Show #88, July 2009: Update on Precipitate Formation with Ceftriaxone and Calcium-containing Products

Update on Precipitate Formation with Ceftriaxone and Calcium-containing Products

FDA is updating earlier recommendations about the interaction between the antibiotic ceftriaxone and intravenous products that contain calcium. In certain circumstances, this interaction can cause dangerous precipitates to form. Ceftriaxone is sold as Rocephin and also as a generic. Products that contain calcium include Ringer's solution, Hartmann's solution and parenteral nutrition formulations that contain calcium.

FDA had previously recommended that ceftriaxone and calcium-containing IV products not be administered within 48 hours of one another for patients of all ages. This has now changed. It is no longer necessary to wait 48 hours in patients over 28 days old, provided that certain precautions are followed. And FDA is still stressing that ceftriaxone must not be used in neonates if they are receiving or will receive calcium-containing IV products.

Ceftriaxone and products that contain calcium may now be administered sequentially to patients older than 28 days of age, as long as the infusion lines are thoroughly flushed between infusions with a compatible fluid. However, ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions through a Y-site. FDA also continues to advise practitioners not to reconstitute or mix ceftriaxone with products that contain calcium.

There are no data on whether ceftriaxone might interact with calcium-containing products that are given orally. It's also not clear whether intramuscular ceftriaxone might interact with calcium-containing products, either IV or oral.


Additional Information:
FDA MedWatch Safety Alert. Ceftriaxone (marketed at Rocephin and generics). April 14, 2009.


II - Ceftriaxone (marketed as Rocephin and generics)
Last updated: 4/21/2009

This Alert highlights important revisions to the Warnings, Dosage and Administration, Contraindications, and Clinical Pharmacology sections of the full prescribing information for ceftriaxone (Rocephin and its generics). This information updates a previous Alert and addresses the interaction of ceftriaxone with calcium-containing products, based on previously reported fatal cases in neonates. At the request of FDA, the manufacturer of ceftriaxone (Roche) conducted two in vitro studies to assess the potential for precipitation of ceftriaxone-calcium when ceftriaxone and calcium-containing products are mixed in vials and in infusion lines. These two in vitro studies were conducted in neonatal and adult plasma to assess the potential for precipitation of ceftriaxone-calcium using varying ceftriaxone and calcium concentrations, including concentrations in excess of those achieved in vivo.* Based on the results from these studies, FDA has the following updated recommendations:

Concomitant use of ceftriaxone and intravenous calcium-containing products is contraindicated in neonates (<28 days of age). Ceftriaxone should not be used in neonates (<28 days of age) if they are receiving (or are expected to receive) calcium-containing intravenous products.
In patients >28 days of age, ceftriaxone and calcium-containing products may be administered sequentially, provided the infusion lines are thoroughly flushed between infusions with a compatible fluid.
Ceftriaxone must not be administered simultaneously with intravenous calcium-containing solutions via a Y-site in any age group.
FDA now recommends that ceftriaxone and calcium-containing products may be used concomitantly in patients >28 days of age, using the precautionary steps above because the risk of precipitation is low in this population. FDA had previously recommended, but no longer recommends, that in all age groups ceftriaxone and calcium-containing products should not be administered within 48 hours of one another.
In addition, FDA is reiterating three of the previous recommendations or considerations from September 2007:

Do not reconstitute or mix ceftriaxone with a calcium-containing product, such as Ringer’s or Hartmann’s solution or parenteral nutrition containing calcium, because particulate formation can result.
There are no data on interactions between intravenous ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and intravenous or oral calcium-containing products.
Report patients who have adverse events following ceftriaxone administration to the FDA’s MedWatch program (see reporting information at the bottom of this page).
* Two in vitro studies, one using adult plasma and the other neonatal plasma from umbilical cord blood have been carried out to assess interaction of ceftriaxone and calcium. Ceftriaxone concentrations up to 1 mM (in excess of concentrations achieved in vivo following administration of 2 grams ceftriaxone infused over 30 minutes) were used in combination with calcium concentrations up to 12 mM (48 mg/dL). Recovery of ceftriaxone from plasma was reduced with calcium concentrations of 6 mM (24 mg/dL) or higher in adult plasma or 4 mM (16 mg/dL) or higher in neonatal plasma. This may be reflective of ceftriaxone-calcium precipitation.


