FDA Patient Safety News: Show #59, January 2007

FDA Approves New Treatment for Type 2 Diabetes

FDA has approved the first in a new class of drugs called DPP-4 inhibitors for treating type 2 diabetes. Januvia (sitagliptin phosphate) is made by Merck and Co. Januvia works by blocking the enzyme DPP-4, or dipeptidyl peptidase, which results in an increased release of insulin in response to a rise in blood sugar.

Januvia is approved to treat type 2 diabetes in combination with diet and exercise. The drug can be taken alone, or along with other commonly prescribed oral diabetes medications. The most common side-effects during clinical studies were URIs, nose and throat soreness and headache.

Additional Information:

FDA Press Release. FDA Approves New Treatment for Diabetes - First in a New Class of Diabetes Drugs. October 17, 2006.

Cardiovascular Risk with Erythropoietic Agents

FDA is warning health care professionals that patients treated with erythropoietic agents may have an increased risk of cardiovascular complications if the dosing recommendations in the labeling are exceeded. These agents are used to stimulate the production of red blood cells in patients with severe anemia, and they are sold under the brand names Procrit, Epogen and Aranesp.

FDA's advisory follows a recent study in the New England Journal of Medicine. In this study, anemic patients with chronic kidney disease were randomized to be dosed with Procrit to either a higher average target hemoglobin level (13.5 g/dL) or a lower level (11.3 g/dL). The patients being treated to the higher level experienced more cardiovascular complications than those being treated to the lower level. These complications included myocardial infarction, hospitalization for congestive heart failure, stroke and death.

The labeling for Procrit, Epogen and Aranesp already recommends treating patients to achieve blood hemoglobin levels no higher than 12 g/dL. To reduce the risk of serious complications with these drugs, FDA's advisory says to be sure to follow the labeling recommendations, and maintain a hemoglobin range between 10 and 12 g/dL.

In addition, after adjusting the dose of one of these agents, FDA recommends measuring the patient's hemoglobin twice a week for 2 to 6 weeks to ensure that hemoglobin levels have stabilized. Decrease the dose if the hemoglobin increase exceeds 1g/dL in any 2 week period.

FDA also suggests talking to your patients about the importance of keeping appointments for simple blood tests to monitor hemoglobin levels. Advise them to call if they experience increased shortness of breath, pain, leg swelling or blood pressure while they're on the drug.

Additional Information:

FDA MedWatch Safety Alert. Erythropoiesis Stimulating AgentsProcrit, Epogen, and Aranesp. November 17, 2006

Caution on Neuropsychiatric Events with Tamiflu

Roche Laboratories has alerted healthcare professionals about neuropsychiatric events that have occurred in influenza patients taking Tamiflu (oseltamivir phosphate). Tamiflu is used to treat or prevent the flu in patients 1 year and older.

The company's letter says that there have been reports of self-injury and delirium in flu patients who were taking Tamiflu. Most of these events occurred in Japan, and the majority were in children. The possible role of the drug in contributing to these events isn't known. However, the labeling for Tamiflu now says that people with the flu, particularly children, may be at increased risk of self-injury and confusion shortly after taking Tamiflu, and so they should be closely monitored for signs of unusual behavior throughout the treatment period. Caregivers or patients should be told to contact a healthcare professional immediately if a patient taking Tamiflu shows any signs of unusual behavior.

The company's letter also alerts practitioners to the potential interaction between Tamiflu and FluMist, the intranasal flu vaccine. It notes that if they are given together, Tamiflu may inhibit the desired replication of the live virus in the intranasal vaccine. Because of this, FluMist should not be administered within two weeks before, or 48 hours after administering Tamiflu. This potential interaction is not a problem with the injectable trivalent flu vaccine.

Additional Information:

FDA MedWatch Safety Alert. Tamiflu (oseltamivir phosphate). November 13, 2006.

Fatal Overdoses with Effexor

Wyeth is alerting healthcare professionals about the risk of fatal overdoses occurring in patients taking Effexor and Effexor XR. Effexor (venlafaxine HCl) is an SNRI used to treat major depressive disorder.

Wyeth's letter says that patients who overdose on Effexor may have a higher risk of death than patients who overdose on SSRIs, but a lower risk of death than those who overdose with tricyclic antidepressants. It is not clear whether this is due to the toxicity of Effexor in overdose or the characteristics of patients who are treated with this drug.

The company points out that the reported overdoses usually occurred in combination with alcohol or other drugs. Several of the most common events associated with overdose include:

• Tachycardia
• Changes in level of consciousness
• Seizures
• Mydriasis
• Vomiting

Other events reported in patients who overdosed included rhabdomyolysis, liver necrosis, serotonin syndrome and death.

To reduce the risk of overdose, the company says that healthcare professionals should prescribe Effexor and Effexor XR in the smallest quantity that is consistent with good patient management.

Additional Information:

FDA MedWatch Safety Alert. Effexor XR (venlafaxine HCl) and Effexor (venlafaxine HCl) Tablets

Change in iPledge Program for Isotretinoin

The iPledge program is a risk management program to reduce the possibility of fetal exposure to the acne drug isotretinoin, which can cause serious birth defects if taken during pregnancy. Isotretinoin is sold under the brand names Accutane, Amnesteen, Claravis and Sotret.

