FDA Patient Safety News: Show #78, August 2008

Warning Added to Regranex Label

A boxed warning alerting healthcare professionals to an increased risk of cancer death has been added to the labeling for Regranex (becaplermin), a topical medication used to treat certain diabetic foot and leg ulcers.

Based on a review of an earlier epidemiologic study, FDA has concluded that patients who use three or more tubes of Regranex experience a five-fold increase in the risk of cancer death compared to patients who do not use the drug. The duration of the study was not long enough to establish whether there is also an increased risk of new cancers.

In March 2008, FDA announced that it had received the epidemiologic study, described what the overall study findings were, and promised to analyze the study and communicate its findings to the healthcare community. The new boxed warning in the labeling is the result of that analysis.

Foot ulcers are a serious problem among diabetics, and yet there are few treatment options. FDA says that Regranex can be effective when it is used along with good ulcer care practices, such as controlling infection, removing dead tissue and relieving pressure. However, the boxed warning says that Regranex should only be used when the benefits are expected to outweigh the risks, and that it should be used with caution in patients with known malignancies.

Additional Information:

FDA MedWatch Safety Alert. Regranex (becaplermin) Gel. June 6, 2008.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm094968.htm


Cellcept and Myfortic Linked to Birth Defects and Fetal Loss

FDA is advising healthcare professionals about an increased risk of fetal harm when women become pregnant while being treated with the immunosuppressant drugs Cellcept (mycophenolate mofetil) or Myfortic (mycophenolic acid).

Myfortic is approved to prevent kidney transplant rejection. CellCept is approved to prevent heart, liver and kidney transplant rejection. These drugs are also sometimes used to treat immune-mediated conditions such as lupus and erythema multiforme, which are not approved indications.

Taking CellCept and Myfortic during pregnancy increases the risk of spontaneous abortion during the first trimester, and can cause serious congenital malformations, especially external ear and facial abnormalities, including cleft lip and palate. Anomalies of the distal limbs, heart, esophagus, and kidney have also been reported.

Before prescribing these drugs to women of childbearing potential, clinicians should inform them about these risks. They should be counseled about their contraceptive options and must use two effective forms of birth control. In addition, before being started on Cellcept or Myfortic, a woman should have a negative serum or urine pregnancy test within one week before taking the drug.

Warnings about the potential for fetal harm have been added to the labeling for Cellcept and Myfortic. FDA is continuing to work with the manufacturers of these drugs to find ways to further reduce the risks of fetal exposure.

Additional Information:

FDA MedWatch Safety Alert. Mycophenolate Mofetil [MMF] (marketed as CellCept) Mycophenolic Acid [MPA] (marketed as Myfortic) Inosine Monophosphate Dehydrogenase Inhibitors (IMPDH) Immunosuppressants. May 16, 2008.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm092745.htm


Possible Association between TNF Blockers and Cancer

FDA has informed healthcare professionals that it is investigating a possible association between drugs that block tumor necrosis factor (TNF) and the development of lymphoma and other cancers in children and young adults.

This is part of FDA's commitment to inform healthcare professionals and the public about its ongoing drug safety reviews. Because this information is preliminary and there is scientific uncertainty, FDA is not taking regulatory action at this point, nor advising healthcare professionals to stop using the drugs.

The TNF blockers in question, Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab) and Cimzia (certolizumab pegol), are used to treat juvenile idiopathic arthritis, Crohn's disease, and other inflammatory conditions. The labeling for these drugs already warns about a possible risk of cancer.

Over the past ten years, FDA has received about 30 reports of cancer in patients who were treated with TNF blockers when they were under 18 years old. These patients also took other immunosuppressive agents, such as methotrexate and azathioprine. Although these reports are cause for concern, in and of themselves they do not establish that TNF blockers increase the risk of cancer above background levels.

FDA is investigating all the available evidence about a possible link between TNF blockers and cancer, and is consulting with experts in this area to determine whether there are children with juvenile idiopathic arthritis and Crohn's disease who may be at special risk of developing cancer if they take the drugs. This evaluation will take about six months, after which FDA will let health professionals and the public know about its conclusions.

In the meantime, health care professionals, parents and caregivers should be aware of the possible cancer risk in deciding the best way to treat these patients. FDA also encourages both healthcare professionals and patients to report side effects from the use of Remicade, Enbrel, Humira, and Cimzia, to the FDA's MedWatch adverse event reporting program.

Again, this is preliminary information and it is part of FDA's effort to keep the public informed about its ongoing drug safety reviews.

