1. What is FDA announcing?

FDA is announcing recent reports of serious allergic-type hypersensitivity reactions and cases of severe hypotension in association with the use of intravenous bolus doses of heparin sodium for injection manufactured by Baxter.  In order to minimize the risks associated with use of this product, FDA is providing recommendations to physicians and healthcare providers to avoid bolus dosing with Baxter heparin whenever possible and recommendations for strategies that may limit the occurrence or severity of adverse reactions if the use of heparin is medically necessary and Baxter heparin is the only heparin product available

  2. What products and what patients will be affected by this?

Products affected are:  Baxter’s Heparin Sodium Injection multiple-dose vials (1000 units/mL concentration, 10 mL and 30 mL vials; 5000 units/mL concentration, 10 mL vials; and 10,000 units/mL, 4 mL vials).  These are used when patients need large intravenous doses given quickly, sometimes called “bolus doses” in order to thin their blood over a very short period of time.  Patients affected are:  patients with kidney failure on hemodialysis; patients undergoing certain types of cardiovascular surgery; patients undergoing other specialized treatments called photopheresis and plasmapheresis and some patients who have blood clots in arteries or veins.

3. Are there other patients who may be treated with heparin that this will not affect?  (small dose, flush, etc.)

Heparin is used in many other medical settings, but these do not usually require the higher doses that are of concern with the Baxter product.  Other uses which are not of concern include small doses of heparin used to flush, or clear out, intravenous catheters or to prevent clotting in indwelling catheters, and slow heparin infusions to treat clotting in various hospital settings.

4. What other companies make heparin and is FDA sure that their product(s) do not have the same risk?

Heparin sodium in multiple dose vials is also manufactured by APP Pharmaceuticals.  Hospira and B. Braun also supply some heparin sodium for injection:  Hospira in single-use syringes, vials and bags and B. Braun in pre-mixed bags for infusion.  FDA is currently investigating whether similar adverse events have been reported for heparin products from other manufacturers. 

5. Is APP Pharmaceuticals able to provide enough heparin to avoid a shortage?

Baxter currently manufacturers about 50% of the heparin sodium used in the U.S.  Since manufacture of Baxter’s multiple-dose heparin sodium vials, which accounts for approximately 75% of Baxter’s heparin production, is being suspended, there is a real potential for a shortage of heparin sodium for bolus dosing, especially in the short term.  FDA is working with APP and other manufacturers (outside the US) to increase production and/or provide alternate sources of heparin sodium.

6. What kinds of serious adverse events have occurred?  How many?

From mid-December 2007 through January 2008 Baxter has received 350 reports of adverse events reported with their product, many of them serious.  These include severe allergic reactions, severe nausea, vomiting, diaphoresis, difficulty breathing, and very low blood pressure.   Four patients who received heparin bolus during this time died; the relationship between heparin and these deaths is uncertain.

7. When did FDA learn about the adverse events? 

FDA learned of the occurrence of adverse events on January 9 from CDC investigators who were evaluating small clusters of these events in dialysis centers.  On January 16, 2008, FDA initiated an inspection of Baxter’s manufacturing plant in Cherry Hill, New Jersey.  At the time of the inspection, Baxter notified the Agency that nine lots of its heparin sodium were being recalled due to an increase in the rate of adverse events with these lots. The recall was initiated on January 17, 2008. 

8. Why is FDA not taking the Baxter heparin off pharmacy and hospital shelves, but instead is allowing them to use what product they have?

Heparin sodium is a medically necessary product with some uses for which there are no well-established substitutes.  Abrupt withdrawal of all Baxter heparin product would likely lead to severe shortage of heparin sodium for all uses.  The increase in occurrence of adverse events with Baxter’s heparin appears to be related to administering large amounts of the heparin product over a very short time. An increase in serious reactions has not been seen with use of small amounts and/or slow infusions of heparin sodium.  Therefore, the Agency has determined that in the short term, with measures being undertaken to advise caution and careful monitoring of patients receiving heparin, the public health is best served by continued availability of Baxter’s existing heparin sodium for clinical situations in which it is needed.  The Agency is working with heparin sodium manufacturers to identify and ensure adequate supplies of heparin sodium for future clinical use.     

9. What is the cause of the adverse events?  What is FDA doing to learn more?  When will results of investigations be available?

At this time the cause of the adverse events is unknown.  FDA has been working with Baxter and independently to investigate the root cause of the problem since it was first identified and led to the January 17th limited recall.  We will continue intensive and in-depth investigation and testing to determine the root cause of the problem.

10. Why did FDA not require Baxter to take this measure at the time of their first recall?

In January it appeared that the adverse events being reported were linked only to a small number of manufacturing lots of Baxter’s heparin sodium.  Therefore, only those lots were recalled (taken off of hospital and facility pharmacy shelves).   However, serious adverse events continued to be reported at an increased rate and involved additional lots of heparin sodium.    

11. What other products does Baxter sell?  Are any of those products having similar problems?

Baxter sells a wide variety of pharmaceutical products used to treat a number of medical disorders.  We have no evidence that the company’s other products are associated with an increase in adverse events

12. How is FDA investigating this problem?

We are investigating all possible sources of the problem, including evaluating the active pharmaceutical ingredient manufacturing facility, located in China, and finished dosage form manufacturing facility, located in New Jersey.  We will be inspecting these facilities as soon as possible.  In addition, FDA is performing comprehensive laboratory analysis of the heparin.  FDA is collaborating with the CDC and other experts to determine the root cause of the problem.  FDA is also working closely with its international counterparts, in case they have any relevant information

13. What are the alternatives to using the Baxter product?

Heparin sodium in multiple dose vials is also manufactured by APP Pharmaceuticals.  Hospira and B. Braun also supply some heparin sodium for injection:  Hospira in single-use syringes, vials and bags and B. Braun in pre-mixed bags for infusion.  There are other FDA approved anticoagulants, including low molecular weight heparins and direct thrombin inhibitors; however, these products are not approved for use in all the same clinical settings as heparin.  There is no experience with the other anticoagulants to achieve the immediate anticoagulation needed for hemodialysis, phereses, and certain cardiac procedures.

14.  What should I do if there are no suitable alternative products and my health care provider cannot obtain heparin manufactured by APP?

FDA is recommending that providers consider administering heparin as an infusion rather than a bolus if at all possible.   If a heparin bolus is required, FDA recommends that providers use the lowest dose and administer at the slowest rate possible to achieve the desired effect.  FDA is advising physicians to monitor patients carefully during the infusion, particularly at the onset, for evidence of allergic reactions, and have resuscitation equipment readily available.  FDA is also advising physicians to consider the potential benefits and risks in individual patients of pretreatment with corticosteroids or antihistamines.  At this time FDA does not have data to determine if such pretreatment is effective.

15. I received the Baxter product in the past.  Am I at risk for a serious reaction?

The serious reactions have generally occurred rapidly; usually within minutes of when the bolus dose was started.  However, some patients undergoing cardiac procedures have developed very low blood pressures as late as an hour following the start of the heparin bolus.  There is no evidence that the product causes very delayed or late onset allergic reactions.