The U.S. Food and Drug Administration has received reports of dosing errors and confusion with the labeled strength expression for certain compounded injectable products. Conventional manufacturers label their injectable products with the strength per total volume as the primary and prominent expression of strength on the label, whereas some compounders label their injectable products differently. Below is a description of the case reports received by FDA. The case reports illustrate how differences in the product labels of conventional manufacturers and compounders may lead to dosing errors.
Case Reports
FDA received two MedWatch reports concerning medication errors associated with overdoses of compounded injectable products. In the first report, a patient was prescribed 50 mcg of fentanyl. The product administered to the patient was compounded by an undisclosed facility location owned by Central Admixture Pharmacy Services. According to the report, the fentanyl IV bag was labeled with the strength per milliliter (50 mcg/mL) in large font and the strength per total volume (2,500 mcg/50 mL) below in smaller font. The patient was inadvertently administered 2,500 mcg of fentanyl (equivalent to 50 times their prescribed dose). The report noted that the cause of the error was attributed to the prominently stated 50 mcg/mL strength, which was misunderstood as the total amount of fentanyl in the bag.
In the second report, a patient was prescribed 5 to 10 mg of ketamine as needed for pain. The ketamine injection administered to the patient was compounded by QuVa Pharma, Inc., located in Sugar Land, Texas. According to the report, the product was labeled as Ketamine HCl 10 mg/mL highlighted in yellow. The strength per total volume in the syringe was printed beneath the highlighted text in smaller font. The patient inadvertently received 50 mg of ketamine (equivalent to 5 to 10 times their prescribed dose) and became somnolent (abnormally drowsy). The report noted that the cause of the error was attributed to the prominently stated 10 mg/mL strength, which was misunderstood as the total amount of ketamine in the syringe.
Additionally, FDA has received multiple complaints raising concerns that displaying the strength per milliliter in larger, more prominent font, instead of the strength per total volume, may lead to confusion about how much drug is in the container. One such complaint is in reference to phenylephrine 200 mcg/5 mL syringes, compounded by New England Lifecare Inc. dba Advanced Compounding Solutions, located in Woburn, Massachusetts. According to the report, the product was labeled with the strength per milliliter (40 mcg per mL) in large font, and the strength per total volume (200 mcg per 5 mL) underneath in smaller font.
Another report was received describing similar complaints with the labeling of neostigmine 1 mg/mL injectable syringes and succinylcholine 20 mg/mL injectable syringes compounded by KRS Global Biotechnology, Inc., located in Boca Raton, Florida. The strength per total volume is not the most prominent expression of strength on the labels of the syringes.
An additional report was received describing label confusion with an IV bag containing 4 mg of norepinephrine bitartrate added to 250 mL 5% dextrose injection (16 mcg per mL) compounded by PharMEDium Services, LLC, located in Sugar Land, Texas. As described in this report, the IV pump was incorrectly programmed with a concentration of 16 mg/mL when the concentration ordered was 4 mg/250 mL. As described in the report, the product label could have led to confusion as the strength per milliliter concentration of 16 mcg per mL was misinterpreted to mean 16 mg/250 mL.
Discussion
FDA issued a draft guidance in April 2013 titled “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” which applies to marketed prescription drugs and CDER-regulated biological products. This draft guidance recommends that “[f]or small volume parenteral products, the strength per total volume should be the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses.” FDA believes such measures, if adopted, would help avoid or minimize commonly reported dosing errors. These recommendations were proposed in response to overdoses that occurred “because of healthcare practitioner and patient failure to determine the total amount of drug in the container.” FDA’s draft guidance is consistent with the labeling requirements required by the United States Pharmacopeia (USP) in General Chapter 7 (USP < 7 >) on Labeling.
The Institute for Safe Medication Practices (ISMP) has issued medication safety alerts related to this topic. In a newsletter issued March 22, 2018, ISMP states that they have “observed that the strength per mL has often been used as the primary expression on compounders’ labels, leading to inconsistencies between products available in the hospital, thus creating unsafe conditions. Errors have occurred when the more prominent per mL strength is mistaken as the total amount of drug in the syringe. Such errors were the impetus for the USP < 7 > requirement for prominence of the strength per total volume on labels.
Risk Summary
Compounded drugs are not evaluated by FDA for safety, effectiveness, and quality. When FDA reviews an application for an injectable drug, the overall safety of the product is evaluated, including, as relevant here, the product’s label. As these case reports illustrate, there are differences in labeling practices between conventional manufacturers and compounders in their display of strength on the product label. This may lead to dosing errors when health care professionals, who are more familiar with conventional expression of strength information, are administering compounded drugs. These types of dosing errors could be avoided for small volume parenteral products, by expressing the drug strength per total volume as the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses.
