Pharmacology

FDA Boxed Warning Updates: December 2017


 

The FDA’s MedWatch program safety labeling changes for boxed warnings are compiled quarterly for drugs and therapeutic biologics where important changes have been made to the safety information. These and other label changes are searchable in the Drug Safety Labeling Changes (SLC) database, where data are available to the public in downloadable and searchable formats. Boxed warnings are ordinarily used to highlight either adverse reactions so serious in proportion to the potential bene t from the drug that it is essential that it be considered in assessing the risks and bene ts of using the drug; or serious adverse reactions that can be prevented/reduced in frequency or severity by appropriate use of the drug; or FDA approved the drug with restrictions to ensure safe use because FDA concluded that the drug can be safely used only if distribution or use is restricted. For complete FDA Drug Safety Labeling changes, please visit http://www.accessdata.fda.gov/scripts/cder/safetylabelingchanges.

CODEINE SULFATE

  • Edited and updated warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRARAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Codeine sulfate tablets are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of codeine sulfate tablets in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

TUXARIN ER (CODEINE PHOSPHATE AND CHLORPHENIRAMINE MALEATE):

  • Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN AND RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a CYP2D6 polymorphism. Tuxarin ER is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuxarin ER in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Concomitant Use with Benzodiazepines, CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound
sedation, respiratory depression, coma, and death. Avoid use of opioid cough medications in patients taking benzodiazepines, other CNS depressants, or alcohol.

TUZISTRA XR (CHLORPHENIRAMINE POLISTIREX; CODEINE POLISTIREX):

  • Edited warning August 2017

ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultrarapid metabolizer of codeine due to a
CYP2D6 polymorphism. Tuzistra XR is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Tuzistra XR in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORICET W/CODEINE (ACETAMINOPHEN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

  • Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and HEPATOTOXICITY

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Butalbital, acetaminophen, caffeine, and codeine phosphate capsules are contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of butalbital, acetaminophen, caffeine, and codeine phosphate capsules in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

FIORINAL W/CODEINE (ASPIRIN; BUTALBITAL; CAFFEINE; CODEINE PHOSPHATE):

  • Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS; ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; and INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES.

Risks From Concomitant Use With Benzodiazepines or Other CNS Depressants

Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death.

  • Reserve concomitant prescribing of Fiorinal with codeine and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate.
  • Limit dosages and durations to the minimum required.
  • Follow patients for signs and symptoms of respiratory depression and sedation.

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a
CYP2D6 polymorphism. Fiorinal with codeine is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Fiorinal with codeine in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

PHENERGAN VC W/CODEINE (CODEINE PHOSPHATE; PHENYLEPHRINE HYDROCHLORIDE; PROMETHAZINE HYDROCHLORIDE): PHENERGAN W/CODEINE (CODEINE PHOSPHATE; PROMETHAZINE HYDROCHLORIDE):

  • Edited warning August 2017

WARNING: ULTRA-RAPID METABOLISM OF CODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received codeine. Most of the reported cases occurred following tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Promethazine HCl and codeine phosphate oral solution is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of promethazine HCl and codeine phosphate oral solution in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of codeine.

Promethazine and Respiratory Depression in Children

Postmarketing cases of respiratory depression, including fatalities have been reported with use of promethazine in pediatric patients. Children may be particularly sensitive to the additive respiratory depressant effects when promethazine is combined with other respiratory depressants, including codeine.

SYNALGOS-DC (ASPIRIN; CAFFEINE; DIHYDROCODEINE BITARTRATE):

  • Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF DIHYDROCODEINE AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Life-threatening respiratory depression and death have occurred in children who received codeine; most cases followed tonsillectomy and/or adenoidectomy, and many of the children had evidence of being an ultra-rapid metabolizer of codeine due to a CYP2D6 polymorphism. Synalgos-DC is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Synalgos-DC in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of dihydrocodeine.

CONZIP (TRAMADOL HYDROCHLORIDE): ULTRAM (TRAMADOL HYDROCHLORIDE): ULTRACET (ACETAMINOPHEN; TRAMADOL HYDROCHLORIDE):

  • Edited warning August 2017

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFETHREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; ULTRA-RAPID METABOLISM OF TRAMADOL AND OTHER RISK FACTORS FOR LIFE-THREATENING RESPIRATORY DEPRESSION IN CHILDREN; NEONATAL OPIOID WITHDRAWAL SYNDROME; INTERACTIONS WITH DRUGS AFFECTING CYTOCHROME P450 ISOENZYMES; and RISKS FROM CONCOMITANT USE WITH BENZODIAZEPINES OR OTHER CNS DEPRESSANTS

Ultra-Rapid Metabolism of Codeine and Other Risk Factors for Life-Threatening Respiratory Depression in Children

Life-threatening respiratory depression and death have occurred in children who received tramadol. Some of the reported cases followed tonsillectomy and/or adenoidectomy; and at least one case, the child had evidence of being an ultra-rapid metabolizer of tramadol due to a CYP2D6 polymorphism. Ultram is contraindicated in children younger than 12 years of age and in children younger than 18 years of age following tonsillectomy and/or adenoidectomy. Avoid the use of Ultram in adolescents 12 to 18 years of age who have other risk factors that may increase their sensitivity to the respiratory depressant effects of tramadol.

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FDA Boxed Warning Updates
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