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FDA Consumer magazine
VOL. 29 No. 9  NOVEMBER 1995

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Features

FDA's Rx for Better Medication Information
Under a newly proposed program, by the turn of the century at least 75
percent of patients getting new prescriptions would receive easily
understandable written information. The public has until Nov. 22 to
comment.

A Status Report on Breast Implant Safety
Though recent studies do not show a greatly increased risk of some
well-defined autoimmune diseases among women with silicone gel-filled
breast implants, other safety questions remain. FDA is also requiring
manufacturers to collect safety data on saline-filled implants.

Guarding Against Glaucoma
Glaucoma is a group of eye diseases sharing certain features, but also
differing from one another in their prevalence, ease of detection, and
symptoms. Treatments include drugs and laser surgery. 

For Goodness Snakes: Treating and Preventing Venomous Bites
Twenty kinds of poisonous snakes inhabit the United States (except for
Maine, Alaska and Hawaii), and coping with a bite from any one of them
is no picnic. There are ways to prevent getting bitten, however, and
effective treatment if prevention fails.

Interstitial Cystitis: Progress Against Disabling Bladder Condition
Interstitial cystitis is a bladder condition far more common in women
than in men. It can be devastating to quality of life. Treatments
include drugs and special diets. Sometimes a diagnostic
tool--cystoscopy--can temporarily improve the condition.


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Departments


Updates 

The latest information on FDA-related issues, gathered from FDA Press
Releases, Talk Papers, and other sources.


Notebook 

A potpourri of items of interest gathered from the Federal Register and
other sources.


Investigators' Reports 

Selected cases illustrating regulatory and administrative actions--such
as inspections, recalls, seizures, and court proceedings--by FDA's
regional and district offices across the country


Summaries of Court Actions 

Cases involving seizure, criminal and injunction proceedings.

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FDA Proposes Program to Give Patients
Better Medication Information

by Dixie Farley

More patients would receive more and better medication information with
their prescriptions under a patient education program recently proposed
by the Food and Drug Administration.

"This program will increase patient participation in decisions about
their health, and encourage adherence to medical regimens," says FDA
Commissioner David A. Kessler, M.D.

Under the new program, by the turn of the century, at least 75 percent
of patients getting new prescriptions filled would receive adequate,
useful, and easily understood written information that meets quality
standards. After reaching this goal, the agency would seek to ensure
that by 2006, such information is provided to at least 95 percent of
patients receiving new prescriptions.

If these goals are not met, FDA would either institute a mandatory
comprehensive program of patient information or seek public comment on
the issue.

FDA welcomes comments from the public on the proposed program. (See
accompanying article, "You Can Comment.")

Lack of information is one of the main reasons why 30 to 50 percent of
patients do not use medicines as prescribed. And that's a lot of
medicine misuse, considering that U.S. pharmacists dispensed more than 2
billion prescriptions in 1994, according to the annual National
Prescription Audit by IMS America Ltd., of Plymouth Meeting, Pa. 

The Costs

Medical costs due to prescription medicine misuse and adverse reactions
total more than $20 billion a year. When consequences such as lost
productivity are included, annual costs are as high as $100 billion,
reports the National Pharmaceutical Council, Inc. (NPC), of Reston, Va. 

Most common misuses are: 

 * taking incorrect doses
 * taking doses at wrong times
 * forgetting to take doses
 * stopping medicine too soon.

Treatment failure can be directly traced to medicine misuse. For
example, missed doses of glaucoma medicine can lead to optic nerve
damage and blindness. And in patients taking certain medicines for high
blood pressure, missing doses or stopping the medicine suddenly can
cause a rebound rise in blood pressure higher than it was before the
medicine was begun. 

A factor increasing the risk for misuse is chronic illness causing no
symptoms or erratic ones, according to NPC. Such illnesses include
mental disorders, heart and blood vessel diseases, asthma, glaucoma, and
osteoporosis.

Another factor is old age. Older people tend to have serious illnesses
and take several medicines. They often have vision so poor it interferes
with reading labels. One in four prescriptions is for a person 65 or
older, NPC states.

The American Association of Retired Persons says people have an
increased risk of medicine misuse if they:


 * are depressed

 * are going thorough a life change such as death of a loved one,
   retirement, moving, divorce, or remarriage

 * frequently drink alcohol

 * live alone and don't get out much

 * suffer from pain

 * can't easily talk to the doctor because they have language or hearing
   difficulty or feel uncomfortable asking questions.

What Can Patients Do?

With each new prescription, a patient's first step to safe and effective
treatment is to ask the doctor questions.

Some patients need to overcome a certain barrier, says FDA's Ellen
Tabak, Ph.D., of the agency's division of drug marketing, advertising
and communications. "There is a feeling among some patients that it will
be a bother if they ask a question." In Tabak's research before coming
to FDA, patients who asked questions were more satisfied with their
medical visits.

Pharmacist Michael Cohen, president of the Institute for Safe Medication
Practices, Warminster, Pa., adds, "If you can't ask questions
comfortably, get someone to do it for you. There are patient advocates
in the hospital, and relatives or friends on the outside."

It's vital to ask for written information about side effects and
interactions with other prescription or over-the-counter (OTC)
medicines, tobacco, alcohol, or food, including dietary supplements, and
ways to prevent or counteract them.

Patients should ask if a medicine will affect sleep or activity level,
Cohen says, and how to handle a missed dose. "To prevent mix-ups,
patients ought to insist that the medicine's purpose be put on the
label."

Following Regimens

For whatever reasons, intentional or not, some people may never fully
comply with their prescribed medicine regimens. Others manage this
responsibility easily. Still others want to comply, but have difficulty.

When help is needed, there's a medicine expert nearby--the pharmacist.

Also, various compliance aids are available. Women taking birth control
tablets already know one: the calendar blister pack. Each tablet is
encased on a card in a plastic "blister" marked for each day of the
month. There's no mistaking whether a day's dose is taken.

Aids listed in the catalog of the National Council on Patient
Information and Education, Washington, D.C., from which pharmacists can
order, include a container that beeps when it's time for a dose, a
computerized organizer-dispenser, and a cap fitting over the
prescription vial cap that counts openings, indicating whether the day's
doses were taken.

Pharmacies commonly carry simple compliance aids such as convenience
containers (some with compartments labeled for meals and bedtime, some
with braille markings) and spoons and syringes clearly marked with
dosages for liquids.

While convenience containers aid compliance by helping to organize
medicines in advance, it's a good idea to ask the pharmacist whether the
container you're planning to use will affect your medicines' stability.

Even with one day's poor storage, tablets containing certain medicines
could break down, says FDA chemistry reviewer Jeanne Taborsky. "It
depends on where the medicine is stored and how sensitive it is to
moisture, light or oxygen. Pharmacists consider a medicine's particular
sensitivities when selecting its prescription container."

States and the U.S. Pharmacopoeia (USP) have set standards for testing
prescription medicine containers, and drug firms use these standards to
meet FDA's good manufacturing practices (GMPs) for proper packaging.
GMPs do not generally apply to OTC convenience containers, Taborsky
says, but manufacturers may use the same procedures to test them.
Whether any OTC convenience containers in fact meet the standards is
unknown at this time, she says.

At its convention last March, USP voted to look into the problem of
medicine storage.

"It can be a significant problem," says L. Timothy Grady, Ph.D., USP
vice president and director of standard development, "when you carry
medicine around in a poorly sealed container under high humidity, as
occurs along the Gulf Coast. Carrying medicine in a pocket next to the
body can raise the temperature." As some medicines break down, Grady
says, they may no longer dissolve properly, and the body therefore can't
use them. But this is hard to document, he says. "Someone who doesn't
get blood pressure control for a few days may not notice it.
Scientifically, you know it could happen, but there's no immediate
data." 

USP plans to identify drugs whose deterioration could be critical, Grady
says, and then advise pharmacists to attach time-temperature strips to
the vials. The strips would alert patients by a color change if the
environment will likely cause deterioration.