Labeling compounded injectables using the strength convention adopted by conventional manufacturers could avoid confusion and reduce the risk of medication errors. Because labels of compounded products are not reviewed by FDA prior to marketing, health care professionals should be vigilant when administering compounded products to patients to avoid confusion and ensure that each patient is administered the prescribed dose of the intended drug. Health care professionals may consider requesting compounders to label products with the strength per total volume as the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses to minimize the risk of errors
Additionally, FDA has received multiple complaints raising concerns that displaying the strength per milliliter in larger, more prominent font, instead of the strength per total volume, may lead to confusion about how much drug is in the container. One such complaint is in reference to phenylephrine 200 mcg/5 mL syringes, compounded by New England Lifecare Inc. dba Advanced Compounding Solutions, located in Woburn, Massachusetts. According to the report, the product was labeled with the strength per milliliter (40 mcg per mL) in large font, and the strength per total volume (200 mcg per 5 mL) underneath in smaller font.
Another report was received describing similar complaints with the labeling of neostigmine 1 mg/mL injectable syringes and succinylcholine 20 mg/mL injectable syringes compounded by KRS Global Biotechnology, Inc., located in Boca Raton, Florida. The strength per total volume is not the most prominent expression of strength on the labels of the syringes.
An additional report was received describing label confusion with an IV bag containing 4 mg of norepinephrine bitartrate added to 250 mL 5% dextrose injection (16 mcg per mL) compounded by PharMEDium Services, LLC, located in Sugar Land, Texas. As described in this report, the IV pump was incorrectly programmed with a concentration of 16 mg/mL when the concentration ordered was 4 mg/250 mL. As described in the report, the product label could have led to confusion as the strength per milliliter concentration of 16 mcg per mL was misinterpreted to mean 16 mg/250 mL.
Discussion
FDA issued a draft guidance in April 2013 titled “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors,” which applies to marketed prescription drugs and CDER-regulated biological products. This draft guidance recommends that “[f]or small volume parenteral products, the strength per total volume should be the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses.” FDA believes such measures, if adopted, would help avoid or minimize commonly reported dosing errors. These recommendations were proposed in response to overdoses that occurred “because of healthcare practitioner and patient failure to determine the total amount of drug in the container.” FDA’s draft guidance is consistent with the labeling requirements required by the United States Pharmacopeia (USP) in General Chapter 7 (USP < 7 >) on Labeling.
The Institute for Safe Medication Practices (ISMP) has issued medication safety alerts related to this topic. In a newsletter issued March 22, 2018, ISMP states that they have “observed that the strength per mL has often been used as the primary expression on compounders’ labels, leading to inconsistencies between products available in the hospital, thus creating unsafe conditions. Errors have occurred when the more prominent per mL strength is mistaken as the total amount of drug in the syringe. Such errors were the impetus for the USP < 7 > requirement for prominence of the strength per total volume on labels.
Risk Summary
Compounded drugs are not evaluated by FDA for safety, effectiveness, and quality. When FDA reviews an application for an injectable drug, the overall safety of the product is evaluated, including, as relevant here, the product’s label. As these case reports illustrate, there are differences in labeling practices between conventional manufacturers and compounders in their display of strength on the product label. This may lead to dosing errors when health care professionals, who are more familiar with conventional expression of strength information, are administering compounded drugs. These types of dosing errors could be avoided for small volume parenteral products, by expressing the drug strength per total volume as the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses.
Labeling compounded injectables using the strength convention adopted by conventional manufacturers could avoid confusion and reduce the risk of medication errors. Because labels of compounded products are not reviewed by FDA prior to marketing, health care professionals should be vigilant when administering compounded products to patients to avoid confusion and ensure that each patient is administered the prescribed dose of the intended drug. Health care professionals may consider requesting compounders to label products with the strength per total volume as the primary and prominent expression on the principal display panel of the label, followed in close proximity by strength per milliliter enclosed by parentheses to minimize the risk of errors
MedWatch Reporting Information
FDA encourages consumers, patients, and health care professionals to report medication errors, adverse events, and quality problems experienced with the use of compounded drug products to FDA’s MedWatch Adverse Event Reporting program:
FDA encourages consumers, patients, and health care professionals to report medication errors, adverse events, and quality problems experienced with the use of compounded drug products to FDA’s MedWatch Adverse Event Reporting program:
- Complete and submit the report online at www.fda.gov/medwatch/
report.htm; or - Download and complete the form, then submit it via fax at 1-800-FDA-0178.
For more information, please visit: Differences in strength expression - Compounding Risk Alert.
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