Single Entity Injectable Drug Products

The FDA is requiring the removal of ratio expressions of strength from the labeling of single-entity injectable drug products (i.e., drug products that contain only one active ingredient) and replacement with the amount per unit of volume (e.g., mg/mL).

For example, Epinephrine Injection 1:1,000 will now be labeled as Epinephrine Injection 1 mg/mL.

This revision affects Epinephrine Injection, Isoproterenol Hydrochloride Injection, and Neostigmine Methylsulfate Injection.

A graphic has been created to help explain the changes in a user friendly format.

Important Labeling Changes to Critical Care Medications

What are the changes?

• The FDA is requiring removal of ratio expressions of strength from the drug labeling of single-entity injectable drug products (i.e., drug products that contain only one active ingredient). Strength will be expressed only as the amount per unit of volume (i.e., mg/mL).
• This revision affects Epinephrine Injection, Isoproterenol Hydrochloride Injection, and Neostigmine Methylsulfate Injection.

   

  Established Name	Ratio	Amount per Unit of Volume
  Epinephrine Injection, USP	1:1,000 1:10,000	1 mg/mL 0.1 mg/mL
  Isoproterenol Hydrochloride Injection, USP	1:5,000	0.2 mg/mL
  Neostigmine Methylsulfate Injection, USP	1:1,000 1:2,000	1 mg/mL 0.5 mg/mL

When will health care providers start seeing the changes?

• You may already be seeing the revised drug labeling in the marketplace. The FDA continues to work with some manufacturers on these revisions to the epinephrine injection labeling.

Why are we requiring the changes?

• The FDA is requiring the changes to help prevent medication errors related to strength being expressed as a ratio on labeling. There have been several reports of medication errors indicating that ratio expressions are confusing to health care providers and contributed to the errors. Some of the medication errors resulted in serious adverse outcomes, including death. The United States Pharmacopeia (USP) instituted a new labeling standard in an effort to reduce medication errors related to confusion with ratio expressions.

How will the changes affect health care providers?

• Health care providers should start prescribing, communicating, dispensing, and labeling these drugs in mg/mL rather than ratios. Health care facilities should review systems and processes to ensure order sets, protocols, references, dispensing labels and labels for drug storage bins are updated to reflect this change.

Frequently Asked Questions

1. What are ratio expressions of strength?
   • Ratios are a way to express the strength of a solution or liquid preparation.
   • For example, a 1:1,000 ratio for epinephrine represents 1 gram of epinephrine in 1,000 mL of solution, so the amount per unit of volume is 1 mg/mL. A 1:10,000 ratio for epinephrine represents 1 gram of epinephrine in 10,000 mL of solution, so the amount per unit volume is 0.1 mg/mL.

2. What products are impacted by the new labeling standard?

   
   The new labeling standard will affect 3 products currently available in the United States: epinephrine injection, isoproterenol hydrochloride injection, and neostigmine methylsulfate injection.

   Established Name	Ratio	Amount per Unit of Volume
   Epinephrine Injection, USP	1:1,000 1:10,000	1 mg/mL 0.1 mg/mL
   Isoproterenol Hydrochloride Injection, USP	1:5,000	0.2 mg/mL
   Neostigmine Methylsulfate Injection, USP	1:1,000 1:2,000	1 mg/mL 0.5 mg/mL

3. Why is the FDA doing this?

   • In 2010, after receiving a petition from the Institute for Safe Medication Practices (ISMP), the United States Pharmacopeia (USP) established an Expert Panel to create a standard to help prevent medication errors related to confusion with ratio expressions of strength on labeling
   • ISMP cited incidents of confusion as well as serious medication errors where undiluted epinephrine 1:1,000 (1 mg/mL) was given intravenously to patients instead of the 1:10,000 (0.1 mg/mL) concentration. Ratio expressions may be hard to differentiate since 1,000 may easily look like 10,000 in small print, especially when typed without the comma (1:1000 and 1:10000). ISMP also found that healthcare providers misunderstood the concentrations represented by ratios. The errors resulted in serious adverse outcomes, including death.
   • USP published the standard, eliminating the ratio expression of strength from the labeling of single-entity injection drug products in USP 39-NF 34, and it became official on May 1, 2016. The standard states:

     “Single-entity drug products that can also be expressed as a ratio, such as epinephrine, shall be labeled only in terms of strength/mL. A ratio expression such as 1:1000 is an unacceptable format for single-entity drug products.”