Informing Patients of Proper Use

Federal law requires labeling on OTC medicines to include adequate
directions for proper use and warnings against misuse, because consumers
take these medicines pretty much on their own. FDA and others have long
worked to better inform patients about prescription medicines, too.

A Health Care Financing Administration (HCFA) rule, effective January
1993, requires pharmacists or assistants to offer medicine counseling to
Medicaid patients. Mail-order pharmacies must provide toll-free
telephone service.

"States must set counseling standards," says HCFA health insurance
specialist Christina Lyon, "on such issues as whether to extend the
offer to counsel to refills."

Lyon says the offer to counsel (patients may refuse) must include all
important aspects of the medicine, such as its description, dosage form,
length of treatment, special directions, common severe side effects,
interactions and their avoidance or remedy, storage, the way to handle a
missed dose, and techniques for self-monitoring treatment, such as blood
testing by diabetics.

The vast majority of states require a face-to-face offer for counseling
for all patients, according to the National Association of Boards of
Pharmacy, Park Ridge, Ill.

However, a July 1994 survey sponsored by the association found only 38
percent of patients receiving a verbal offer for counseling. And
preliminary results of an FDA survey last winter show only 55 percent
receiving written information beyond the label and warning stickers on
the container.

In proposing its new program to provide useful, written patient
information on prescription medicines, FDA urges patients to ask their
health-care professionals questions about their medicines and urges
professionals to counsel patients verbally and reinforce the verbal
counseling with written information, says Thomas McGinnis, R.Ph., FDA
associate director for pharmacy affairs. 

Practically every pharmacy has a computer and printer, and patient
information software is widely available, McGinnis says. "Yet only just
over half the pharmacies generate computer information for patients. We
would like that number to increase substantially."

FDA also would like better quality information.

"Too many brochures and leaflets give too much information about
benefits and not enough about risks, such as adverse reactions and
warnings," McGinnis says. "Some people think risk information will scare
patients, and they won't take their medicines properly. That isn't true.
Studies show patients can handle it and, in fact, want the information."

McGinnis says FDA wants pharmacists to dispense more comprehensive
information about the medicine. Many handouts he and colleagues studied
had only a few bullets of information or a simple paragraph.

The agency also wants to explore a standard format, he says, "as we did
with food labeling, so that, for instance, if you wanted adverse
reaction information, you'd always look at the lower right side of the
sheet. And if you wanted dosing information, you'd always look at the
lower left." 

Profiles and Reviews

In addition to generating patient information, pharmacists can use
computers to maintain profiles on their patients.

Profiles are required by all states except Alaska, Arizona, Colorado,
Maryland, and Missouri; neither are they required by the District of
Columbia or Puerto Rico, says Carmen Catizone, executive director of the
National Association of Boards of Pharmacy. Profiles may include patient
information such as chronic conditions, medicines dispensed, allergies,
and adverse reactions.

Pharmacists use profiles to meet another HCFA requirement: to review
their Medicaid patients' medicine usage.

A recent Texas law requires doctors to include in all prescriptions the
medicine's intended use. This law helps pharmacists better perform drug
regimen reviews, says Steve Morse, R.Ph., assistant director of
compliance with the Texas State Board of Pharmacy, in Austin. (An
exception exists if the prescriber decides that providing the intended
use isn't in the patient's best interest. Texas also strengthened its
confidentiality requirements.)

"Having some idea of what the physician intends the drug to do," Morse
says, "is a key ingredient to finding and identifying problems, working
with the doctor to resolve those problems before they harm the patient,
and then counseling the patient to get maximum benefit from the
medication."

An additional benefit from a container label's stating the intended use,
Morse says, is "patients are less confused about which of their
medications treats which health condition."

Texas requires that patient counseling be reinforced with written
information.

Except for Colorado, Connecticut, Hawaii, Maryland, Minnesota, South
Carolina, Wyoming, the District of Columbia, and Puerto Rico, state laws
have extended HCFA's rules to give all patients a legal right to
counseling on their medicines, says Catizone.

"Patients should exercise that right," he says, "to make sure they've
received the correct medicine and that they completely understand how to
take that medicine and what side effects there may be."

Dixie Farley is a staff writer for FDA Consumer.


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You Can Comment

The public has until Nov. 22 to send comments to FDA on a proposed
agency program to provide adequate and useful written information to
patients about their prescription medicines.

Comments on the proposal, published in the Aug. 24, 1995, Federal
Register (carried in some libraries), may be sent to: FDA Dockets
Management Branch (HFA-305), Rockville, MD 20857.

Working closely with health professional and consumer groups, FDA would
establish broad standards for the information's content and format and
its distribution. Pharmacists and other health professionals would
select and distribute the information.

Medicines posing serious and significant health concerns would have to
be accompanied by a Medication Guide leaflet providing information
reviewed and approved by FDA.

Among other proposed standards, the information would:

give the medicine's approved uses, circumstances when it should not be
used, possible serious adverse reactions, and proper use, including
related cautions

be scientifically accurate, consistent in format, nonpromotional,
specific, comprehensive, understandable, and legible

be in a form that is permanent, easily accessed, and convenient to
carry--most likely, in leaflets, brochures, or computer-generated
printouts, but possibly in audiotapes, computer disks, or videotapes if
they meet the proposed standards.

The agency intends to hold a public meeting after the comment period to
further discuss the proposed program.

--D.F.


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Tips for Taking Your Medicine

Whether prescription or over-the-counter (OTC), no medicine is without
risk. Besides benefits, medicines may cause side effects, allergic
reactions, and interactions with other medicines, alcohol, tobacco, and
even foods, including dietary supplements.

The National Council on Patient Information and Education, Washington,
D.C., recommends asking the doctor these questions:

 * What is the medicine's name, and what is it supposed to do?

 * How and when do I take it, and for how long?

 * What foods, drinks, other medicines, or activities should I avoid
   while taking this medicine?

 * Are there side effects, and what do I do if they occur?

 * Will this new prescription work safely with other prescription and
   OTC medicines I'm taking?

 * Is there written information available about the medicine?

It's wise to write down the answers to these questions immediately, to
make sure you'll remember all the details.

Here are more tips for helping your medicines work as safely and
effectively as possible.


General Advice

 * Keep a record of names, doses and regimens of current medicines;
   record medicine problems and the reasons for the problems.
 * Ask the doctor or pharmacist to write out complicated directions and
   medicine names.

 * Using adequate light, read labels carefully before taking doses.

 * Ask the doctor's or pharmacist's advice before crushing or splitting
   tablets; some should be swallowed whole.

 * Contact the doctor or pharmacist if new or unexpected symptoms
   appear.

 * Never stop medicine the doctor has told you to finish just because
   symptoms disappear.

 * Ask the doctor periodically to reevaluate long-term treatments.

 * If
you have questions, talk to your pharmacist or doctor before using an
OTC medicine the first time, especially if you use other medicine.

*
Carefully read OTC medicine labels for ingredients, proper uses,
directions, warnings, precautions, and expiration dates.

* Discard outdated medicine.

* Store medicine in the original container, where the label identifies
  it and gives direction If, however, you choose to use an OTC
  convenience container, ask the pharmacist whether the container will
  affect your medicines' stability.

* Never store medicine in the bathroom. Unless instructed otherwise,
  keep it away from heat, light and moisture.

* Never store medicine near a dangerous substance, which could be taken
  by mistake.

* Never take someone else's medicine.

* Tell your health professional if you:

 * are breast-feeding or are, or may be, pregnant
 * are allergic to drugs or foods
 * have diabetes or kidney or liver disease
 * take other prescription or OTC medicines regularly
 * follow a special diet or take dietary supplements
 * use alcohol or tobacco.


Children and Medicine

 * Keep all medicine out of children's reach. Some medicines, such as
   iron supplements, are very toxic to children.

 * Use child-resistant caps, and never leave containers uncapped.

 * Examine dose cups carefully. Cups may be marked with various
   measurement units and may not use standard abbreviations. Follow
   label directions. Never substitute a cup from another product.

