Drugs Log

Drug maker Amgen Inc. said Friday it expanded black box warnings about risks of death and tumor growth of its blockbuster anemia drugs.

The warnings approved by the Food and Drug Administration state that the company’s drugs increased death and accelerated tumor growth in patients with early stage breast cancer and cervical cancer. Earlier labeling warned of similar risks in other types of cancer.

The changes apply to Thousand Oaks, Calif.-based Amgen’s Aranesp and Epogen, as well as Johnson & Johnson’s Procrit. The drugs treat the blood-disorder anemia in patients with kidney failure and those on chemotherapy. Amgen manufacturers all three, though New Brunswick, N.J.-based J & J sells Procrit.

The language states that the problems occurred when doctors treated patients with elevated levels of the drugs, which increase red blood cell levels.

The action came less than a week before a meeting where government advisers are scheduled to review the risks of the blockbuster medications.

Since FDA began scrutinizing the drugs last March, shares of Amgen have sunk 27 percent. U.S. sales of its anemia treatments fell more than 10 percent to $6.3 billion for the year.

Wall Street analysts expect sales to fall further in 2008 following next week’s review by FDA’s cancer experts. The panel could recommend halting use of the drugs for certain types of cancers, or in all cancer patients. Recommendations will not apply to Amgen’s Epogen, which is used almost exclusively by kidney failure patients on dialysis.

If FDA removes only some cancer indications, Amgen’s anemia drug sales could lose between $150 million to $250 million for 2008, according to estimates by Goldman Sachs’ analyst May-Kin Ho.

FDA twice updated anemia drug labels last year, most recently in November. Amgen disclosed new data in December on the drugs’ risks in early stage breast cancer and cervical cancer patients, sending shares downward nearly 20 percent. The new label incorporates detail from those studies.

Bear Stearns analyst Mark Schoenebaum said the effect of Friday’s changes would be minimal for Amgen, since cervical cancer accounts for about 1 percent of the Aranesp market. He also noted that the previous label already highlighted the breast cancer risks.

But Stanford Group Co. analyst Gregory Frykman said the new warnings could attract tougher regulations from Medicare, the government’s health plan for seniors. Last summer Medicare ruled that it would only pay doctors to administer anemia drugs if they were prescribed at low levels.

Frykman said the new warnings could convince Medicare to scale back its policy again, perhaps only paying for the drugs when used in certain types of cancer.

Wall Street reacted positively to the news, sending shares up 1.02 cents, or 2.3 percent, to $45.20 in after-hours trading. Shares fell 14 cents to close at $44.18 in regular trading.

Reference Material on Anemia

Anemia, condition in which the concentration of hemoglobin in the circulating blood is below normal. Such a condition is caused by a deficient number of erythrocytes (red blood cells), an abnormally low level of hemoglobin in the individual cells, or both these conditions simultaneously. Regardless of the cause, all types of anemia cause similar signs and symptoms because of the blood’s reduced capacity to carry oxygen. These symptoms include pallor of the skin and mucous membranes, weakness, dizziness, easy fatigability, and drowsiness. Severe cases show difficulty in breathing, heart abnormalities, and digestive complaints.

One of the most common anemias, iron-deficiency anemia, is caused by insufficient iron, an element essential for the formation of hemoglobin in the erythrocytes. In most adults (except pregnant women) the cause is chronic blood loss rather than insufficient iron in the diet, and, therefore, the treatment includes locating the source of abnormal bleeding in addition to the administration of iron.

Pernicious anemia causes an increased production of erythrocytes that are structurally abnormal and have attenuated life spans. This condition rarely occurs before age 35 and is inherited, being more prevalent among persons of Scandinavian, Irish, and English extraction. It is caused by the inability of the body to absorb vitamin B12 (which is essential for the maturation of erythrocytes).

There are several conditions that cause the destruction of erythrocytes, thereby producing anemia. Allergic-type reactions to bacterial toxins and various chemical agents, among them sulfonamides and benzene, can cause hemolysis, which requires emergency treatment. In addition, there are unusual situations in which the body produces antibodies against its own erythrocytes; the mechanism triggering such reactions remains obscure.

A year ago:

FDA issues new warnings on widely used anemia drugs

Federal health officials have issued stern new warnings for doctors to more carefully prescribe widely used anemia drugs that can increase the risk of death and other serious problems in patients with cancer and kidney disease.

At issue are drugs sold under the brand names Procrit, Epogen and Aranesp. These drugs are genetically engineered versions of a natural protein, erythropoietin, that increases the number of red blood cells.

Anemia is common with certain forms of kidney disease, especially once a patient is on dialysis, and when cancer patients take chemotherapy.

But the Food and Drug Administration pointed to recent studies that found using too much of the drugs increased the risk of death, blood clots, strokes and heart attacks in patients with chronic kidney failure. In other studies, patients with head and neck cancer had more rapid tumor growth if they used higher-than-recommended doses.

Even when the anemia drugs were used at FDA-recommended doses, giving them to cancer patients not on chemotherapy increased the risk of death, the agency warned. Moreover, some doctors have begun giving the drugs to patients following orthopedic surgery, also increasing the risk of blood clots, FDA said.

Last week, the agency added stern warnings to each of the drug’s labels urging that:

• doctors monitor patients’ levels of red blood cells and use the lowest possible dose to avoid the need for blood transfusions.

• doctors and patients carefully weigh the risks of using anemia drugs vs. the risk of a transfusion if anemia gets too bad.

Amgen Inc. and Johnson & Johnson, companies that manufacture and market the drugs, both said they would work to inform doctors about the new warnings, outlined in a so-called “black box.” The warnings are the most serious a drug label can bear.

