NOTORIOUS THALIDOMIDE OKD FOR USE BY LEPERS

Drug has caused severe birth defects

Thalidomide, a drug whose very name became synonymous with birth defects
three decades ago, won approval yesterday from the Food and Drug
Administration as a treatment for leprosy.

New Jersey-based Celgene Corp. will market the drug under the trade name
Thalomid to treat serious and disfiguring skin sores suffered by some
people with leprosy, now called Hansen's Disease.

Widely prescribed in Europe in the 1950s and early 1960s, thalidomide
turned out to cause flipper-like arms and legs in children whose mothers
took the drug in early pregnancy to combat morning sickness.

The FDA is ordering extreme precautions to assure that the use of Thalomid
is restricted to patients who need it. The move is a careful attempt to
balance the competing interests of patients who can benefit from
thalidomide and society's desire to prevent birth defects.

``Thalidomide will be among the most tightly restricted drugs ever to be
marketed in the United States,'' said FDA spokeswoman Ivy Kupec.

The drug may be prescribed only by doctors registered with the drug
company, and patients who take it must comply with mandatory birth control.

Female patients must take a test to show that they are not pregnant before
receiving the drug, and they must use two ``reliable forms of contraception
simultaneously'' while taking Thalomid. In addition, they must take weekly
pregnancy tests during the first month of use and biweekly or monthly tests
thereafter, depending on the regularity of their menstrual cycle.

Male patients also will be warned that it is unknown whether the dangerous
effects of the drug can be passed through semen, and they will be advised
to use condoms when having sex with any woman of childbearing age.

About 10 percent of leprosy patients develop painful skin nodules, a
condition called erythema nodosum leprosum. The anti-inflammatory quality
of thalidomide relieves symptoms in 8 out of 10 such patients.

``It's an excellent drug for people with Hansen's Disease,'' said Dr. Sonia
Sutherland, who treats nearly 500 Bay Area patients at a federally funded
clinic at Contra Costa Regional Medical Center in Martinez.

Sutherland said her clinic will re-evaluate its own restrictions on
thalidomide use. Currently, only women who have reached menopause or have
had a tubal ligation can be prescribed the drug.

Because thalidomide has been available to her patients on an experimental
basis for several years, Sutherland said the real significance of the
approval is that thalidomide now will be more available to patients with
other conditions that might respond to it.

PAINFUL MOUTH ULCERS

Clinical trials are under way using thalidomide to treat AIDS patients with
painful mouth ulcers, and it is also being studied as a treatment for brain
tumors and autoimmune diseases such as rheumatoid arthritis and lupus.

``The real risk is that doctors may prescribe it for less serious
conditions once the drug becomes available,'' said Dr. Bernard Lo, an
ethicist at the University of California at San Francisco. ``You've got to
be extremely careful who you give this drug to.''

While the drug is extremely dangerous for pregnant women, Lo said, it is
also an extremely effective drug for the patients who need it. ``They would
be grievously harmed by not having access to it,'' he said.

The fear is that wider availability of thalidomide will inevitably lead to
someone taking it during early pregnancy -- the time most likely for the
drug to deform a developing fetus.

Critics point to Brazil, where the drug has been widely available while
most of the world has banned it. In poor neighborhoods, they note,
Brazilian children are born with the same flippered limbs that
characterized ``thalidomide babies'' 35 years ago.

It was only through the efforts of an alert FDA scientist in 1960 that
thalidomide sales were blocked in the United States. Dr. Frances Kelsey's
detection of possible toxicity in the drug, while studying a request for
marketing approval, is legendary in FDA annals.

It spared countless American children the fate of 12,000 European
thalidomide babies.

OVERLY CAUTIOUS FDA?

Critics of the FDA contend that the legacy of thalidomide was to make the
regulatory agency overly cautious, unwilling to give timely approval to
beneficial drugs out of fear that they would be the first to make the
mistake the FDA avoided in the '60s.

The FDA is so concerned about misuse of thalidomide that it has warned
Celgene that any ``statements or implications'' that the drug may be useful
to treat other diseases ``may be a violation of the promotional
provisions'' of the Food and Drug Act.

The mechanism by which thalidomide works is not yet fully understood.
However, it is believed that the birth defects it causes in developing
fetuses are the result of the drug's ability to prevent blood vessels from
proliferating.

Ironically, this quality of anti- angiogenesis is now being feverishly
studied as a strategy to battle cancerous tumors. Many cancers secrete
chemical signals that promote blood vessel growth, providing a source of
nourishment to keep a tumor expanding. So-called anti-angiogenesis drugs
block the growth of blood vessels, in theory starving the tumor.

Ronald Ruggiero, a UCSF-Stanford Health Care pharmacist, noted that this
new class of cancer drugs may produce the same horrendous side effects as
thalidomide.

Ruggiero nonetheless believes that the restrictions placed on thalidomide
prescriptions should protect the public health while making the drug
available to those who can benefit from it. ``There's been enough press
about this drug that people are not going to let it out of their hands,''
he said.

EXTREME PRECAUTIONS

The government set unprecedented safety restrictions on thalidomide:

- -- Pregnant Women -- Women are warned not to become pregnant while taking
thalidomide or within a month after quitting the drug. Just one pill can
cause horrific birth defects.

- -- Pregnancy Test -- Women can receive thalidomide only after a negative
pregnancy test. For the first month of thalidomide therapy, women must
undergo repeat pregnancy tests every week. Thereafter, women are tested
monthly before every refill, or every two weeks if they have irregular
menstrual cycles.

- -- Special Training -- Only doctors and pharmacists trained in
thalidomide's dangers by manufacturer Celgene will be allowed to prescribe
or dispense it.

- -- Written Warning -- Before prescribing, doctors must reveal thalidomide's
dangers and instruct patients to use effective birth control. Men are told
to use condoms because thalidomide might be carried in semen. Women are
told to use two forms of birth control, a hormonal method like the pill
plus a barrier method such as condoms, and are to be prescribed
contraception as necessary.

- -- Video Warning -- Patients must view a video with warnings from a
thalidomide victim and are given brochures that show pictures of
thalidomide-deformed babies.

- -- Release Form -- Patients must sign a form stating that they understand
the risks and agree to use contraception.

- -- Computer Registry -- Pharmacies must enroll every patient in a national
computer registry of thalidomide users, run by Boston University and
monitored by the Food and Drug Administration, before filling the
prescription.

- -- Limited Prescription -- Patients receive only a 28-day thalidomide
supply, with no automatic refills. Each package contains a letter from the
Thalidomide Victims Association reminding users about birth defects.

- -- Long-Term Effect -- Patients also must be warned that long-term
thalidomide use may cause an additional, albeit rare, side effect: nerve
damage in the hands and feet called peripheral neuropathy. Patients should
immediately report symptoms, including numbness and tingling, to a doctor.
The only treatment is to stop the drug.

1998 San Francisco Chronicle Page A1

Checked-by: (Joel W. Johnson)