New anticoagulants getting expanded approval, but also review

Details on anticoagulant regulation and more.

Recalls and warnings

A market withdrawal of drotrecogin alfa (Xigris) after it failed to show a survival benefit for patients with severe sepsis and septic shock in a large recent study. The drug should not be started in new patients and should be stopped in patients currently being treated.

Photo by Thinkstock
Photo by Thinkstock.

A label change on fenofibric acid (Trilipix) to warn that it may not lower a patient's risk of having a heart attack or stroke, based on data from the ACCORD trial. Physicians should consider and counsel patients about the benefits and risks when deciding whether to prescribe the drug.

A class I recall of some of Carefusion's EnVe ventilators, manufactured between December 2010 and May 2011, due to a potential for delay in resuming ventilation after reconnection, automatic reset and disconnection upon transport.

A class I recall of Mizuho OSI Modular Table Systems, used for patient positioning during surgery procedures, because incorrect removal of the T-pins that support the bottom base, instead of the T-pins that support the top, may result in unexpected movement or tilting of the table and patients falling to the floor.

A recall of Fenwal's 4C2223 blood component infusion set due to a labeling issue in which the package label incorrectly lists 80 micron when the actual filter size is a standard 170-260 micron in size.


A new indication for rivaroxaban (Xarelto) to reduce the risk of stroke in patients who have non-valvular atrial fibrillation. The drug's safety and efficacy were evaluated in a clinical trial with more than 14,000 patients, in which it showed similar ability to warfarin in preventing stroke. Bleeding was the most common adverse event. The risk of major bleeding associated with rivaroxaban was similar to that with warfarin; however, rivaroxaban caused less bleeding into the brain and more bleeding into the stomach and intestines. The drug carries a boxed warning to make clear that patients should not discontinue it before talking with their health care professional. On July 1, 2011, the FDA approved rivaroxaban to reduce the risk of blood clots, deep vein thrombosis, and pulmonary embolism following knee or hip replacement surgery.

The first generic versions of olanzapine tablets (Zyprexa and Zyprexa Zydus [orally disintegrating tablets]) to treat schizophrenia and bipolar disorder. The drug carries a boxed warning alerting that this type of drug can raise the risk of death in elderly people with psychosis or dementia and it must be dispensed with a medication guide that describes the risks and adverse reactions, which include hyperglycemia, increased cholesterol and triglycerides and weight gain.

A new indication for cetuximab (Erbitux) for use with chemotherapy to treat patients with metastatic head and neck cancer. The safety and effectiveness for this indication is based on the results of a multi-center clinical study conducted outside the U.S., which used a non-U.S. approved version of cetuximab. Patients received either the combination of cetuximab with chemotherapy or chemotherapy only, and those receiving cetuximab lived, on average, 10.1 months compared with 7.4 months. The drug is already FDA-approved for certain types of colon cancer, and has been approved since 2006 for treatment of non-metastatic head and neck cancer in combination with radiation therapy (first-line) or as a single agent (following standard treatment).

A new indication for tadalafil (Cialis) to treat the signs and symptoms of benign prostatic hyperplasia (BPH) and for the treatment of BPH and erectile dysfunction (ED), when the conditions occur simultaneously. It was approved in 2003 for the treatment of ED. In two clinical trials, men with BPH who took 5 mg of tadalafil once daily experienced a statistically significant improvement in their symptoms compared to men treated with placebo.

The first generic version of atorvastatin calcium tablets (Lipitor). Ranbaxy Laboratories Ltd. will make generic tablets in 10 mg, 20 mg, 40 mg, and 80 mg strengths.

Zolpidem tartrate sublingual tablets (Intermezzo) to treat insomnia characterized by middle-of-the-night waking followed by difficulty returning to sleep. This is the first time the FDA has approved a drug for this condition and it should only be used when a person has at least four hours of bed time remaining. Intermezzo is a lower-dose form of zolpidem than Ambien. The recommended and maximum dose is 1.75 mg for women and 3.5 mg for men, taken once per night. In trials involving more than 370 patients, patients taking the drug fell back asleep sooner than people on placebo. The most commonly reported adverse reactions were headache, nausea and fatigue.

