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Differences in strength expression on product labels of compounders and conventional manufacturers may lead to dosing errors

Updated: May 21, 2024

The article includes information from an FDA draft guidance on safety considerations on labels to minimize medication errors. The agency issued the final guidance in May 2022, “Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors.”

FDA recommends that for small-volume injection products, the product strength should be expressed as quantity per total volume and should be the primary and prominent expression on the principal display panel of the label, followed by quantity per milliliter enclosed by parentheses.

The information below contains terminology that differs from what appears in the final guidance.

September 24, 2018

Summary

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 10mg/mL highlighted in yellowThe strength per total volume in the syringe was printed beneath the highlighted text in smaller font (see Fig. 1). 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.

Fig. 1. Label image for Ketamine HCl 10 mg/mL syringe compounded by QuVa Pharma. The product was labeled with the strength per milliliter highlighted in yellow.

Fig. 1. Label image for Ketamine HCl 10 mg/mL syringe compounded by QuVa Pharma. The product was labeled with the strength per milliliter highlighted in yellowThe strength per total volume in the syringe was printed beneath the highlighted text in smaller font.

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 (see Fig. 2 and Fig. 3). 

Label image for neostigmine 1 mg/mL injectable syringe compounded by KRS Global Biotechnology.

Fig. 2. Label image for neostigmine 1 mg/mL injectable syringe compounded by KRS Global Biotechnology. The strength per milliliter is displayed in one box, the total dose in an adjacent box, and the total volume in the syringe above the box containing the total dose.

Label image for succinylcholine 20 mg/mL injectable syringe compounded by KRS Global Biotechnology.

Fig. 3. Label image for succinylcholine 20 mg/mL injectable syringe compounded by KRS Global Biotechnology. The strength per milliliter is displayed in one box, the total dose in an adjacent box, and the total volume in the syringe above the box containing the total dose.

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 (see Fig. 4). 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.

Label image for 4 mg of norepinephrine bitartrate added to 250 mL 5% Dextrose injection USP (16 mcg per mL) compounded by PharMEDium Services

Fig. 4. Label image for 4 mg of norepinephrine bitartrate added to 250 mL 5% Dextrose injection USP (16 mcg per mL) compounded by PharMEDium Services.

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.”1FDA 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.”1 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.2

The Institute for Safe Medication Practices (ISMP) has issued medication safety alerts related to this topic.3, 4 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.”3, 4

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:

References

  1. Food and Drug Administration (April 2013). Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors. Draft Guidance.
  2. United States Pharmacopeia. General Chapter <7> Labeling.
  3. The Institute for Safe Medication Practices. Warning! Inconsistent expression of strength on outsourced anesthesia syringes. Medication Safety Alert! Acute Care. 2017; 22(6).
  4. The Institute for Safe Medication Practices. FDA Guidance Needed to Assure Safe Labeling Practices by 503A and 503B Compounders. Medication Safety Alert! Acute Care. 2018; 23(6)
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