Additional Information:

FDA MedWatch Safety Alert. Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia). June 3, 2008.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm105999.htm


Danger Giving Topical Thrombin Intravascularly

The Institute for Safe Medication Practices (ISMP) recently warned about the dangers of accidentally giving topical thrombin intravascularly. Thrombin applied topically can help stop oozing blood and minor bleeding from capillaries and small veins. Some thrombin products are produced as a frozen solution. Others come as a powder to be reconstituted, sometimes packaged with a parenteral syringe to help prepare and withdraw the product.

Because of its clotting action, topical thrombin should only be applied to the surface of bleeding tissue. It should never be injected systemically, because that can lead to extensive intravascular clotting and death. ISMP points out that topical thrombin has been mistaken for parenteral medication and administered intravascularly, despite labeling on the thrombin vials that warns against injecting the product. The confusion may arise because the vial-and-syringe packaging of some topical thrombin products makes them look like parenterals.

ISMP describes several events where this kind of dangerous mix-up occurred. In one case, during cardiac surgery, a labeled syringe containing topical thrombin was placed in the warming pitcher along with heparinized saline syringes of similar volume. The topical thrombin was accidentally given intravenously instead of the heparin. The patient survived but required additional monitoring and an extended hospital stay.

And in another example, a hospitalized patient was accidentally given topical thrombin 5,000 units intravenously. Soon afterward, the patient developed cardiopulmonary arrest and could not be resuscitated.

ISMP lists a number of ways to reduce the risk of these kinds of accidents. Here are some of them:

• Have the pharmacy prepare, label, and dispense the drug whenever possible, including doses used in the OR.

• Never leave a topical thrombin vial or syringe at the patient's bedside because it may be confused as a parenteral product.

• Add auxiliary warning labels to syringes containing topical thrombin. ISMP recommends repeating the warning that appears on the cartons and vials: "For topical use only - do not inject".

• If appropriate for the type of surgery, consider using solutions of topical thrombin that can be used with an absorbable gelatin sponge. It may also be helpful to apply a dry form of topical thrombin on oozing surfaces.

• Consider using spray kits, which are available for some topical thrombin products. The spray mechanism can help differentiate the topical thrombin from parenteral products. But never leave reconstituted topical thrombin in an unlabeled syringe before you attach the spray mechanism.

Additional Information:

ISMP Medication Safety Alert. Nurse Advise-ERR. Danger of Giving Topical Thrombin Intravascularly. March 2008. Volume 6, Issue 3, Pages 1-2.
http://www.ismp.org/newsletters/nursing/articles/2008_03-1.asp


Danger Giving Topical Thrombin Intravascularly

The Institute for Safe Medication Practices (ISMP) recently warned about the dangers of accidentally giving topical thrombin intravascularly. Thrombin applied topically can help stop oozing blood and minor bleeding from capillaries and small veins. Some thrombin products are produced as a frozen solution. Others come as a powder to be reconstituted, sometimes packaged with a parenteral syringe to help prepare and withdraw the product.

Because of its clotting action, topical thrombin should only be applied to the surface of bleeding tissue. It should never be injected systemically, because that can lead to extensive intravascular clotting and death. ISMP points out that topical thrombin has been mistaken for parenteral medication and administered intravascularly, despite labeling on the thrombin vials that warns against injecting the product. The confusion may arise because the vial-and-syringe packaging of some topical thrombin products makes them look like parenterals.

ISMP describes several events where this kind of dangerous mix-up occurred. In one case, during cardiac surgery, a labeled syringe containing topical thrombin was placed in the warming pitcher along with heparinized saline syringes of similar volume. The topical thrombin was accidentally given intravenously instead of the heparin. The patient survived but required additional monitoring and an extended hospital stay.

And in another example, a hospitalized patient was accidentally given topical thrombin 5,000 units intravenously. Soon afterward, the patient developed cardiopulmonary arrest and could not be resuscitated.

ISMP lists a number of ways to reduce the risk of these kinds of accidents. Here are some of them:

• Have the pharmacy prepare, label, and dispense the drug whenever possible, including doses used in the OR.

• Never leave a topical thrombin vial or syringe at the patient's bedside because it may be confused as a parenteral product.

• Add auxiliary warning labels to syringes containing topical thrombin. ISMP recommends repeating the warning that appears on the cartons and vials: "For topical use only - do not inject".

• If appropriate for the type of surgery, consider using solutions of topical thrombin that can be used with an absorbable gelatin sponge. It may also be helpful to apply a dry form of topical thrombin on oozing surfaces.

• Consider using spray kits, which are available for some topical thrombin products. The spray mechanism can help differentiate the topical thrombin from parenteral products. But never leave reconstituted topical thrombin in an unlabeled syringe before you attach the spray mechanism.