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

To report any unexpected adverse or serious events associated with the use of this drug, please contact the FDA MedWatch program and complete a form on line or report by fax to 1-800-FDA-0178, by mail using the postage-paid address form provided on line, or by telephone to 1-800-FDA-1088.
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The prior FDA Alert from September 2007 on the topic of the interaction of ceftriaxone with calcium-containing products is shown below. This Alert is now updated above:


FDA ALERT [9/2007]: This Alert highlights important revisions to the CONTRAINDICATIONS, WARNINGS, and DOSAGE and ADMINISTRATION sections of the full prescribing information for Rocephin. This new information addresses the interaction of ceftriaxone with calcium-containing products based on reports of fatal cases in neonates. Although there are no reported cases of ceftriaxone-calcium precipitates in patients other than neonates, the potential for this interaction exists in patients of any age. Generally, fatalities have been associated with simultaneous administration of ceftriaxone and calcium-containing products. However, administration of the two products at different times and via different infusion lines has also been fatal. Therefore, ceftriaxone should not be mixed with calcium-containing products and not administered in the same or different infusion lines or sites in any patient within 48 hours of each other. The information in the August 2007 ceftriaxone label clarifies the ceftriaxone labeling revision in May 2007 that first included information on this interaction.


The ceftriaxone full prescribing information includes new information in the CONTRAINDICATIONS, WARNINGS, and DOSAGE and ADMINISTRATION sections about the interaction of ceftriaxone with calcium-containing products and the resulting potential risk of life-threatening and fatal.
Recommendations and considerations for healthcare professionals:

Do not reconstitute or mix ceftriaxone with a calcium-containing product, such as Ringer’s or Hartmann’s solution or parenteral nutrition containing calcium, because particulate formation can result.
There are no data on interactions between intravenous ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and intravenous or oral calcium-containing products.
Report patients who have adverse events following ceftriaxone administration to the FDA’s MedWatch program (see reporting information at the bottom of this page)
Information for the patient: Physicians who are prescribing ceftriaxone should discuss with their patients or their caregivers:

Ceftriaxone and calcium-containing products can interact with each other and cause life-threatening reactions.
Tell your healthcare provider about all medicines that have been given to you, especially those given to you through your veins in the past two days.
Background Information and Data
The Rocephin full prescribing information was updated in May 2007 to add new information about the interaction between ceftriaxone and calcium-containing products based on post-marketing reports in neonates. In August 2007, the full prescribing information was modified to further clarify this issue.

Roche, the manufacturer of ceftriaxone, had provided to FDA post-marketing reports of five neonatal deaths related to the interaction between ceftriaxone and calcium-containing products. According to the reports, the deaths occurred suddenly. In four neonates, ceftriaxone was co-administered with calcium-containing fluids using the same infusion line and in the fifth neonate ceftriaxone and calcium gluconate were administered by different routes and at different times (the exact time difference was not reported). Two autopsies found evidence of crystalline material in the renal and pulmonary vasculature. In a third neonate there was evidence of a precipitate in the intravenous tubing and the neonate’s death occurred soon after the crystalline material was injected.

In addition to the five post-marketing reports provided by Roche, FDA has received four additional post-marketing reports of interactions between ceftriaxone and calcium-containing products in patients up to one year of age since FDA first approved Rocephin in 1984. Three of the interactions resulted in death; in one instance the patient was receiving parenteral nutrition. An autopsy in one patient revealed evidence of crystals in the lungs.

Although FDA is not aware of any cases of ceftriaxone-calcium interactions in adults there is a theoretical possibility that this interaction may occur based on the physical incompatibility of ceftriaxone and calcium-containing solutions. Ceftriaxone-calcium incompatibilities have been reported in the literature.1,2Precipitates can be observed when ceftriaxone is reconstituted or mixed with a calcium-containing product.

There are no data on interactions between intravenous ceftriaxone and oral calcium-containing products or between intramuscular ceftriaxone and intravenous or oral calcium-containing products.


References
1. Burkiewicz JS. Incompatibility of ceftriaxone sodium with lactated Ringer’s injection. Am J Health-Syst Pharm 1999;56: 384.
2. Trissel L.A. Handbook on injectable drugs. 14th ed. Bethesda: American Society of Health-System Pharmacists; 2007.