Briefly, iPledge requires registration of wholesalers, prescribers, pharmacies and patients, both women and men. The program also requires that women capable of becoming pregnant have two negative pregnancy tests before the drug can be prescribed for them, and a negative pregnancy test each month while taking the drug.

A recent change to the program will make it easier for certain patients to get isotretinoin without compromising protection of the fetus. Until now, all patients prescribed isotretinoin had to fill their prescription within seven days of their office visit. If a patient missed this seven day window, the prescription could not be filled for another 23 days, in order to prevent possible exposure of a newly formed embryo. Under the new change, this “lockout period” is eliminated for male patients and for females of non-childbearing potential. The change does not affect women of childbearing potential.

Additional Information:

FDA MedWatch Safety Alert. Isotretinoin - Accutane and generic isotretinoin. October 6, 2006.

Warning on Avastin and Brain-Capillary Leaks

Genentech is alerting healthcare professionals about two new safety issues for Avastin or bevacizumab, a drug used to treat certain colorectal and lung cancers.

The first is a rare brain-capillary leak problem called reversible posterior
leukoencephalopathy syndrome (RPLS). RPLS is a neurological disorder associated with hypertension, fluid retention and the cytotoxic effects of immunosuppressive drugs on the vascular endothelium. The onset of symptoms can occur from 16 hours to 1 year after starting Avastin treatment. These symptoms can include headache, seizures, visual disturbances and altered mental function with or without hypertension.

An MRI is needed to establish a diagnosis of RPLS. The company says that if your patient develops RPLS, you should stop Avastin therapy and start treating the hypertension, if present. Symptoms of RPLS usually resolve or improve within days, although some patients continue to have ongoing neurological sequela. It is not known whether it is safe to restart Avastin therapy in patients who have already experienced RPLS.

The second safety issue concerns patients on Avastin who have experienced perforation of the nasal septum. Seven cases of this adverse event have been reported since the drug was marketed.

Additional Information:

FDA MedWatch Safety Alert. Avastin (bevacizumab). September 29, 2006.

Preventing Dosage Errors with Diastat AcuDial

The Institute for Safe Medication Practices recently warned about potentially fatal dosing errors when using Diastat AcuDial. Diastat (diazepam rectal gel) is used to treat epileptic seizures, and it has been available for the past year or so in the AcuDial form. Each AcuDial package contains two pre-filled rectal syringes.

The prescribed patient dose must be dialed on the syringe and locked in place by the pharmacist prior to dispensing. ISMP notes that a number of errors have been reported because the device wasn't properly dialed and locked. In one case a young boy was prescribed a low dose of Diastat AcuDial. The pharmacy dispensed an unlocked 10 mg rectal syringe, and the parents administered the entire contents to the child. He developed respiratory depression and required emergency treatment.

One way to help prevent situations like this is to educate patients and caregivers about how to use the device. They should know the prescribed dose, confirm that it shows in the display window, and check that green “ready” band is visible.

But the most important safeguard is for the pharmacist to be sure that the prescribed dose has been dialed and locked for both syringes in the pack before dispensing. Here's how to do that:

• First, remove a Diastat syringe from the case, holding the barrel vertically so that the cap is facing downward. Be sure not to remove the cap.

• Second, grasp the cap firmly with your other hand and turn it to adjust the dose.

• Third, confirm that the correct dose shows in the window on the syringe.

• And fourth, lock the dose by grasping the locking ring and pushing it upward to lock both sides of the ring. The green “ready” band is now exposed, showing that the dose has been locked.

Be sure to repeat this procedure for the second syringe in the pack before dispensing.

Additional Information:

ISMP Medication Safety Alert! Diastat AcuDial: Dial, set, and lock the dose. September 7, 2006.

What Women Need to Know about Silicone Gel-Filled Breast Implants

Patients may be asking about FDA's recent decision to approve the marketing of certain silicone gel-filled breast implants. They may want to know more about the safety of these devices, and they may need guidance in deciding whether or not to have them.

The approved implants are made by two companies, Allergan and Mentor. They're approved for breast reconstruction in women of all ages, and for breast augmentation in women 22 and older.

Although certain saline-filled breast implants have been available for a number of years, silicone gel-filled implants have not been available for widespread use for a long time. In fact, FDA turned down several applications to market silicone gel filled implants in the past.

However, now there is enough information about benefits and risks so that a woman can make an informed decision about whether to have the implants and what to expect if she gets them. To ensure that women get the information they need, physicians are expected to give women who are thinking about having the implants a patient brochure. The brochure lays out in some detail the benefits and complications that can occur -- complications like hardening of the tissue around the implant, breast pain, and changes in nipple sensation. One of the most important things the brochure stresses is that these implants are not lifetime devices. A woman who receives the implants will probably need additional breast surgery at least once. The brochure also informs women that the implant can rupture without causing symptoms (a “silent” rupture), and that she will need periodic MRI exams to detect these ruptures.

FDA is requiring that the companies continue to study the safety of the implants for about 10 more years after they are marketed. Each company will study about 40,000 women, and this can give more information about possible rare adverse effects.

A report by the Institute of Medicine several years ago concluded that there was no convincing scientific evidence that women with the implants are at greater risk for systemic problems like increased risk of neurological disorders, connective tissue diseases and cancer, and other studies have borne that out. But this question will continue to be addressed in the long-term studies that will be conducted by the companies.

Additional Information:

FDA Breast Implant Web Page.

FDA Patient Safety News is available at www.fda.gov/psn