 * When using a dosing syringe with a cap, discard the cap before use.

 * Never guess when converting measuring units--from teaspoons or
   tablespoons to ounces, for example. Consult a reliable source, such
   as the pharmacist.

 * Never try to remember the dose used during previous illnesses; read
   the label each time.

 * Check with the doctor or pharmacist before giving a child more than
   one medicine at a time.

 * Never give medicine to children unless it is recommended for them on
   the label or by a doctor.

 * Never use medicine for purposes not mentioned on the label, unless so
   directed by a doctor.

 * Check with the doctor before giving hild aspirin products. Never give
   aspirin to a child or teenager who has or is recovering from
   chickenpox, flu symptoms (nausea, vomiting or fever), or flu. Aspirin
   may be associated in such patients with an increased risk of Reye
   syndrome, a rare but serious illness.


Protect Against Tampering

 * Read the label about the product's tamper-evident features.

 * Look at the package for tampering signs such as broken seals,
   puncture holes, or open or damaged wrappings.

 * Look at the medicine. Never take medicine that is discolored, has an
   unusual odor, or seems suspicious in some other way.

 * Return suspicious medicine to the store manager or pharmacist.

 * Look again when you take a dose. Never take medicine if you're not
   alert or can't see clearly.


--D.F.


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Facing a Hospital Stay?

For people in the hospital, the Institute for Safe Medication Practices,
Warminster, Pa., offers this advice:

 * Before taking medicine, to prevent mix-ups, make sure the medicine is
   the same size, shape, color, and dosage form as before. If not, ask
   why; the reason may be proper replacement with a generic.

 * Before taking a new medicine, ask the name, dose, possible side
   effects, and reason for use.

 * Have whoever gives you medicine check your ID bracelet or armband.

 * Ask whether scheduled tests require drugs or dyes. If you've had a
   bad reaction to such substances before, tell the staff.

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News About Breast Implants

by Marian Segal

Recently published studies have shown that women with silicone
gel-filled breast implants do not have a greatly increased risk of some
well-defined autoimmune diseases, which were among the serious health
concerns surrounding the devices. These include potentially fatal
connective tissue diseases such as scleroderma and lupus erythematosus. 

Widespread reports of adverse reactions to silicone gel-filled implants
and a lack of evidence supporting their safety led the Food and Drug
Administration to order the devices off the market in April 1992. They
remained available only to women in clinical studies, mostly women
seeking breast reconstruction after breast cancer surgery. (See
"Silicone Breast Implants: Available Under Tight Controls" in the June
1992 FDA Consumer.) Saline-filled implants were allowed to remain on the
market for all uses. 

The new studies do not, however, rule out the possibility that a subset
of women with implants may have a small increased risk of these
conditions, or that some women might develop other immune-related
symptoms that don't conform to "classic" disease descriptions.

Nor did the studies address other important safety questions, including
implant rupture rates and the incidence of capsular contracture
(shrinking of scar tissue around the implant, which can cause painful
hardening of the breast or distort its appearance). Answers to these and
other questions await the results of new or ongoing studies.

Reasons for New Studies 

Breast implants had been marketed since the early 1960s--several years
before the first medical device law was enacted in 1976, charging FDA
with regulation of medical devices. Every year, thousands of American
women had had implant surgery for augmentation (to enlarge or reshape
their breasts) or for reconstruction following mastectomy (removal of
the breast) to treat breast cancer. Most of the implants consisted of a
rubber silicone envelope filled with silicone gel; about 10 percent were
filled with saline (salt water). 

Under the 1976 law, implants and many other devices already in use were
allowed to remain on the market, with the understanding that the agency
would at some time ask manufacturers to submit scientific data showing
these "grandfathered" products were safe and effective.

FDA requested this information for silicone gel-filled implants in April
1991 in response to a growing number of adverse reaction reports that
raised safety concerns about the devices. The data submitted did not
prove the devices safe, as required by law, so the agency restricted
their use to clinical trials designed to resolve the safety questions. 

Between Jan. 1, 1985, and March 16, 1995, FDA received 91,322 adverse
reaction reports associated with silicone breast implants and 19,296
reports involving the saline implants. These reports included risks
clearly associated with the devices, as well as adverse effects
attributed to the implants, but not proved to be linked to them. (See
accompanying articles, "Known Risks of Breast Implants" and "Possible
Risks of Breast Implants.")

Silicone Implant Studies

Some recent studies comparing the rates of immune-related diseases in
women with implants versus those without implants have provided
reassurance that women with implants are not at a greatly increased risk
of these disorders.

The largest of these retrospective, or "look-back," studies is the
Harvard Nurses' Health Study. The study used data from 87,501 nurses
followed for other research purposes from 1976 through May 31, 1990,
before there was widespread media coverage of the possible association
between breast implants and connective tissue disease. None of the women
had connective tissue disease at the start of the study. 

In an article published in the June 22, 1995, New England Journal of
Medicine, the researchers reported that 516 of the nurses had developed
definite connective tissue diseases. Women with breast implants numbered
1,183. The types of implants included 876 silicone gel-filled, 170
saline-filled, 67 double lumen (silicone gel-filled implants with a
saline-filled outer envelope), 14 polyurethane-coated, and 56 of unknown
type. Only three of the 516 women with definite connective tissue
disease had implants (one silicone-gel filled, one saline, and one
double lumen).

The authors reported they "did not find an association between silicone
breast implants and connective tissue disease, defined according to a
variety of standardized criteria, or signs and symptoms of these
diseases."

Similarly, a 1994 study conducted at the Mayo Clinic found no increased
risk of connective tissue diseases among implant recipients. The
investigators based their conclusion on comparison of the medical
histories of 749 women with breast implants in Olmsted County, Minn.,
with a similar group of women who did not have implants.

"Because of the limitations in the size and type of the studies,
however, the true risk of these diseases is not known," says S. Lori
Brown, Ph.D., a research scientist officer in the epidemiology branch of
the agency's Center for Devices and Radiological Health. "Although the
criteria others may be using to assess those studies show that some
concerns are eliminated," Brown says, "unfortunately, they don't rule
out a small, but significant, increased risk." 

An immunology and epidemiology expert, Brown explains that an inherent
problem in the studies is that some connective tissue diseases are
extremely rare. "If you have a disease that has an incidence of 1 in
100,000 in the general population, for example, and you do a study of
750 women with implants, like the Mayo Clinic Study, then you wouldn't
really expect to see even a single case of that disease," she says,
"unless there's an exceedingly high--more than a hundredfold--increase
in risk." 

Small studies like these can rule out huge risks, but not smaller, yet
significant risk increases that would only show up in studies that
include several thousand women with implants, Brown says. Nor do the
studies fully examine or answer whether the implants might in some women
lead to symptoms not typical of classical disease manifestations.

Other Concerns

Brown also stresses that connective tissue diseases are not the only
issue of concern, especially since they may affect a much smaller
proportion of women with implants. The larger issue, she says, is the
local complications that are clearly related to breast implants, such as
rupture and migration of the silicone gel, capsular contracture, and
infection. 

"Of the two groups of women who consider getting implants--for breast
reconstruction or for augmentation," Brown says, "the larger group wants
them for cosmetic purposes. These are healthy women who may go out and
get implants without a clear picture of what the possible risks are.
They may end up going back in for surgery time and again and never be
happy with the cosmetic effect." 

In testimony before a congressional subcommittee in August 1995, FDA
Commissioner David A. Kessler, M.D., stated that "Published studies to
date suggest a rupture rate between 5 and 51 percent--an enormous
range--and unfortunately, we do not know with any confidence where
within that range the real rupture rate lies." He also cited two studies
that indicate the risk of rupture increases as the implants age.

Another concern--increased risk of breast cancer--has not been borne out
by studies. "Several studies have indicated there is no increased risk
of breast cancer in women with implants," Brown says. However, she adds,
these women are not yet in the age group that is more prone to breast
cancer, and it remains to be seen whether they will eventually have a
higher incidence of breast cancer than women without implants. Long-term
studies to look at this are under way.

