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The FDA approved Injectafer (ferric carboxymaltose) in July 2013 for the treatment of iron deficiency anemia in adult patients. The product is injected directly into the bloodstream, where it can quickly replenish iron levels and relieve symptoms. Injectable iron supplements are preferred to oral pills in some cases, such as when patients can’t tolerate iron pills, or when they have lost a lot of blood.

Several recent studies, however, have indicated that Injectafer, more than other injectable forms of iron, can increase the risk of severe hypophosphatemia (HPP), a condition in which a patient is dangerously low on phosphate. Symptoms can include muscle wasting, seizures, respiratory failure, coma, and fatal arrhythmias.

Despite the evidence, Injectafer manufacturer Luitpold Pharmaceuticals, a wholly owned subsidiary of Daiichi Sankyo, has not updated the product label to warn doctors and patients about this risk.

FDA Withholds Injectafer Approval Because of Side Effects

The company first submitted a new drug application to the FDA in May 2007. They noted then that they had studied the treatment in patients with heavy uterine bleeding and with inflammatory bowel disease, comparing it to oral iron supplements.

They believed the treatment would work well in these patients, because those with heavy bleeding usually need to replenish iron stores more quickly than pills will allow, and those with inflammatory bowel diseases typically can’t tolerate oral iron supplements. They stated that the results of their clinical trials had been “favorable.”

In February 2008, the company announced that the FDA had voted that the available safety and efficacy data supported a favorable risk/benefit profile for the treatment of iron deficiency anemia in patients with heavy uterine or postpartum bleeding, but with a restriction—it would be used only in patients who did not respond well to oral iron supplements.

Mary Jane Heleneck, President and CEO, stated that while “we are disappointed that the Advisory Committee didn’t support our proposed indication, we are pleased with their recommendation for approval with a restricted indication.”

But then in March 2008, the company announced that the FDA had decided, ultimately, not to approve Injectafer for women suffering from heavy bleeding. The FDA asked for more safety data from additional clinical studies “to address concerns over safety of Injectafer in this population.”

In the summary review, the FDA noted that they were concerned because the studies on the product

“showed an imbalance of deaths observed in controlled trials. More deaths occurred in ferrous carboxymaltose [Injectafer] treatment arms than in the control subjects.”

In other words, patients taking Injectafer suffered from more adverse events than those taking iron pills, including hypophosphatemia and severe hypophosphatemia.

In the non-approval letter, the FDA told the company that they would need “Clinical data to resolve the safety risks identified (excess mortality and severe hypophosphatemia) and verify the safety of more than one replenishment cycle.”

Company Fails a Second Time to Get FDA Approval for Injectafer

In October 2011, Luitpold Pharmaceuticals tried again. It submitted another new drug application for Injectafer for the treatment of iron deficiency anemia. The new application included data and information from two new large randomized controlled clinical trials that looked at the cardiovascular risks associated with the product. One trial compared Injectafer to another iron supplement in patients with iron deficiency anemia and chronic kidney disease, and the other compared Injectafer to either oral or IV iron in various patients with iron deficiency anemia.

Yet the result was not what they hoped. In July 2012, the company announced that the FDA had decided to “withhold approval at this time,” because during an inspection of one of the company’s manufacturing facilities, the FDA found “issues.” This was the same facility that was to be used to manufacturer Injectafer. The company stated they were “working with” the FDA to resolve the issues.

FDA Finally Approves Injectafer—with Restrictions

Finally, in July 2013, the FDA approved the use of Injectafer in patients with iron deficiency anemia, but with a restriction—it was approved only for those patients who could not tolerate oral iron supplements, who had experienced an unsatisfactory response to these supplements, or who had non-dialysis dependent chronic kidney disease.

Since the product has been on the market, studies have found that Injectafer can increase the risk of HPP and severe HPP more than competitive products.

There is still no warning on Injectafer regarding the risk of severe HPP.

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