WASHINGTON, June 12 — Leukotriene inhibitors must include a warning regarding increased risk of neuropsychiatric events including suicide and depression, according to the FDA.

The requirement applies to montelukast (net/20/1/Singulair/”>Singulair), zafirlukast (Accolate), and zileuton (Zyflo and Zyflo CR). All are approved to treat asthma, and montelukast is also approved to treat symptoms of allergic rhinitis and to prevent exercise-induced asthma.

Upon completing a review of the agents in April, the FDA found reports of agitation, aggression, anxiousness, dream abnormalities and hallucinations, depression, insomnia, irritability, restlessness, suicide, suicidal ideation, and tremor associated with use of the drugs.

The FDA based its review on postmarket reports and clinical trial data submitted by the manufacturers of the drugs.

Neuropsychiatric events were not common, but the available data were limited because the trials weren’t designed to look for neuropsychiatric events, the agency said.

Sleep disorders — primarily insomnia — were also reported more frequently with all three products compared with placebo, according to the FDA.

The agency started its review in March 2008 after announcing that montelukast may be associated with suicidality and suicide. (See FDA Investigates Possible Suicide Link With Montelukast (Singulair))

It published an update in January, although the review was still incomplete. (See FDA Updates Review of Leukotriene Antagonist Suicide Risk)

Montelukast manufacturer Merck issued a statement saying that since the drug was approved in 1998, the company has communicated “a range of adverse events reported with postmarketing use of the drug, including the types of neuropsychiatric events addressed in the FDA’s communication.”

“Merck will continue to work with the FDA to revise the prescribing information for [montelukast] in the U.S. to include a precaution related to those events,” the company said.

The FDA said physicians should consider discontinuing the medications if patients develop neuropsychiatric symptoms.

Related Article(s):

• FDA Investigates Possible Suicide Link With Montelukast (Singulair)
• FDA Updates Review of Leukotriene Antagonist Suicide Risk

LITTLE FALLS, N.J., June 12 — Certain pacemakers manufactured by Medtronic have been withdrawn from the market because of wiring problems, the FDA announced.

Of the more than 1.7 million Kappa and Sigma pacemakers implanted worldwide, about 21,300 are included in the recall.

They include devices in the Kappa Series 600/700/900 and Sigma Series 100/200/300 manufactured primarily between November 2000 and November 2002.

Patients can enter the serial number of their device at this Web site to find out whether it is included in the recall.

The FDA explained that the “devices may fail due to a separation of wires that connect the electronic circuit to other pacemaker components, such as the battery.”

In its letter to physicians, Medtronic estimated the failure rates of Kappa and Sigma pacemakers to be 1.1% and 4.8%, respectively.

In rare cases, patients who are pacemaker-dependent may experience serious injury or death resulting from the defect, the FDA said.

WASHINGTON, June 16 — The FDA has warned patients to stop using zinc-containing Zicam intranasal cold remedy products in light of reports of anosmia, the agency announced today.

The agency also issued a warning letter to Scottsdale, Ariz.-based drugmaker Matrixx Initiatives to stop marketing the products, and the company must now seek FDA approval in order to keep them on the market.

“The loss of sense of smell is serious,” Charles E. Lee, M.D., medical officer at the agency’s Center for Drug Evaluation and Research, said during a press teleconference. “[It] . . . is potentially life-threatening and it may be permanent.”

Dr. Lee said anosmia can be dangerous if patients can’t detect gas leaks or smoke from a fire, or can’t tell whether food is spoiled before eating it.

The FDA has received more than 130 reports of anosmia from patients who used zinc-containing nasal products, Dr. Lee said.

“While the number of adverse events may not seem high, we believe they are significant,” he said, explaining that the agency hasn’t seen a corresponding number of anosmia reports with other common cold products.

Also, he said, consumers typically file complaints directly with the manufacturer, not the FDA.

Until 2007, there were no requirements for over-the-counter product manufacturers to provide adverse event reports to the agency.

In the warning letter, the FDA asked Matrixx to hand over more than 800 reports “that we know they have relating to loss of sense of smell associated with these products,” said Deborah M. Autor, director of the office of compliance at the Center for Drug Evaluation and Research.

The FDA first started receiving adverse event reports about the drug in 1999, but the majority came after 2004, Dr. Lee said.

In 2006, the company paid $12 million to settle 340 lawsuits brought by consumers who claimed the zinc nasal gel adversely affected their sense of smell.

While the FDA has asked the company to stop marketing the products, the agency said it will “work with Matrixx to address products on the market,” and will allow the firm to seek FDA approval in the future.

The zinc products are sold as homeopathic remedies, and Autor explained that as part of the FDA’s compliance policy guide, homeopathic drugs can “stay on market without FDA approval in certain circumstances if they are in compliance with labeling and manufacturing requirements.”

In this case, Autor said, Zicam products containing zinc will now need FDA approval.

The agency stressed that the warning pertains only to zinc-bearing, intranasal Zicam products. That includes Zicam Cold Remedy Nasal Gel, Zicam Cold Remedy Nasal Swabs, and Zicam Cold Remedy Swabs Kids Size — the last of which has already been discontinued.

Dr. Lee said there is information from both the historical literature and animal studies that show zinc to be “toxic to nerve receptors within the nose. Damage to those receptors can cause anosmia.”

Autor added that Matrixx has already conducted trials involving a small number of patients with regard to zinc-containing Zicam products, but said there were “not enough patients in those trials to detect adverse events.”