Manufacturers' Studies

The events that led to removal of silicone implants from the market made
it clear that prospective, or forward-looking, studies were also needed
to answer important safety questions. Implant manufacturers agreed to
conduct human trials in three phases: urgent need, adjunct, and core
studies.

"The purpose of the first phase [urgent need] actually was simply to
quickly provide implants to women who were already in the process of
getting them for breast reconstruction or for another medical reason,
and to bridge the time until the adjunct studies were begun," says Sahar
M. Dawisha, M.D., a rheumatologist and medical officer who joined FDA's
division of general and restorative devices in April 1993.

The women did, however, have to sign an informed consent form that
summarized the risks and benefits of the implants. This form had not
previously been required.

"The second phase, or adjunct, studies were intended to follow
reconstruction patients for five years to assess short-term safety data,
including rates of capsular contracture, rupture, and complications such
as infection and hematoma [collection of blood that may cause swelling,
pain and bruising]," Dawisha says. "These studies are open to all women
wanting breast reconstruction with implants because of mastectomy,
traumatic injury to the breast, or a disease or congenital disorder
causing a severe breast abnormality. They do not include augmentation
patients."

Mentor Corporation of Santa Barbara, Calif., began adjunct studies in
1992. According to Pamela Powell of the company's Clinical Programs
Department, as of July 5, 1995, 12,125 patients were enrolled in the
studies. 

The third phase, or core studies, Dawisha says, were intended to
determine the full safety and effectiveness profile of the device,
including rupture rates, quality-of-life benefits, extent of
interference with mammography, and many more safety concerns--including
rheumatologic assessments--that would need a large number of women. They
were also to include augmentation patients. The sponsors, however, have
not initiated these studies.

Saline Implants 

Although many of the local complications of gel-filled implants are also
associated with saline implants, the latter were permitted to remain on
the market unrestricted for both reconstruction and augmentation. FDA
considers saline-filled implants less risky, because although they have
the same silicone rubber envelope as gel-filled implants, leakage or
rupture would release only salt water, not silicone gel, into the body. 

Nevertheless, FDA is requiring manufacturers to collect data on the
saline implants as well, because the incidence of known risks (for
example, deflation and capsular contracture) is not well defined. When
the Medical Device Amendments were passed, it was determined that these
devices would also eventually require premarket approval. In January
1993, FDA notified saline implant manufacturers that they would have to
submit safety and effectiveness data for their products. In December
1994, the agency told them what type of safety and effectiveness data
were needed, and delineated objectives and time frames for the trials.
Saline implants will stay on the market while the studies are conducted,
but the companies must report the laboratory, animal and clinical data
in stages, and must provide written information on the known and
possible risks of their products. 

"Women considering saline implants should ask their doctor for a copy of
the manufacturer's information sheet, a copy of the product insert sheet
for the specific implant to be used, and a copy of the hospital informed
consent form," says Barbara Stellar, FDA's breast implant information
and outreach coordinator. 

Stellar recommends women be given these documents at least a month
before surgery is planned, if possible, so they can thoroughly discuss
benefits and possible risks with surgeons, radiologists, and other
women. These women should also ask their physicians about participating
in the saline breast implant trials.

Brown hopes that further studies will more clearly define risks
associated with all types of implants. 

"We need to be able to tell women considering breast implants--whether
for augmentation or reconstruction--the specific risks on which they can
base their decision," she says. "It should be made clear that implants
do not last forever, that they may break, and in what time period it is
thought they might break. Most women have no idea implants break and
there's very little information about rupture rates. 

"The same is true for other complications, some of which may require
further surgery or may cause the woman to be displeased with the
cosmetic effect, which, of course, is the reason she got them," Brown
says. "For a product that a person is putting in her body presumably for
20 years or more, we should have this information."

Marian Segal is a member of FDA's public affairs staff.


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Known Risks of Breast Implants

Signing a consent form is now part of the procedure for all women
undergoing breast implant surgery. They must also be given information
about the devices' known and possible risks. Surgical Risks

 * possible complications of general anesthesia, as well as nausea,
   vomiting and fever

 * infection

 * hematoma (collection of blood that may cause swelling, pain and
   bruising, perhaps requiring surgical draining)

 * hemorrhage (abnormal bleeding)

 * thrombosis (abnormal clotting)

 * skin necrosis--skin tissue death resulting from insufficient blood
   flow to the skin. The chance of skin necrosis may be increased by
   radiation treatments, cortisone-like drugs, an implant too large for
   the available space, or smoking.

Implant Risks

 * capsular contracture (hardening of the breast due to scar tissue)

 * leak or rupture--silicone implants may leak or rupture slowly,
   releasing silicone gel into surrounding tissue; saline implants may
   rupture suddenly and deflate, usually requiring immediate removal or
   replacement

 * temporary or permanent change or loss of sensation in the nipple or
   breast tissue

 * formation of calcium deposits in surrounding tissue, possibly causing
   pain and hardening

 * shifting from the original placement, giving the breast an unnatural
   look

 * interference with mammography readings, possibly delaying breast
   cancer detection by "hiding" a suspicious lesion. Also, it may be
   difficult to distinguish calcium deposits formed in the scar tissue
   from a tumor when interpreting the mammogram. When making an
   appointment for a mammogram, the woman should tell the scheduler she
   has implants to make sure qualified personnel are on-site. At the
   time of the mammogram she should also remind the technician she has
   implants before the procedure is done, so the technician can use
   special techniques to obtain the best mammogram and to avoid
   rupturing the implant.

--M.S.


------------------------------------------------------------------------


Possible Risks of Breast Implants

 * Autoimmune-like disorders--signs include joint pain and swelling;
   skin tightness, redness or swelling; swelling of hands and feet;
   rash; swollen glands or lymph nodes; unusual fatigue; general aching;
   greater chance of getting colds, viruses and flu; unusual hair loss;
   memory problems; headaches; muscle weakness or burning; nausea or
   vomiting; and irritable bowel syndrome.

Recent studies have shown, however, that there is not a large increased
risk of traditional autoimmune, or connective tissue disease, from
silicone gel implants. 

 * Fibrositis/fibromyalgia-like disorders (pain, tenderness and
   stiffness of muscles, tendons and ligaments).

--M.S.


------------------------------------------------------------------------


Polyurethane-Coated Implants

About 110,000 women have silicone gel-filled implants with a
polyurethane coating, intended to reduce the risk of capsular
contracture. In April 1991, an FDA analysis showed that polyurethane
foam could break down under human body conditions to form a chemical
called TDA, which can cause cancer in animals. As a result, the
manufacturer immediately stopped selling the product.

Recently, however, a study to measure TDA in women with polyurethane
implants found that a woman's risk of cancer from exposure to TDA
released by the implant is negligible--about one in a million over a
lifetime. FDA considers it unlikely that even one woman would develop
cancer from these implants. The study supports the agency's original
recommendation that women who are not having problems should not have
the implants removed solely because of concern about cancer from TDA
exposure.

--M.S.


------------------------------------------------------------------------


Immunology Tests


Several laboratories are offering tests that claim to detect levels of
antibodies to silicone that presumably indicate a leaking or ruptured
implant. 

FDA has not cleared or approved these tests for such purposes, and the
agency has sent letters to several companies, warning of future
regulatory action if they continue to promote the devices without a
premarket approval application.

"There are important unresolved issues with these tests," says Peter
Maxim, Ph.D., chief of the Center for Devices and Radiological Health's
immunology branch of the division of clinical laboratory devices. "For
one thing, the very existence of silicone antibodies has not been proven
to the satisfaction of all scientists," he says. "Secondly, if
antibodies are detected, is there in fact a correlation with the
presence or the status of implants, or do they reflect prior
environmental exposure? Silicone is in a myriad of products, including
foods, medicines, and antiperspirants absorbed by the skin, to name a
few." 

The next problem, Maxim says, is that there are claims that extremely
high antibody levels may indicate a leaking or ruptured implant. This,
then, raises the question of what medical intervention, if any, should
be taken.