Ruxolitinib (Jakafi), the first drug approved specifically to treat myelofibrosis. The pill inhibits enzymes involved in regulating blood and immunological functioning. Approval was based on two trials with 528 patients who were resistant or refractory to available therapy or ineligible for allogeneic bone marrow transplantation. More patients receiving ruxolitinib had reductions in spleen size and other myelofibrosis-related symptoms than those receiving placebo or best available therapy. The most serious side effects include thrombocytopenia, anemia, fatigue, diarrhea, dyspnea, headache, dizziness and nausea.

Sapien THV, the first artificial heart valve to treat senile aortic valve stenosis without open-heart surgery. The valve is made of cow tissue and polyester supported with a stainless steel mesh frame and is inserted by catheter through the femoral artery. Approval is based on a study in 365 patients not eligible for open-heart surgery. Patients receiving the valve experienced two and a half times more strokes and eight times as many vascular and bleeding complications than patients receiving other treatments; however, they were more likely to survive one year after surgery. The valve is approved for patients who are not eligible for open-heart surgery for replacement of their aortic valve and have a calcified aortic annulus.

Current investigations

Enhanced safety surveillance is being required on the use of tumor necrosis factor (TNF) blockers in patients under 30, the FDA said. An ongoing safety review by the FDA will analyze malignancies in this patient group. Healthcare professionals should remain vigilant for cases of malignancy in patients treated with TNF blockers and report them to the FDA MedWatch program or to the manufacturer.

The FDA has not yet reached a conclusion, but remains concerned, about the potential increased risk of blood clots with the use of drospirenone-containing birth control pills. Preliminary results of an FDA-funded study suggest an approximately 1.5-fold increase in the risk of blood clots with drospirenone-containing birth control pills compared to other hormonal contraceptives. Given the conflicting nature of the existing research findings on this issue, the FDA has scheduled a joint meeting of the Reproductive Health Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Prescribing clinicians should consider the risks and benefits of drospirenone-containing combination oral contraceptives on an individual patient basis and counsel patients about the current information regarding the risk of VTE. The FDA also noted that studies assessing the risk of blood clots have evaluated only the combination of 3 mg of drospirenone with 0.03 mg of ethinyl estradiol. It is not known whether these study results apply to other drospirenone-containing products with a lower dose of estrogen.

The FDA recently alerted the public to serious bleeding events that have been reported in patients taking dabigatran (Pradaxa). Labeling for the drug has not changed, and the agency continues to believe that dabigatran provides an important health benefit when used as directed. But the agency will be investigating the drug's bleeding risk. In a large clinical trial (18,000 patients) comparing dabigatran and warfarin, major bleeding events occurred at similar rates with the two drugs. However, the FDA is working to determine whether the reports of bleeding are occurring more commonly than would be expected and will communicate any new information on the risk of bleeding when it becomes available.


Varenicline (Chantix) does not appear to be associated with an increase in neuropsychiatric hospitalizations but an increased risk of other neuropsychiatric events cannot be ruled out, a recent FDA review concluded. The FDA is continuing to evaluate the issue but in the meantime the agency has concluded that the drug's benefits outweigh the risks and the current label warnings are appropriate.

Additional information has been provided by the FDA about the risks of prescribing either methylene blue or linezolid to patients taking serotonergic psychiatric medications. The agency had previously warned about reports of serotonin syndrome associated with these drug combinations. The new report notes that most incidents with methylene blue occurred in the context of parathyroid surgery, which involved the intravenous administration of the drug as a visualizing agent in doses ranging from 1 mg/kg to 8 mg/kg. It is not known whether there is a risk of serotonin syndrome in patients taking serotonergic psychiatric medications who are given methylene blue by other routes (e.g., orally or by local tissue injection) or at lower intravenous doses. Most problems with linezolid occurred in patients taking a selective serotonin reuptake inhibitor (SSRI) or a serotonin norepinephrine reuptake inhibitor (SNRI). It is unclear whether linezolid administration in patients receiving other psychiatric drugs with lesser degrees of serotonergic activity poses a comparable risk, the FDA said.

Medications for attention-deficit/hyperactivity disorder (ADHD) were not associated with adverse cardiovascular events in a large, recently-completed study in children and young adults, the FDA said. The medications studied include stimulants (amphetamine products and methylphenidate), atomoxetine, and pemoline (no longer marketed).

Approval has been revoked of the breast cancer indication for bevacizumab (Avastin), because the FDA has concluded that the drug has not been shown to be safe and effective for that use. Bevacizumab will still remain on the market as an approved treatment for certain types of colon, lung, kidney and brain cancer (glioblastoma multiforme).