Updated Questions and Answers on Heparin Sodium Injection (Baxter) (6/18/2008)
1. What is heparin? (new question added 6/18/2008)
Heparin is one of a class of medications called anticoagulants that are commonly referred to as blood thinners. Heparin makes an anti-clotting protein in your body work better, thus decreasing the clotting ability of the blood.
Heparin is made from pig intestines and has been marketed in the United States since the 1930s.
Heparin is available as a solution (liquid) to be injected intravenously (into a vein) or deeply under the skin and as a dilute (less concentrated) solution to be injected into intravenous catheters. It may be given to you by a nurse or other health care provider, or you may be told to inject the medication by yourself at home.
2. What is heparin used for? (new question added 6/18/2008)
The medication is used to prevent and treat blood clots in the veins, arteries and lungs. Heparin is commonly used before certain types of surgery, including coronary artery bypass graft surgery, and in kidney patients before they undergo dialysis.
Some medical devices contain or are coated with heparin, and some diagnostic testing products are manufactured using heparin. FDA is aware that some of these products have been affected by the recent contamination. Questions and Answers on Heparin, Medical Devices and In-vitro Diagnostic Assays
3. What did FDA announce? (answer revised 6/18/2008)
In January, FDA announced it had learned about an increase in the number 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 provided 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. On February 28, 2008, Baxter Healthcare Corporation recalled all multi-dose and single-dose vials of heparin sodium for injection as well as HEP-LOCK heparin flush products.
4. What products and what patients were affected by this? (answer revised 6/18/2008)
Products known to be 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). The multiple-dose vials typically are used in patients who 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, such as patients treated for blood clots in the lung (pulmonary embolism). Contaminated heparin may also be found in association with some medical devices, such as heparin lock flushes, oxygenators, and certain catheters. Some of these devices have been recalled due to the contaminant. For additional information about potentially contaminated medical devices and recalls, please refer to the Center for Devices and Radiological Health Questions and Answers.
5. When did FDA learn about the adverse events? (answer revised 6/18/2008)
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 associated with these lots. The first limited recall was initiated on January 17, 2008.
6. What other companies make heparin for the US market? Is FDA sure that these product(s) do not have the same risk? (question and answer revised 6/18/2008)
On February 28, 2008, Baxter recalled its heparin sodium injection single-dose vials, the remainder of its multiple-dose vials, and the heparin flush products from the market. APP Pharmaceuticals, a heparin manufacturer and supplier of heparin sodium injection, shared the majority of the US market with Baxter. When Baxter recalled on February 28th, APP Pharmaceuticals was able to increase its production capacity and take over as the major supplier of the US market. 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. Baxter continues to produce large volume bags of heparin for injection; the heparin is obtained from a different source than the source used for the recalled products.
Prior to APP Pharmaceuticals becoming the major supplier of heparin sodium to the US market, its heparin active pharmaceutical ingredient (API) was screened to ensure that it did not contain the identified contaminant using the test methods posted on FDA’s website. The major heparin suppliers to the US market have committed to test their heparin API prior to use and to only use non-contaminated API for products to the US market.
7. Is APP Pharmaceuticals able to provide enough heparin for injection to avoid a shortage? (revised answer 6/18/2008)
At this time, the supply of heparin sodium for injection appears sufficient to meet medical need within the US market. FDA continues to work with manufacturers to monitor production and supplies.
8. What has FDA announced about heparin since Baxter’s recalls? (answer revised 7/3/2008)
After launching a disciplined, methodical examination, FDA scientists have identified a previously unknown contaminant in heparin active pharmaceutical ingredient (API) from China. The contaminant is oversulfated chondroitin sulfate. The contaminant activates enzymes that can generate inflammatory mediators (N Engl J Med 358;23 June 5, 2008 p2457). These mediators (chemicals that are released by immune cells) can lead to many of the observed symptoms such as low blood pressure, abdominal symptoms and shortness of breath. This provides additional support to the association of the adverse events with oversulfated chondroitin sulfate. The agency has made available information on two tests that FDA scientists have conducted to detect the contaminant in heparin and recommend their use to manufacturers and suppliers for screening the heparin API.
9. What is an Active Pharmaceutical Ingredient or API? (new question and answer added 6/18/2008)
An API or active pharmaceutical ingredient is a substance or mixture of substances that, when delivered in a finished drug product, directly affects the structure or function of the body.
10. What steps has FDA taken? (answer revised 6/18/2008)
Along with overseeing the recall, FDA scientists have
- Provided recommendations to health care professionals about strategies to limit the occurrence or severity of adverse reactions in cases where the use of heparin was medically necessary and Baxter heparin was the only heparin product available to the healthcare provider.
- Launched a far-ranging investigation in the United States and abroad.