Sahar M. Dawisha, M.D., a rheumatologist in FDA's division of general
and restorative devices, adds that no one really knows what the clinical
significance of an antibody to silicone means or at what level it is
harmful.

"Furthermore," she says, "in autoimmune or connective tissue
disease--where antibody tests are generally used--the presence of
antibodies doesn't define the disease. A disease is defined by clinical
signs and symptoms, and antibodies are used as supporting evidence."

Finally, John Nagle, consumer safety officer in the Center for Devices
and Radiological Health's diagnostic devices branch, says, "The tests
themselves may be harmless, but they sure are expensive, somewhere
between $500 and $1,000," adding that "a lot of them are being done for
litigation purposes rather than to help the patient medically."

--M.S.


------------------------------------------------------------------------


Information Packet

To obtain a comprehensive packet of information on breast implant
issues, request FDA's publication, "Breast Implants, An Information
Update," by calling the agency's breast implant information line at
(1-800) 532-4440. 

------------------------------------------------------------------------

Guarding Against Glaucoma

by S.J. Ackerman

An outstanding scholar still in his 30s, John felt his "sight getting
weak and dull"--occupational eyestrain, he supposed. Soon his left eye
dimmed, starting from the left side. Then his right eye failed,
"perceptibly and gradually over three years." By age 43, he was totally
blind.

That was in 1652. John Milton triumphed over blindness, still serving
the British foreign office and writing literary classics like "Paradise
Lost." Yet he never ceased lamenting "how my light is spent/Ere half my
days, in this dark world and wide."

What relegated him to seeing "a universal blank" was probably open-angle
glaucoma, which today needlessly blinds 80,000 Americans each year. It
causes another 900,000 to lose some vision. Yet now we have means Milton
lacked to thwart "the sneak thief of sight" with a number of treatments
approved by the Food and Drug Administration.

Glaucomas are a group of diseases sharing certain features, commonly
including high intraocular pressure (IOP), damaged optic nerves, and
loss of peripheral vision. Early detection can contain two glaucomas:
chronic (sometimes called common) and acute. 

Primary open-angle glaucoma (chronic glaucoma) affects mostly adults
over age 35. This most prevalent glaucoma is the sneak-thief disease
without noticeable symptoms. By the time it's detected, it has started
doing damage. 

The uncommon primary angle-closure glaucoma (acute glaucoma) may seem
the opposite of common glaucoma, erupting in a sudden, violent attack.
It's also possible to get both common and acute ("combined-mechanism")
glaucoma together. The unusual low-pressure glaucoma is another variant.
Regular eye examinations can help protect against the onset of
open-angle and closed-angle glaucomas. 

The cornea is the clear outer covering of the eye. Separating it from
the iris (the colored part) is the anterior chamber, a space filled and
inflated by aqueous humor. This fluid (unrelated to the tears which
bathe the outside surface of the cornea) originates in the ciliary body
just behind the iris. It circulates in the anterior chamber, nourishing
the eye's delicate tissue and keeping it from collapsing, at a pressure
usually measuring between 10 and 20 millimeters of mercury. To maintain
equilibrium, the aqueous humor drains through a porous tissue in the
angle in front of the iris, where it meets the cornea, called the
trabecular meshwork.

If the aqueous humor cannot drain properly, either because the drainage
canals become clogged (as in chronic glaucoma) or because the iris is
pushing against the cornea (as in angle-closure glaucoma), it backs up,
exerting pressure on the gel in the vitreous cavity at the center of the
eye. Eventually the building pressure affects the delicate optic nerve
at the rear. Since the optic nerve transmits visual images to the brain,
damage to parts of it correspondingly reduces vision.

Pressure over 21 millimeters may prompt concern, while pressure over 24
mm can indicate glaucoma level--but not always. These measures are not
absolute. Some individuals tolerate higher pressures than others. Half
the people with undiagnosed glaucoma have pressures below 22 mm, while
others with higher pressures never develop glaucoma, with optic nerve
damage causing loss of vision. Low-pressure glaucoma can be especially
elusive. Moreover, tonometry (the measurement of eye pressure) can be
affected by many factors, even by the time of day (IOP measuring highest
in the morning). 

Tonometry measures the force necessary to indent the eye. One method is
to anesthetize the eye, then press a tonometer onto it. Another is to
measure the force needed for a puff of air to indent the cornea. 

While widespread eye-puff testing at health fairs detects pressure
levels, a more thorough examination calls for an ophthalmoscopic test
enabling doctors to see into your eye to examine the optic nerve for
damage or a high ratio of its central cup to the surrounding disc. (See
accompanying article.) They must also take personal characteristics into
account in evaluating an individual's risk of glaucoma.

Chronic (Primary Open-Angle) Glaucoma

Physicians do not like to begin therapy prematurely in individuals
identified as at risk for chronic glaucoma. Patients considered
"pre-glaucoma" should have their eyes examined as often as their doctors
think necessary.

Increasingly frequent dosages of medications may be needed as the eye
develops tolerance to the medicine. Drug therapy can effectively thwart
the progress of glaucoma, but it can mean taking an escalating variety
of eye drops and pills, with various side effects, for life.

Topical medications for glaucoma are serious medicine, not to be
confused with over-the-counter eye drops for easing common eye
irritations. The most popular maintenance eye drop, Timoptic (timolol
maleate), may have side effects on the nerves, digestion, vision, skin,
respiration, and heart of some individuals. Timoptic is a beta-blocker
eye drop. Taken usually twice daily, beta blockers decrease production
of aqueous humor. Side effects may include lowered pulse rate and blood
pressure, exacerbated asthma, and fatigue. In June 1995, British
researchers reported that drops in this class may be related to
breathing impairment in elderly people with previously unrecognized
respiratory problems.

Timoptic's century-old predecessor, pilocarpine, requires more frequent
use to do its job, increasing drainage of aqueous fluid in both open-
and closed-angle glaucomas. Pilocarpine is a miotic, designed to
increase aqueous fluid drainage. Because miotics work by making the
pupil smaller, they can result in dim vision and may increase the risk
of cataracts. 

Another class of medications, adrenergic agonists, such as epinephrine,
also increases aqueous humor drainage, with possible side effects of
allergic reactions, blurred vision, headache, and increased heart rate.
Alpha adrenergic agonists decrease aqueous humor production after
surgery or aid patients taking maximum dosages of other medications.
Side effects include red eyes, allergic reactions, and dry mouth.

Diamox carbonic anhydrase inhibitor tablets, like beta blockers,
decrease production of aqueous fluid, but these drugs seem to provoke
more prominent side effects in some people, including mental depression,
kidney stones, tingling in the hands and feet, and sometimes anemia. 

FDA's May 1995 approval of a Carbonic Anhydrase Inhibitor in eye drop
form as Trusopt (dorzolamide) provides a medication that may have fewer
and reduced incidence of these severe side effects.

Since reactions to medications vary so much from person to person, a
drug that causes one individual problems may be easily tolerated by
another. An appropriate drug regimen, therefore, needs to be worked out
carefully between patient and health professional.

Glaucoma medications are potent drugs. Those who take them should
consult a pharmacist to be certain that they won't interact adversely
with any other prescriptions or over-the-counter drugs being taken. For
example, some over-the-counter products, including decongestants, may
not be suited for people at risk of glaucoma.

Acute (Closed-Angle) Glaucoma

A century after Milton gradually lost his sight, composer Johann
Sebastian Bach went blind in a violent flash, probably from acute
(closed-angle) glaucoma. Bach thought he aggravated his weak vision by a
lifetime of copying music in the dim light of church organ lofts; his
portrait shows a characteristic squint. Though a surgeon claimed to have
operated successfully on Bach's eyes, the composer's vision failed again
in a few days. He died a few months later, after a futile--and possibly
harmful--second operation. 

Acute glaucoma may seem the opposite of open-angle because it erupts in
violent attacks and intense pain, rather than emerging subtly. Yet
patients may not notice minor preliminary episodes, which pave the way
for serious seizures. People beset by a major seizure must get to an
ophthalmologist, or at least a hospital emergency room, promptly to save
their vision.

