (see WARNINGS – Codeine Phosphate - Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).

WARNINGS

Codeine Phosphate
  • Death Related to Ultra-Rapid Metabolism of Codeine to Morphine Respiratory depression and death have occurred in children who received codeine in the postoperative period following tonsillectomy and/or adenoidectomy and had evidence of being ultrarapid metabolizers of codeine (i.e., multiple copies of the gene for cytochrome P450 isoenzyme 2D6 [CYP2D6] or high morphine concentrations). Deaths have also occurred in nursing infants who were exposed to high levels of morphine in breast milk because their mothers were ultrarapid metabolizers of codeine (see PRECAUTIONS -Nursing Mothers). Some individuals may be ultra-rapid metabolizers because of a specific CYP2D6 genotype (gene duplications denoted as *1/*1xN or *1/*2xN). The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5 to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may have life-threatening or fatal respiratory depression or experience signs of overdose (such as extreme sleepiness, confusion, or shallow breathing) (see OVERDOSAGE).
  • Children with obstructive sleep apnea who are treated with codeine for post-tonsillectomy and/or adenoidectomy pain may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in all pediatric patients undergoing tonsillectomy and/or adenoidectomy (see CONTRAINDICATIONS).
  • When prescribing codeine-containing drugs, healthcare providers should choose the lowest effective dose for the shortest period of time and inform patients and caregivers about these risks and the signs of morphine overdose (see OVERDOSAGE).

PRECAUTIONS

Information for Patients/Codeine Phosphate
  • added..... 7. Advise patients that some people have a genetic variation that results in codeine changing into morphine more rapidly and completely than other people. Most people are unaware of whether they are an ultra-rapid codeine metabolizer or not. These higher-than-normal levels of morphine in the blood may lead to life-threatening or fatal respiratory depression or signs of overdose such as extreme sleepiness, confusion, or shallow breathing. Children with this genetic variation who were prescribed codeine after tonsillectomy and/or adenoidectomy for obstructive sleep apnea may be at greatest risk based on reports of several deaths in this population due to respiratory depression. As a result, codeine is contraindicated in all children who undergo tonsillectomy and/or adenoidectomy. Advise caregivers of children receiving codeine for other reasons to monitor for signs of respiratory depression (see WARNINGS- Death Related to Ultra-Rapid Metabolism of Codeine to Morphine).
Pediatric Use
  • added ...... Respiratory depression and death have occurred in children with obstructive sleep apnea who received codeine in the post-operative period following tonsillectomy and/or adenoidectomy and had evidence of being ultra-rapid metabolizers of codeine (i.e., multiple copies of the gene for CYP2D6 or high morphine concentrations). These children may be particularly sensitive to the respiratory depressant effects of codeine that has been rapidly metabolized to morphine. Codeine is contraindicated for post-operative pain management in these patients (see WARNINGS - Death Related to Ultra-Rapid Metabolism of Codeine to Morphine and CONTRAINDICATIONS).
     
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