“Amgen is committed to providing timely and appropriate communications to physicians and patients whenever we become aware of new safety information that could affect clinical practice,” said Dr. Roger Perlmutter, Amgen’ s executive vice president of research and development.

The FDA also said it would take a new look at how the drugs are marketed, including claims they can improve the quality of life of cancer patients. The Web site for Procrit, for example, says the drug “helps you find the strength you need.”

“With the new label being revised today, we will certainly evaluate any marketing claims and revise them as needed,” said Stephanie Fagan, a spokeswoman for J&J’s Ortho Biotech Products LP.

A panel of FDA advisers is scheduled to discuss the drugs at a May 10 meeting. Their recommendations could lead to further revisions of the drugs’ labels, FDA officials said.

In December, lawmakers and some experts raised concerns that Medicare’s payment system encouraged overuse of Epogen, endangering patient lives and wasting taxpayer money. FDA officials said they would forward the recent data on the class of drugs to the Centers for Medicare and Medicaid Services.

The three drugs are huge sellers, with combined 2006 U.S. sales of $10 billion, according to IMS Health Inc.

Studies Show Anemia Drugs May Harm Cancer Patients

New studies are raising questions about whether drugs that have been used by millions of cancer patients might actually be harming them.

The drugs, sold by Amgen, Roche and Johnson & Johnson, are used to treat anemia caused by chemotherapy and meant to reduce the need for blood transfusions and give patients more energy. But the new results suggest that the drugs may make the cancer itself worse.

In the studies, the drugs have generally been used in ways not approved on the labels. And the companies say that, when used according to instructions, the drugs have a long history of safety.

In a statement yesterday, Amgen said it strongly believed its drugs were ‘’safe and effective medicines when used in approved populations consistent with label dosing recommendations.”

Nevertheless, some cancer specialists and securities analysts say the new information may make doctors more cautious in using the drugs, which have combined sales for the three companies exceeding $11 billion and have been heavily promoted through efforts that include television commercials.

”These are drugs that were presumed to be entirely safe, given for supportive care and to improve quality of life,” not to actually treat cancer, said Dr. Eric Winer, director of breast oncology center at the Dana-Farber Cancer Institute in Boston. ”So any concern that they could shorten someone’s life are taken quite seriously.”

The Food and Drug Administration is planning to convene an advisory committee meeting to review the products, Dr. Richard Pazdur, the agency’s director for cancer drugs, said in an e-mail message last week alerting cancer doctors to the new findings.

All the drugs are versions of erythropoietin, or Epo, a substance made by the human kidney that increases levels of hemoglobin, the oxygen-carrying component of red blood cells.

Amgen makes Aranesp, with sales of $4.1 billion last year, as well as Epogen, which had sales of $2.5 billion, although Epogen is supposed to be used only to treat anemia in kidney dialysis patients.

Under license from Amgen, Johnson & Johnson sells Procrit in the United States and Eprex abroad, with combined sales last year of $3.2 billion.

Roche’s drugs NeoRecormon and Epogin, now sold only outside the United States, had sales last year of $1.8 billion. But Roche is hoping to enter the American market with a new drug called Cera.

Amgen has the most to lose from any setback because it relies more heavily on the Epo drugs, which account for nearly half its revenue. Amgen’s stock touched above $75 briefly in late January, before word of the negative studies began emerging. The shares closed yesterday at $66.20, down 3 cents.

The new doubts about cancer safety add to those raised recently regarding the drugs’ other major use — to treat anemia caused by kidney disease. A study published in The New England Journal of Medicine in November found that patients treated aggressively with Procrit had a higher risk of heart problems or death than those treated less aggressively.

The run of bad news for cancer treatment started in late January when Amgen announced that in one of its clinical trials, patients getting Aranesp were more likely to die than those getting placebo. The trial was testing the drug in patients whose anemia was caused by the cancer itself, not by chemotherapy.

On Feb. 16, the Cancer Letter, an influential Washington newsletter, reported that a Danish study in patients with head and neck cancer had been stopped early because the cancer seemed to recur more in patients being treated with Aranesp.

Last week, The Journal of Clinical Oncology published a paper online describing a small Canadian trial in lung cancer patients that had been stopped early because those getting Eprex were dying sooner.

And on Friday, Roche said it was suspending patient enrollment in a lung cancer trial comparing its Cera against Amgen’s Aranesp because of apparently greater than expected number of deaths in at least some of the arms of the trial.

It is not known why the drugs cause problems, if they do. It is known that raising hemoglobin levels too high increases the risk of blood clots. And most of these new trials did aim to increase hemoglobin above the levels recommended in the drugs’ labels, though that was not the case with Amgen’s own trial.

But there is some evidence that clots were not the problem in these trials. Rather, some experts say, Epo may spur tumor growth. Some studies suggest that certain tumor cells, such as those in head and neck cancer, have proteins on their surface that bind to Epo. When that happens it sets off a cascade of reactions spurring growth.

”I think there’s enough biologic plausibility to the argument that they can serve as a growth factor for the cancer cell,” said Dr. Jennifer R. Grandis, a professor at the University of Pittsburgh who has done studies of the matter. She said the head and neck cancer practice at her institution does not routinely use Epo and that she would not want it herself.

But Dr. David P. Steensma at the Mayo Clinic, who has reviewed studies of Epo safety, said the existence of Epo receptors on tumors had not been proved because the studies have been flawed. He said that there have been previous studies of the drugs that suggested they actually had a positive effect on survival.

A combined analysis of 57 trials concluded the impact of the drugs on survival was uncertain.

Dr. Steensma said he was still comfortable using the drugs to correct severe anemia, but added, ”I think we need to be real careful about going beyond that.”

Concerns about the safety of the drugs for cancer were first raised in 2003 by two studies that showed patients getting Epo had worse outcomes. But some experts said those studies were flawed and not convincing.