Baxter's Multiple-Dose Vial Heparin Linked to Severe Allergic Reactions
FDA advises health care practitioners to switch suppliers and
limit use of drug until problem identified
ROCKVILLE, Md., Feb. 11, 2008--The U.S. Food and Drug Administration announced today that Baxter Healthcare Corporation has temporarily stopped manufacturing multiple-dose vials of the injectable blood-thinning drug heparin due to reports of serious allergic reactions and hypotension (low blood pressure) in patients who receive high "bolus" doses of the drug.
Serious reactions to the drug have included difficulty breathing, nausea, vomiting, excessive sweating, and rapidly falling blood pressure that can lead to life-threatening shock. Four people have died after receiving heparin, although the relationship to the drug is unclear.
Heparin sodium is derived from pig intestines and has been marketed in the United States since the 1930s. Millions of patients benefit from the intravenous administration of this drug every year to avoid potentially life-threatening blood clots in the veins, arteries, and lungs.
"FDA concurs with Baxter's decision to halt manufacture of heparin sodium in multiple-dose vials," said Janet Woodcock, M.D., FDA's deputy commissioner for scientific and medical programs, chief medical officer, and acting director of its Center for Drug Evaluation and Research. "FDA is vigorously investigating to determine the root cause of these serious reactions associated with the use of heparin made by Baxter. In the meantime, patients and health care professionals who cannot obtain alternative sources of heparin should use caution in administering any Baxter multiple-dose vials that remain."
Heparin is commonly used before certain types of surgery, including coronary artery bypass graft surgery, and in kidney patients before they undergo dialysis. In some situations, heparin treatment is initiated using a high bolus dose given directly into the bloodstream (intravenously) over a short period of time, usually less than one hour. The reported adverse events occurred in patients who were given heparin in this form of administration. There are many other uses of heparin involving lower doses or administration over a longer period of time; adverse events have not been seen with those uses.
About 350 adverse events associated with the Baxter product have been reported since the end of last year compared to less than 100 reports in 2007. Most of the events have taken place at hemodialysis centers, almost exclusively involving patients receiving a bolus dose – which is a high dose administered over a short time. While most of the reports involve multiple-dose vials, several cases include patients who received a bolus dose after their health care professional combined heparin from single-dose vials.
The Missouri Department of Health and Senior Services first notified the Centers for Disease Control and Prevention (CDC) in January of several severe allergic-type reactions to heparin that occurred at a single pediatric hospital beginning in November. The CDC in turn alerted FDA and Baxter, prompting the company's voluntary recall of nine lots of heparin on Jan. 17.
Since then, FDA has learned of adverse events that extend beyond the recalled lots and involve patients receiving heparin for other purposes besides hemodialysis. Recent cases have included patients undergoing cardiac surgery and a specialized blood cell treatment known as photopheresis.
Over one million multiple-dose vials of heparin are sold per month in the United States; half of the vials are manufactured by Baxter of Deerfield, Ill. FDA is currently investigating whether similar events have been seen with other heparin manufacturers.
Physicians, dialysis center staff and health care providers are advised to use an alternate source of heparin or another blood-thinning drug when possible. When only Baxter product is available:
Administer the heparin as an infusion (not a bolus) whenever
Use the lowest dose necessary at the slowest infusion rate acceptable to obtain the desired clinical effect.
Closely monitor the patient for adverse events, particularly hypotension and signs and symptoms of hypersensitivity and ensure that resuscitation equipment is available.
Consider pretreatment with corticosteroids (cortisone type medicines) or antihistamines (drugs that relieve the symptoms of allergic reactions) although it is not known if such pretreatment is effective.
Any allergic-type reaction to heparin infusion should be reported to FDA's MedWatch Program by phone at 800-FDA-1088, by fax at 800-FDA-0178, by mail at MedWatch, HF-2, FDA, 5600 Fishers Lane, Rockville, M.D. 20852-9787, or on the MedWatch Web site at www.fda.gov/medwatch.
Karen Riley, 301-827-6244
The Food and Drug Administration is issuing this alert to:
- inform the public about reports of serious adverse events in patients who received bolus injections of heparin sodium for injection primarily from multiple-dose vials manufactured by Baxter Healthcare Corporation, and to
- recommend measures that may help to minimize these risks if this product must be used due to medical necessity.
