Information for Healthcare Professionals - Intravenous Promethazine and Severe Tissue Injury, Including Gangrene

[09/16/2009] FDA is requiring a Boxed Warning for promethazine hydrochloride injection, USP products to better communicate the risks of severe tissue injury associated with administration of this drug.  Perivascular extravasation, unintentional intra-arterial injection and intraneuronal or perineuronal infiltration of the drug may result in irritation and tissue damage, including gangrene. The Boxed Warning will remind practitioners that due to the risks of intravenous injection, the preferred route of administration is deep intramuscular injection and that subcutaneous injection is contraindicated.

This action is based on FDA’s analysis of post-marketing reports of severe tissue injury, including gangrene, requiring amputation following intravenous administration of promethazine as well as FDA’s review of the current prescribing information for these products.  FDA has determined that the presentation, organization, and content of the prescribing information should be revised to more effectively communicate the risk of severe tissue injury following intravenous administration. 

In addition to the Boxed Warning, FDA is requiring a revision to the Dosage and Administration section to increase the visibility and accessibility of specific recommendations for the maximum concentration (25 mg per mL) and rate of administration (25 mg per minute) when intravenous administration of promethazine is required.

FDA is requiring the changes to the prescribing information under the authorities granted to FDA by the Food and Drug Administration Amendments Act (FDAAA) of 2007.

Promethazine hydrochloride injection, USP is approved for a variety of uses including allergic reactions, sedation, motion sickness, nausea, and vomiting associated with anesthesia and surgery, and as an adjunct to analgesics for control of postoperative pain. 

This information reflects FDA’s current analysis of data available to FDA concerning this drug. FDA intends to update this sheet when additional information or analyses become available.

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To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program using the contact information at the bottom of this sheet.

Considerations for Healthcare Professionals:

• Intravenous administration of promethazine can cause severe tissue injury, including gangrene, requiring fasciotomy, skin graft, and/or amputation
• Severe tissue injury can occur from perivascular extravasation, unintentional intra-arterial injection, and intraneuronal or perineuronal infiltration
• Deep intramuscular injection is the preferred way to administer promethazine hydrochloride injection, USP products
• Intra-arterial and subcutaneous administration of promethazine are contraindicated
• Promethazine hydrochloride injection, USP is available in two strengths, 25 mg/mL and 50 mg/mL
• The 50 mg/mL promethazine hydrochloride injection, USP product is for deep intramuscular injection only
• The 25 mg/mL promethazine hydrochloride injection, USP product may be administered by deep intramuscular injection or intravenous injection (see maximum dosage and rate below)
• If intravenous administration of promethazine is required, the maximum recommended concentration is 25 mg per mL and the maximum recommended rate of administration is 25 mg per minute through the tubing of an intravenous infusion set known to be functioning properly
• Be alert for signs and symptoms of potential tissue injury including burning or pain at the site of injection, phlebitis, swelling, and blistering
• Injections should be stopped immediately if a patient complains of pain during injection
• Inform patients that side effects may occur immediately while receiving the injection or may develop hours to days after an injection
• Refer to the prescribing information for additional information on warnings, contraindications, adverse events, and dosage and administration of promethazine hydrochloride injection, USP products
• Promethazine should not be used in patients less than 2 years of age due to the risk of fatal respiratory depression 

Information for Patients:

• Discuss any concerns you may have about the risks and benefits of promethazine with a health care professional

• Pay close attention for any signs or symptoms of adverse events including burning or pain at the injection site, redness, swelling, and blistering, and report these symptoms immediately

• Understand that side effects may occur immediately while receiving a promethazine injection or may develop hours to days after an injection

Background and Data Summary: 
Promethazine was previously sold under the brand name Phenergan Injection but this formulation has been discontinued by Wyeth Pharmaceuticals, Inc. Currently multiple generic formulations of promethazine hydrochloride injection, USP are marketed in the United States.

FDA has been aware of the risks of perivascular extravasation and inadvertent intra-arterial administration causing severe tissue injury that are associated with intravenous administration of promethazine, and communicated these risks to healthcare professionals and consumers in the December 2006 and February 2008 FDA Patient Safety News (see links to previous communications below).  Furthermore, the current prescribing information for promethazine hydrochloride injection, USP products contains information regarding the risk of intra-arterial injection and severe tissue injury, including gangrene. Despite the previous safety communications and the current prescribing information, cases of severe tissue injury following intravenous administration of promethazine continue to be reported to FDA.

FDA reviewed the published literature and post-marketing adverse event reports submitted to FDA’s Adverse Event Reporting System (AERS) from 1969 to 2009 and identified cases of gangrene requiring amputation associated with intravenous administration of promethazine. The most common amputations involved the fingers and hands. Numerous other cases of injection reactions such as injection site pain, redness, phlebitis, cyanosis, swelling, blistering, necrosis, and nerve damage were also found.

Additionally, FDA’s review of the current prescribing information for these products found that the warnings for gangrene and intra-arterial injection were present, but their organization and presentation in the labeling could be improved to better convey the risk information.  Therefore, based on the above case reports and conclusions from the prescribing information review, FDA is requiring manufacturers of these products to revise the labeling for promethazine, including addition of a Boxed Warning describing the risk of severe tissue injury, including gangrene, requiring amputation following intravenous administration of promethazine.