Monitoring can protect people prone to acute glaucoma from major
attacks. 

Acute glaucoma attacks are emergencies because aqueous fluid gets
trapped in the angle of the eye suddenly. Having nowhere to go, its
abrupt backup can damage the optic nerves, eventually squashing them
irreparably. 

Regular, thorough eye checkups can detect the risk of acute glaucoma.
High IOP, family history, and other indicators resemble those for common
glaucoma, but very farsighted people and those of Asian descent are most
vulnerable to angle-closure glaucoma. Once a major angle-closure attack
seems imminent, preventive laser surgery is advisable, since an attack
can damage the eye quickly.

Regular monitoring of people diagnosed with narrow-angle conditions
looks for increased IOP or tissue damage. Telltale symptoms of an attack
include blurred vision, halos around lights, and eye pain sharp enough
to induce vomiting. The eye becomes reddened, feeling as if it could
burst (though it can't). Persons experiencing such attacks should go
immediately to an ophthalmologist or an emergency room, ideally calling
in advance to ready staff to receive a case of closed-angle, acute
glaucoma. 

Emergency procedures use eye drops and clinical eye massage to reduce
IOP and prevent the eye from hardening. Once stabilized, the patient may
have laser surgery to create an artificial opening for aqueous fluid to
drain. Acute glaucoma usually attacks one eye before the other, so laser
surgery on the unaffected eye may be recommended at the time to
forestall a second attack there.

Laser Surgery

Some patients may require traditional scalpel surgery, but in recent
years laser operations have come into favor. Laser surgery can't repair
existing damage, but it usually stops glaucoma, both in acute
emergencies and open-angle cases. It may involve minor side effects,
including restrictions on wearing contact lenses, but its risks are
quite low. Sometimes it must be repeated if its drainage openings begin
to close.

Light amplification by stimulated emission of radiation--LASER--sends a
uniform, focused beam of light to pinpoint applications. In glaucoma
surgery for angle closure, the laser creates a minute hole in the iris,
just large enough to allow aqueous fluid to flow freely. 

Despite its high-tech wizardry, most laser surgery for glaucoma seems
quite undramatic to the patient undergoing it. (See "Light for Sight,"
FDA Consumer, July-August 1990.) An acute glaucoma patient peers into
the eyepiece on one side of a boxy device while a surgeon manipulating
controls peers into an eyepiece opposite. There's little or no
additional pain, often not even unpleasant sensation, as the surgeon
beams an intense beam of light to "burn" an escape channel for aqueous
fluid, usually in the upper edge of the iris.

The Nd:YAG (neodymium:yttrium aluminum garnet crystal) laser has emerged
with several advantages over the earlier argon laser, including lower
energy requirement, fewer pulses, reduced obstruction, and a lower rate
of subsequent closure of incisions. Its portability allows the YAG laser
to serve even remote Inuit villages in Alaska previously inaccessible
for sophisticated optical surgery.

No wonder that laser surgery in just 25 years has largely displaced
traditional scalpel surgery, which involves hospital stays and higher
risks. Its low risk allows use earlier in the course of the disease,
when its potential benefit is greater. 

On the Horizon

Diligence in countering early the subtle onset of glaucoma is the best
protection. Research is making such diligence easier. 

Ongoing research aims to simplify dosage demands while reducing side
effects. For instance, the nuisance of taking preventive eye medications
several times a day discourages some people from protecting themselves
fully. Work is under way to perfect a once-a-week eye preparation and
one-a-day eye drops to ease the use of topical eye medications. Already,
dispenser tips that measure more consistent doses of eye drops are
improving their use.

Even the standard course of escalating treatment for common glaucoma is
being reconsidered. The practice more common in Europe suggests that
reversing this order by starting with surgery may be promising. In
August 1993, the National Eye Institute announced the Collaborative
Initial Glaucoma Treatment Study to compare the long-term effect of
treating newly diagnosed primary open-angle glaucoma with standard
treatment versus immediate laser surgery.

S.J. Ackerman is a writer in Washington, D.C.


------------------------------------------------------------------------


Risks and Responses

Elevated eye pressure and detectable damage to the optic nerves are
significant risk indicators for glaucoma. To prevent needless blindness
from undetected, untreated glaucoma, the American Academy of
Ophthalmology offers additional guidelines for assessing risk.

The academy's guidelines include comparing the diameter of the eye's cup
to that of its disc to obtain a physical gauge of the likelihood of
glaucoma. Estimates are made vertically along an imaginary line drawn
through the center of the disc from the 12 o'clock to the 6 o'clock
position. The normal optic nerve illustrated with a small cup has a
cup-to-disc ratio of less than 0.5, indicating a low probability of
glaucoma. Moderately advanced cupping, with a cup-to-disc ratio of 0.6
to 0.8 and a neural rim starting to thin, increases the suspicion of
glaucoma. Almost total cup-to-disc ratio of 0.9, exhibiting a very thin
neural rim, creates a high level of glaucoma suspicion.

Personal history factors also enter the assessment; these are shown in
both table format and in chart form (for browsers that do not support
tables). Other variables in risk assessment include extreme
nearsightedness or farsightedness, high blood pressure, and steroid use.

People at risk of glaucoma should faithfully have eye checkups at the
intervals recommended by their ophthalmologists. Everyone over 40 should
have a full eye examination every two years, regardless of risk factors;
African Americans should be vigilant after age 30. Adult relatives of
persons diagnosed with glaucoma should have regular eye checkups.
Glaucoma seems to be hereditary, and even cousins may be at risk if you
are.

Glaucoma treatment decisions are personalized. Even eye color may affect
the rate at which a person absorbs eye medications.


------------------------------------------------------------------------


For More Information

For more information about glaucoma, contact:


 * your doctor

 * American Academy of Ophthalmology's Glaucoma 2001 Campaign (for
   chronic open-angle glaucoma): (l-800) 39l-EYES

 * Foundation for Glaucoma Research: (1-800) 826-6693 or (415) 986-3162

 * National Eye Institute: (301) 496-5248.


------------------------------------------------------------------------


For Goodness Snakes!
Treating and Preventing Venomous Bites

by John Henkel

They fascinate. They repel.

Some pose a danger. Others are harmless.

And whether they are seen as slimy creatures or colorful curiosities,
snakes play important environmental roles in the fragile ecosystems of
the nation's wildlife areas.

People who frequent these wilderness spots, as well as those who camp,
hike, picnic, or live in snake-inhabited areas, should be aware of
potential dangers posed by venomous snakes. Every state but Maine,
Alaska and Hawaii is home to at least one of 20 domestic poisonous snake
species. A bite from one of these, in which the snake may inject varying
degrees of toxic venom, should always be considered a medical emergency,
says the American Red Cross.

About 8,000 people a year receive venomous bites in the United States;
nine to 15 victims die. Some experts say that because victims can't
always positively identify a snake, they should seek prompt care for any
bite, though they may think the snake is nonpoisonous. Even a bite from
a so-called "harmless" snake can cause an infection or allergic reaction
in some people.

Medical professionals sometimes disagree about the best way to manage
poisonous snakebites. Some physicians hold off on immediate treatment,
opting for observation of the patient to gauge a bite's seriousness.
Procedures such as fasciotomy, a surgical treatment of tissue around the
bite, have some supporters. But most often, doctors turn to the antidote
to snake venom--antivenin--as a reliable treatment for serious
snakebites. 

Antivenin is derived from antibodies created in a horse's blood serum
when the animal is injected with snake venom. In humans, antivenin is
administered either through the veins or injected into muscle and works
by neutralizing snake venom that has entered the body. Because antivenin
is obtained from horses, snakebite victims sensitive to horse products
must be carefully managed. The danger is that they could develop an
adverse reaction or even a potentially fatal allergic condition called
anaphylactic shock. 