Heparin sodium is an anticoagulant (blood thinner) that is commonly administered intravenously. It is used in patients undergoing kidney dialysis, certain types of cardiac surgery, and treatment or prevention of other serious medical conditions, including deep venous thrombosis (DVT) and pulmonary emboli. In many settings heparin treatment is initiated using high doses (5000-50,000 units) given directly into the blood stream (intravenously) as a bolus (over a short period of time, usually a few minutes). Serious adverse events have recently been reported in patients who received these higher bolus doses. The serious adverse events include allergic or hypersensitivity-type reactions, with symptoms of oral swelling, nausea, vomiting, sweating, shortness of breath, and cases of severe hypotension requiring treatment. Most events developed within minutes of heparin initiation although the possibility for a delayed response has not been excluded.. The reports have largely involved use of multiple-dose vials. However there have been several cases in which product from multiple, single-dose vials have been combined to administer a bolus dose.
Heparin is also used in other clinical settings at lower doses or over longer periods of time; adverse events like those described above have not been seen with those uses. FDA is currently investigating whether similar adverse events have been reported for heparin products from other manufacturers.
Because of concern about the occurrence of these serious adverse events, Baxter has temporarily suspended manufacture of its multiple-dose vials of heparin sodium pending the completion of an extensive ongoing investigation to determine the root cause of the problem. Heparin is a medically necessary product and serious public health consequences would result if there were a sudden shortage of the drug. Therefore, Baxter and FDA agree that multiple-dose vials of heparin manufactured by Baxter that are currently in distribution will not be recalled. These vials may be used with caution in situations where alternative products are either not available or would be inappropriate for the individual medical situation.
FDA is providing the following recommendations to physicians, dialysis center staff, and other health care providers when using heparin sodium for injection.
- When bolus use is required, try to use a heparin product from another manufacturer or an alternate anticoagulant
- When Baxter product is the only heparin product available and
use of heparin is considered to be medically necessary:
- Administer infusions without using a bolus dose whenever possible
- Use the lowest dose necessary at the slowest infusion rate acceptable to obtain the desired effect
- Closely monitor the patient for adverse events, particularly hypotension and signs and symptoms of hypersensitivity, and ensure that resuscitation equipment is available.
- Consider the potential risks and benefits in individual patients of pretreatment with corticosteroids or antihistamines before the heparin is administered. At this time FDA does not have data to determine if such pretreatment is effective.
Heparin sodium is a pork-derived product that has been marketed in the United States for nearly 70 years. It is estimated that over 1 million multiple-dose vials of heparin are sold per month in the U.S., about half of which are manufactured and distributed by Baxter Since late December 2007 Baxter and FDA have received nearly 350 reports of adverse reactions, and about 40% of the cases are estimated as serious, based upon preliminary and ongoing review. The number of reports seen in the past two months is a marked increase from the number of reports associated with heparin use normally received in a similar time period.
The majority of reported events occurred at hemodialysis centers. In early January, 2008, clusters of these allergic adverse event reports came to the attention of the CDC and to Baxter. Available data at that time suggested a link of these cases to product from specific heparin manufacturing lots. This resulted in Baxter recalling 9 product lots on January 17, 2008. FDA initiated inspections of Baxter’s U.S. manufacturing plant and processes the same day.
Since the January product recall, new reports indicate that adverse events are not limited to only the recalled heparin lots. Baxter and FDA have learned of cases occurring in hospitals where heparin was used during cardiac surgery and in patients undergoing photopheresis. Like the events associated with dialysis, most have resolved with medical management. Four patients have died since these adverse events were noted; the relationship between the deaths and the heparin use is not certain.
The underlying cause for the abrupt increase in the number of adverse events reported for Baxter’s heparin sodium is under investigation. FDA inspectors and scientists are working independently and in collaboration with the Centers for Disease Control and Baxter to discover the underlying cause of the adverse events. FDA personnel and laboratories are conducting intensive inspection and testing related to Baxter’s heparin sodium. FDA is also seeking advice from outside experts in the manufacture and clinical use of heparin in order to help guide our investigation.
FDA continues to monitor its post-marketing safety database for additional cases and has initiated contact with international regulators to determine whether similar events have been seen in other countries with similar products. Health care providers should report any allergic-type reaction to heparin infusion to FDA’s MedWatch on line at http://www.fda.gov/medwatch/report/hcp.htm , 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.
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.
Posted: February 2008