4. Who is USP?

   • The U.S. Pharmacopeial Convention (USP) is a scientific nonprofit organization that sets standards for the identity, strength, quality, and purity of medicines, food ingredients, and dietary supplements manufactured, distributed, and consumed worldwide. These standards are published in the United States Pharmacopeia (USP) and the National Formulary (NF), which are both recognized under the Food, Drug, and Cosmetic Act as official compendia.
   • This federal law also states that a drug product named in the USP or NF must be packaged and labeled as described in the compendium. Therefore, manufacturers must comply with the new labeling standard for single-entity drug products. If the labeling does not follow the new standard, the FDA will consider the drug product to be misbranded under the Food, Drug, and Cosmetic Act.

5. What should health care providers and facilities do to ensure a successful transition?

   ISMP¹ created a checklist that can be used to ensure a successful transition as manufacturers comply with the new labeling standard for epinephrine injection, isoproterenol hydrochloride injection, and neostigmine methylsulfate injection (available from: https://www.ismp-canada.org/download/safetyBulletins/2016/ISMPCSB2016-02_ChangesInExpressionStrength.pdf).

   Recommendations on the checklist include:

   • Review systems, processes, and care areas that will be affected by this labeling standard:
     • Computerized pharmacy and prescriber order entry systems
     • Order sets and protocols
     • References and reference algorithms used by clinicians (e.g., hospital formulary, Broselow tape)
     • Dispensing labels and labels for drug storage bins in the pharmacy area and in automated dispensing cabinets
     • Drug storage carts for anesthesia, cardiac arrest, and procedures
     • Stock requisition forms (manual and computerized)
   • Prescribe, communicate, and label epinephrine, isoproterenol, and neostigmine in mg/mL rather than ratios.
   • Raise awareness of the labeling transition through educational events, mock code events, safety huddles, and bulletins.
   • Post conversion tables in easy-to-see locations.
   • Develop a standard process for pharmacists to convert existing “ratio strength” orders to “amount per unit volume” orders for already-admitted patients, so that medication administration records will be consistent with the revised labeling standard.
   • As products with the revised labeling become available, segregate them from older products that still express strength as a ratio on the labeling.
   • Be aware of potential opportunities for drug name mix-ups between epinephrine and ePHEDrine. Epinephrine looks and sounds like ePHEDrine, and both drugs have similar uses. Because ePHEDrine is prescribed in milligrams, the elimination of ratio expression of strength for epinephrine may add to the potential for a look-alike error.
   • After transitioning to products and systems that use amount per unit volume to express strength, verify all shipments from the supplier and the distributor contain only product with the revised labeling.
6. What types of medication errors were reported with using ratio expressions of strength on labeling?
   • Most of the medication error reports described healthcare providers selecting Epinephrine Injection 1:1,000 (1 mg/mL) instead of the intended Epinephrine Injection 1:10,000 (0.1 mg/mL). Thirty percent of the cases specifically stated that the ratios contributed to the errors.
   • ISMP has published several articles that further describe the types of errors associated with confusion over ratio expressions of strength:
     • http://www.ismp.org/Newsletters/acutecare/articles/20040729.asp
     • https://www.ismp-canada.org/download/safetyBulletins/2016/ISMPCSB2016-02_ChangesInExpressionStrength.pdf
     • http://www.ismp.org/newsletters/acutecare/articles/20040812.asp

¹Institute for Safe Medication Practices is a non-profit organization educating the healthcare community and consumers about safe medication practices

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