The Food and Drug Administration regulates antivenins as part of its
oversight of biological products. The agency requires certain criteria
to be met before these materials are sold, including standards for
purification, packaging and potency. FDA also regulates antivenin
labeling, ensuring that data on potential side effects and other
pertinent information are available. The agency also periodically
inspects antivenin production facilities to ensure compliance with
regulations. 

Types of Poisonous Snakes

Two families of venomous snakes are native to the United States. The
vast majority are pit vipers, of the family Crotalidae, which include
rattlesnakes, copperheads and cottonmouths (water moccasins). Pit vipers
get their common name from a small "pit" between the eye and nostril
that allows the snake to sense prey at night. They deliver venom through
two fangs the snake can retract at rest but can spring into biting
position rapidly. About 99 percent of the venomous bites in this country
are from pit vipers. Some--Mojave rattlesnakes or canebrake
rattlesnakes, for example--carry a neurotoxic venom that can affect the
brain or spinal cord. Copperheads, on the other hand, have a milder and
less dangerous venom that sometimes may not require antivenin treatment.

The other family of domestic poisonous snakes is Elapidae, which
includes two species of coral snakes found chiefly in the Southern
states. Related to the much more dangerous Asian cobras and kraits,
coral snakes have small mouths and short teeth, which give them a less
efficient venom delivery than pit vipers. People bitten by coral snakes
lack the characteristic fang marks of pit vipers, sometimes making the
bite hard to detect. 

Though coral snakebites are rare in the United States--only about 25 a
year by some estimates--the snake's neurotoxic venom can be dangerous. A
1987 study in the Journal of the American Medical Association examined
39 victims of coral snakebites. There were no deaths, but several
victims experienced respiratory paralysis, one of the hazards of
neurotoxic venom.

Some nonpoisonous snakes, such as the scarlet king snake, mimic the
bright red, yellow and black coloration of the coral snake. This
potential for confusion underscores the importance of seeking care for
any snakebite (unless positive identification of a nonpoisonous snake
can be made).

The bites of both pit vipers and coral snakes can be effectively treated
with antivenin. But other factors, such as time elapsed since being
bitten and care taken before arriving at the hospital, also are critical
(see accompanying article). 

First Aid for Snakebites

Over the years, snakebite victims have been exposed to all kinds of
slicing, freezing and squeezing as stopgap measures before receiving
medical care. Some of these approaches, like cutting into a bite and
attempting to suck out the venom, have largely fallen out of favor. 

"In the past five or 10 years, there's been a backing off in first aid
from really invasive things like making incisions," says Arizona
physician David Hardy, M.D., who studies snakebite epidemiology. "This
is because we now know these things can do harm and we don't know if
they really change the outcome."

Many health-care professionals embrace just a few basic first-aid
techniques. According to the American Red Cross, these steps should be
taken:

 * Wash the bite with soap and water.
 * Immobilize the bitten area and keep it lower than the heart.
 * Get medical help.

"The main thing is to get to a hospital and don't delay," says Hardy.
"Most bites don't occur in real isolated situations, so it is feasible
to get prompt [medical care]." He describes cases in Arizona where
people have caught rattlesnakes for sport and gotten bitten. "They
waited until they couldn't stand the pain anymore and finally went to
the hospital after the venom had been in there a few hours. But by then,
they'd lost an opportunity for [effective treatment]," which increased
the odds of long-term complications. Some medical professionals, along
with the American Red Cross, cautiously recommend two other measures: 

 * If a victim is unable to reach medical care within 30 minutes, a
   bandage, wrapped two to four inches above the bite, may help slow
   venom. The bandage should not cut off blood flow from a vein or
   artery. A good rule of thumb is to make the band loose enough that a
   finger can slip under it.

 * A suction device may be placed over the bite to help draw venom out
   of the wound without making cuts. Suction instruments often are
   included in commercial snakebite kits.

Treatment Drawbacks

Antivenins have been in use for decades and are the only effective
treatment for some bites. "Antivenins have a fairly good safety record,"
says Don Tankersley, deputy director of FDA's division of hematology.
"There are sometimes reactions to them, even life-threatening reactions,
but then you're treating a life-threatening situation. It's clearly a
case of weighing the risks versus the benefits."

People previously treated with antivenin for snakebites probably will
develop a lifelong sensitivity to horse products. To identify these and
other sensitive patients, hospitals typically obtain a record of the
victim's experience with snakebites or horse products. But some people
with no history of such exposures may have become sensitive through
contact with horses, or possibly exposure to horse dander, and not know
they are sensitive. Others may be sensitive without any known or
remembered contact with horses. So hospitals also perform a skin test
that quickly shows any sensitivity. Some hypersensitive patients may
even react severely to the small amount of antivenin used in the skin
test. Hospitals have procedures for reviving patients with serious
reactions. Some victims with positive skin tests can be desensitized by
gradually administering small amounts of antivenin.

Newer kinds of antivenins derived from sheep are under study now and
show some promise, according to FDA officials. But progress has been
slow due to low demand and the small number of venomous bites a year. 

Certain venomous snakebites may be treated without using antivenin. This
is usually a judgment call the doctor makes based on the snake's size
and other factors, which normally involves close monitoring of patients
in a medical facility. 

"In some areas, such as desert areas, most rattlesnakes are small and
don't have as potent a venom," says Edward L. Hall, M.D., a Thomasville,
Ga., trauma surgeon who treats snakebites. "You might get by with those
patients in not using antivenin." But with other snakes, Hall says,
antivenin can be a lifesaver. For example, the Eastern diamondback
rattlesnake--found in large quantities in the region of Georgia where
Hall practices medicine and in other Southern states from the Carolinas
to Louisiana--can reach six feet in length and deliver a potent payload
of venom. "It's an enormously dangerous bite that requires very
aggressive treatment [with antivenin] or the patient will die," Hall
says.

Treatment Dilemmas

Because not all snakebites, including those from the same species, are
equally dangerous, doctors sometimes face a dilemma over whether or not
to administer antivenin. Venomous snakes, even dangerous ones like the
Eastern diamondback, don't always release venom when they bite. Other
snakes may release too small an amount to pose a hazard.

Hall says his experience in Georgia bears this out. "Some 20 to 30
percent of patients we see who have been bitten by a snake, who actually
have fang marks, have not received any venom at all." He says one reason
for this may be poor timing by the snake. "Pit vipers have a very
sophisticated mechanism that allows them to deliver venom at the exact
instant the teeth are sunk into the flesh. So it has to be precise
timing. But what we often see is that the [snake's timing is off and]
venom is squirted on the pants leg or released prematurely."

Another complicating factor is the diverse potency of venom. "Venom can
vary within species and even within litter mates--brothers and sisters,"
says Arizona physician Hardy. For example, he says, a common pit viper
in the Southwest, the Mojave rattlesnake, may carry a powerful
neurotoxic venom in some areas and a less toxic one in others.

Hall's work in Georgia and Florida shows that factors such as genetic
differences among snakes, their age, nutritional status, and the time of
year also can affect venom potency. All these variables make it nearly
impossible for doctors to characterize a "typical" venomous snakebite.
That's why there exists what Hall calls "so much controversy" about
snakebite treatment. 

The solution, Hall says, lies with the patient. "Truly the only way to
look at snakebites is on an individual basis and on the patient's actual
reaction to the venom." Basic signs like pain, swelling and bleeding,
along with more complicated reactions such as ecchymosis (purple
discoloration), necrosis (tissue dies and turns black), low blood
pressure, and tingling of lips and tongue give medical professionals
clues to the seriousness of bites and what treatment route they should
take. 

Some experts emphasize that though antivenin can effectively reverse the
effects of venom and save life and limb, there is no guarantee that it
can reverse damage already done, such as necrosis. Some patients may
later require skin grafts or other treatment. Arizona physician Hardy
says the potential for limiting complications is one compelling reason
to seek medical treatment as soon as possible after a snakebite. 

