Doctors are increasingly prescribing drugs in ways never approved by the FDA as safe and effective, putting patients at risk of deadly side effects when there is sometimes little evidence the treatment will work.

The drug letrozole, marketed under the brand name Femara, is approved to treat breast cancer in women who've undergone menopause. But doctors in the United States and Canada often prescribe it "off-label" to prompt ovulation as part of fertility treatments.

Health Canada, the government national healthcare agency, and Swiss drug maker Novartis have sent letters to Canadian doctors warning them about the off-label, or unapproved, use of the drug. Health Canada posted copies of the letter and a patient safety alert on its Web site on Monday.

Although the US Food and Drug Administration isn't requiring it, Novartis will send a similar letter to US fertility specialists to remind them that Femara is approved only as a breast cancer treatment, said Kim Fox, a Novartis spokeswoman. FDA officials were unavailable for comment Monday.

May Harm the Fetus

Femara's official FDA prescribing information targeted at doctors warns that the drug may harm the fetus when prescribed to pregnant women, citing studies in rats. "If there is exposure to letrozole during pregnancy, the patient should be apprised of the potential hazard to the fetus and potential risk for the loss of pregnancy," the warning states.

Yet the drug, which suppresses the hormone estrogen, is helpful in inducing ovulation and has found favor among some fertility specialists. While the FDA and Health Canada approve drugs as safe and effective for certain treatments, doctors can prescribe drugs any way they see fit.

Fox said that Novartis doesn't know how many women have received the drug as an unapproved infertility treatment. She said that Novartis hasn't promoted Femara or sponsored any studies of it for treatment of infertility.

Adverse Reaction Reports

Numerous Web sites for infertility clinics across the United States, however, discuss the use of Femara as a treatment option, as do postings in infertility chat rooms.

Novartis has received 13 adverse reaction reports worldwide involving women exposed to Femara during pregnancy.

Of those, four involved harm to the baby, said Jirina Vlk, a Health Canada spokeswoman. Two of the three patients who received Femara as an infertility treatment had miscarriages.

A third patient had a baby diagnosed at the age of 1 with a type of cancer, called neuroblastoma. A female baby born to a fourth patient, who received Femara as a cancer treatment while pregnant, was diagnosed with a genital abnormality.

There also are seven cases in which the outcome of the babies is unknown, while two patients had normal babies at delivery, Vlk said.

'High Incidence of Malformation'

Also prompting Health Canada's action was a recent presentation by Dr. Marinko Biljan at the International Conference on Reproductive Medicine in Montreal, which noted an increased rate of birth defects born to mothers treated with the drug at his clinic.

Biljan, the founder of the Montreal Fertility Centre, said Monday it appears that Femara shouldn't be used as an infertility treatment. "It had quite a high incidence of malformation," Biljan said. He said the results of his study are pending publication in a peer-reviewed journal. Biljan has spoken favorably about the drug in the past because it appeared to have fewer side effects than other treatments.

"It's widely used in Canada and in parts of the US," he said. "It has quite a lot of use in Europe."

Dr. David Adamson, who serves on the medical advisory board of Resolve: The National Infertility Association, said doctors should take the Health Canada advisory seriously.

"Clearly the barrier to the use of the drug off label has been raised," said Adamson, who also is director of Fertility Physicians of Northern California in Palo Alto. He said fertility patients taking Femara should discuss with their doctors whether this is still the best treatment for them.

'How Great the Risk for the Benefit?'

Dr. Barry Jacobs, of Texas Fertility in the Dallas suburb of Lewisville, said he hadn't heard about the Health Canada safety alert and is eager to get more information. "Femara is incredibly promising," said Jacobs.

Fewer than 5 percent of his patients use the drug, he said, because of the specific fertility circumstances it is used for. As with any drug, he said, "the question is how great the risk for the benefit?"

A Knight Ridder investigation published in 2003 found that doctors are increasingly prescribing drugs in ways never approved by the FDA as safe and effective, putting patients at risk of deadly side effects when there is sometimes little evidence the treatment will work.