- Inspected the domestic manufacturer (New Jersey facility) to assure there were no other contributing factors to the contamination (e.g., whether the heparin could have been contaminated by its packaging).
- Traveled to China to conduct a thorough investigation at the plant that manufactured the heparin active pharmaceutical ingredient purchased by Baxter.
- Notified FDA's key regulatory international partners.
- Worked closely with the manufacturer and experts in academia and private laboratories to carry out a thorough chemical analysis of the suspect products and to identify the contaminant as oversulfated chondroitin sulfate. The agency made available information on two tests that FDA scientists have conducted to detect the heparin-like substance, and recommended their use to manufacturers and suppliers for screening the heparin active pharmaceutical ingredient (API).
- Worked to ensure that a safe and adequate supply of heparin is available to the U.S. market.
- Issued an Import Alert and Sample Assignment to ensure that all heparin products coming into the United States are tested for the contaminant.
- Hosted a successful meeting of international regulators from eleven countries to discuss what to do about the heparin contamination. Representatives of the U.S. and European Pharmacopoeias also attended.
11. What kind of testing did FDA scientists conduct?
After conventional testing did not prove useful in detecting these contaminants, FDA experts developed new test methods for heparin API that use existing state-of-the-art technologies such as nuclear magnetic resonance, capillary electrophoresis, enzymatic kinetics, and bioassay.
12. What products have been tested? What are the results? (question expanded and answer revised 6/18/2008)
FDA scientists tested samples of heparin crude materials, heparin active pharmaceutical ingredients (API), and finished heparin drug products. The sampled heparin API contained 5 percent to 20 percent of a contaminant that mimicked heparin activity so closely that it was not recognized by routine testing of these samples. Sampled heparin crude materials and finished heparin drug products contained amounts of contaminant in this range.
13. What is the contaminant? (new question and answer added 6/18/2008)
Oversulfated chondroitin sulfate (OSCS), a substance that mimics the biological activity of heparin, was identified as the contaminant.
14. Where is the contaminant found? (new question and answer added 6/18/2008)
The contaminant was found in samples of heparin crude materials, heparin active pharmaceutical ingredients (API), and finished heparin drug products.
15. Is oversulfated chondroitin sulfate unsafe by itself or in combination with heparin? (new question and answer added 6/18/2008)
The adverse events were reported in patients who received heparin contaminated with oversulfated chondroitin sulfate. The lab studies suggest that when oversulfated chondroitin sulfate is given alone or in combination to animals, similar adverse events occur (N Engl J Med 358;23 June 5, 2008 p2457) .
16. Have all heparin products used in the U.S. been tested for the contaminant? (new question and answer added 6/18/2008)
The active pharmaceutical ingredient (API) used for products in the U.S. market has been tested for the contaminant. FDA has been working with manufacturers to analyze the heparin API used to manufacture the existing finished products. This testing will assure that no contaminated finished heparin products are available to the U.S. market.
17. How did the contaminant get into the product?
At this point, FDA does not know how the contaminant got into the heparin active pharmaceutical ingredient (API). The agency is continuing to aggressively investigate the situation.
18. Why does the contaminant cause serious adverse events? (new question and answer added 6/18/2008)
The contaminant activates chemicals in the body called enzymes. These enzymes cause the body to make inflammatory mediators (chemicals that are released by immune cells). Inflammatory mediators can lead to some of the symptoms such as low blood pressure, abdominal symptoms and shortness of breath. This mechanism can explain many of the serious adverse events that occurred immediately after patients were given the contaminated heparin.
19. Has all contaminated heparin been removed from the U.S. market? (new question and answer added 6/18/2008)
Since March 10, FDA has been screening and reviewing all imported heparin products. This gives FDA the opportunity to sample and test products that pose a significant risk to U.S. consumers. FDA can ultimately refuse and request the destruction of products that appear to be contaminated based on the testing. In addition, FDA has been working with manufacturers to retrospectively analyze heparin sodium API. These measures have resulted in a number of recalls to remove contaminated heparin products from the U.S. market.
20. I received the Baxter product in the past. Am I still at risk for a serious reaction? (revised answer 6/18/2008)
The serious reactions have generally occurred rapidly; usually within minutes of when heparin was given. However, some patients undergoing cardiac procedures have developed very low blood pressures as late as an hour following the start of the heparin bolus. Other reports have noted adverse events of one kind or another that occurred even later than that. In this case, it is more likely that the adverse events that occurred right away were related to the heparin. So it is unlikely that an adverse event of this type will happen a long time after the heparin was given.
21. Are there any long-term health effects from exposure to the contaminant? (new question and answer added 6/18/2008)
We do not know whether there could be long term health effects of the contaminant, since the contaminant was only recently discovered. The FDA is in the process of having this question investigated.