Additional Information:

ISMP Medication Safety Alert! Danger of Giving Topical Thrombin Intravascularly. February 8, 2007. Volume 12, Issue 3.
http://www.ismp.org/Newsletters/acutecare/archives/NL_20070208.pdf


Potential Problems with Insulin Pens in Hospitals

In a recent article, the Institute for Safe Medication Practices (ISMP) highlighted several potential safety problems when hospitals switch from multiple dose vials of insulin to insulin pens.

ISMP points out that there are certain safety advantages in using the pens. For example, the pens may reduce the chance of drug mix-ups, since each pen is pre-labeled with product name and strength, and the patient's name can be on the label as well. But ISMP also notes a number of potential safety problems to watch out for when hospitals switch to pens.

One possible problem is needlestick injuries, which could happen because the pen may make it difficult to see the injection site. Also, some needles do not have needle guards, so a needlestick can occur after the injection.

Another difficulty is that part of the insulin in the pen may not be delivered. This can happen because the buttons on some pens are difficult to push down, making it easy to accidentally lift the needle out of the skin during the injection. There can also be leakage around the injection site if the needle is not left in place for at least six seconds after the injection. In addition, uneven dosing of an insulin suspension can occur if the user fails to tip and roll the pen before the injection, causing the suspension to clump.

Sometimes nurses unfamiliar with a particular type of pen will use it as a multiple-dose vial, withdrawing insulin from the pen cartridge with a sterile needle and a conventional insulin syringe. This is not recommended, because aspirating insulin from the cartridge can leave air pockets. When the cartridge is used again, these air pockets can cause dosing errors or air injection.

Another problem is using the same pen for multiple patients, which is potentially hazardous. Attaching a new sterile needle to the pen before using it on another patient cannot solve the problem. That's because the insulin inside the pen's cartridge can become contaminated with biological material after the first injection, while the original needle is still on the pen.

Finally, the design of some pens can lead to dosing errors. For example, in some cases the digital display of the dose can be mis-read if a person holds the pen upside down, as a left-hander might do. In that case, a dose of 21 units looks like 12.

How can these problems be avoided? ISMP says that the key is to prepare for the transition to pens. That means understanding and anticipating the risks beforehand, doing a failure mode and effects analysis, educating the staff about using the pens properly, and closely monitoring their use for the first few months of the transition. ISMP recommends that written guidelines be developed for each type of pen used in the hospital, with specific instructions on handling the pens safely, injection techniques, and prohibitions on sharing pens or using them as multiple dose vials.

Additional Information:

ISMP Medication Safety Alert. Considering Insulin Pens for Routine Hospital Use? Consider This…Volume 13, Issue 9. May 8, 2008.
http://www.ismp.org/Newsletters/acutecare/articles/20080508.asp


Nonoxynol 9 Contraceptives: No Protection against HIV and Other STDs

The Food and Drug Administration wants to be sure that consumers know about new warnings on over-the-counter vaginal contraceptive products that contain the spermicide ingredient nonoxynol 9 (N9). These products include spermicidal gels, foams, films and inserts.

These warnings emphasize that nonoxynol 9 does not protect against infection from HIV, the virus that causes AIDS, or other sexually transmitted diseases. The warnings are intended to correct a mistaken impression that nonoxynol 9 protects against STD infection, including HIV/AIDS. In fact, using it may actually increase the risk of contracting HIV/AIDS from an infected partner, because nonoxynol 9 can irritate the vagina and rectum.

The new labeling makes several other points:

• Nonoxynol 9 contraceptive products are for vaginal use only, not rectal use. If you or your partner experience burning, itching, a rash or irritation of the vagina or penis, stop using it and talk to your doctor.

• You can use nonoxynol 9 for birth control if you are not at risk for getting HIV/AIDS i.e., you have sex with only one partner who is not infected with HIV and who has no other sexual partners or HIV risk factors.

• Don't use nonoxynol 9 spermicides if you or your partner have HIV/AIDS, or if you don't know whether you or your partner are infected, or if either of you has multiple sex partners or other HIV risk factors. Instead, use a condom that doesn't contain nonoxynol 9. Remember, when used correctly every time you have sex, latex condoms can greatly reduce, but don't eliminate the risk of catching or spreading HIV.

• And finally, talk to your doctor, pharmacist or other health care provider if you have questions about your options for birth control or about how to prevent infection with sexually transmitted diseases.

Additional Information:

FDA MedWatch Safety Alert. Nonoxynol 9 (N9) OTC Contraceptive Products. December 18, 2007.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm152690.htm



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