Avoiding Snakebites

Some bites, such as those inflicted when snakes are accidentally stepped
on or encountered in wilderness settings, are nearly impossible to
prevent. But experts say a few precautions can lower the risk of being
bitten:

 * Leave snakes alone. Many people are bitten because they try to kill a
   snake or get a closer look at it.

 * Stay out of tall grass unless you wear thick leather boots, and
   remain on hiking paths as much as possible.

 * Keep hands and feet out of areas you can't see. Don't pick up rocks
   or firewood unless you are out of a snake's striking distance. (A
   snake can strike half its length, Hardy says.)

 * Be cautious and alert when climbing rocks.

What do you do if you encounter a snake when hiking or picnicking? Says
Hardy: "Just walk around the snake, giving it a little berth--six feet
is plenty. But leave it alone and don't try to catch it."

Though poisonous snakes can be dangerous, snake venom may have a
positive side. Clinical trials are presently under way to test the
therapeutic value of a venom-derived product called ancrod in treating
stroke. Earlier proposals, using snake venom to treat neuromuscular
disorders such as multiple sclerosis, never reached the clinical trial
stage.

John Henkel is a staff writer for FDA Consumer.


------------------------------------------------------------------------


How NOT to Treat a Snakebite

Though U.S. medical professionals may not agree on every aspect of what
to do for snakebite first aid, they are nearly unanimous in their views
of what not to do. Among their recommendations:

 * No ice or any other type of cooling on the bite. Research has shown
   this to be potentially harmful.

 * No tourniquets. This cuts blood flow completely and may result in
   loss of the affected limb.

 * No electric shock. This method is under study and has yet to be
   proven effective. It could harm the victim.

 * No incisions in the wound. Such measures have not been proven useful
   and may cause further injury.

Arizona physician David Hardy, M.D., says part of the problem when
someone is bitten is the element of surprise. "People often aren't
trained in what to do, and they are in a panic situation." He adds that
preparation--which includes knowing in advance how to get to the nearest
hospital--could greatly reduce anxiety and lead to more effective care. 

--J.H.

------------------------------------------------------------------------


Interstitial Cystitis
Progress Against Disabling Bladder Condition

by Evelyn Zamula

The woman knew she was going to be fired from her job. Since her 20s,
this insurance firm middle manager has suffered from interstitial
cystitis (IC), an inflammatory disease of the bladder wall. 

The chief symptoms Marsha (not her real name) has are a smaller than
normal bladder capacity, urgent and frequent urination, feelings of
pressure and pain around the bladder and in the pelvic area, and painful
sexual intercourse. Now 46 years old, she has coped with these symptoms
fairly well until recently, when they have worsened. On some days,
Marsha is in such agony that she can barely walk.

Though sympathetic at first, Marsha's supervisor became impatient with
her frequent bouts of pain and trips to the bathroom, as well as time
lost from sick days and doctor's appointments, even though she's made up
every minute. When she started to miss policy meetings, Marsha began to
get indications that she would be fired. Her boss would comment that she
couldn't know what was going on because, "You aren't always here."

Finally, when Marsha needed to urinate every 20 minutes at work and 10
times during the night, leaving her exhausted and depressed in the
morning, she became so fearful of being asked to leave that she decided
to retire on disability instead. She hopes to return to her job when she
feels better, but so far it hasn't been possible. 

Marsha counts herself among the more fortunate of IC sufferers because
she receives long-term disability benefits and has both Medicare and
private medical insurance. Also, unlike many other women, whose
marriages and relationships are put under severe stress by IC, Marsha is
lucky to have a supportive husband.

Cause Elusive 

No one knows what causes IC. It wasn't recognized as a disorder until
about 20 years ago. In 1978, the Food and Drug Administration approved
Rimso-50, a purified form of the industrial solvent dimethyl sulfoxide
(DMSO), for symptomatic relief of IC. Before that, many patients were
neither diagnosed nor treated. 

Because physicians could find no organic cause, the prevailing medical
opinion was that IC was a "hysterical female condition," even though at
least 10 percent of cases are in men. Even Campbell's Urology, the
definitive text of urologic diseases, stated as late as 1986 that IC was
"daunting in its evasion of being understood. [It] may represent the end
stage of a bladder that has been made irritable by emotional
disturbance." The book further states that interstitial cystitis may be
a pathway for the discharge of unconscious hatreds. 

People with IC have had to put up with this type of disbelief for a long
time. Kristene E. Whitmore, M.D., chairwoman of the Department of
Urology, Philadelphia Graduate Hospital, Philadelphia, Pa., says, "The
average number of doctors seen before diagnosis is five, and it takes
three to five years to get that diagnosis."

When the columnist Ann Landers wrote about IC in 1987, she received
10,000 letters from patients or their families, relieved that the
condition was finally being recognized. A 1987 study conducted by the
Urban Institute in Washington, D.C., found that IC makes people so
miserable that they contemplate suicide four times more often than the
general population and that they rate their quality of life lower than
those who undergo kidney dialysis. Nearly 30 percent of IC patients
can't work full-time, according to the study.

Although no bacteria or fungi or viruses are found in patients' urine,
many researchers believe it's possible that IC is caused by an
infectious agent that hasn't yet been identified.

Researchers have also suggested it may be an autoimmune disorder of the
bladder's connective tissue, in which the body's defense mechanisms
against invading bacteria turn suddenly against healthy tissue. In some
patients, special white blood cells called mast cells, which are
associated with inflammation, are found within the bladder's mucous
lining. Or, some scientists theorize that the disorder may be an
allergic reaction, because many patients have a history of allergies.

Some women go into remission during pregnancy, while others get worse,
suggesting that in some patients hormones may be involved. Complicating
the picture, many women with IC also suffer from a variety of other
conditions, such as irritable bowel syndrome, migraine headaches,
fibromyalgia (chronic aching of the muscles, joints, and connective
tissues), low back pain, and similar disorders.

One theory in favor at present holds that the inner lining of the
bladder (the glycosaminoglycan or GAG layer) that protects the bladder
wall from toxic effects of urine may be "leaky," allowing substances in
the urine to penetrate the bladder wall and trigger IC symptoms. A
California study found that 70 percent of IC patients they examined had
a "leaky" bladder lining.

More likely, any or all of these factors may exist, leading many
researchers to conclude that IC is a syndrome, or a collection of signs
and symptoms, rather than a specific disease. Others, such as Whitmore,
believe it's more than one disease and is different in every person.

Making a Diagnosis 

Although there is no test that identifies IC, urologists rely on several
criteria to make a diagnosis:

 * Frequent and urgent urination, and pelvic or bladder pain, especially
   as the bladder is filling.

 * Pinpoint hemorrhages that can often be seen on the bladder wall
   during cystoscopy (an examination of the bladder's interior with a
   long, lighted tube, performed under anesthesia). This is called
   nonulcerative IC, seen in about 95 percent of patients.

 * Cracks, scars, and star-shaped sores called Hunner's ulcers that are
   found in the bladder wall in ulcerative IC. Bladder capacity is
   decreased because the usually elastic bladder walls become stiff and
   don't expand normally.

Because it's easier to define IC by what it isn't than by what it is, a
diagnosis must rule out bacterial cystitis--the most common urinary
tract infection--whose symptoms it most closely resembles. Bladder
cancer, kidney stones, vaginitis, endometriosis, sexually transmitted
diseases, and tuberculous and radiation cystitis, as well as prostate
infections in men, are some other conditions that must be considered.
Thus, interstitial cystitis becomes a diagnosis of exclusion.

Although about 10 times more women than men get IC, it's possible that
men have been underdiagnosed. "We haven't been real sensitive in
screening our prostatitis patients, so maybe more men have IC than we
think," says Whitmore.

Symptoms usually begin between 20 and 50 years of age, but the average
age of onset is 40. Some cases have been diagnosed in children. About
450,000 people in the United States are believed to have IC, but true
numbers are hard to come by, because many cases are either undiagnosed
or misdiagnosed. Although occasionally more than one member of a family
has IC, the disorder is not believed to have a genetic component.

Treating the Condition

There is no cure for IC. All doctors can do is try to relieve the
symptoms, a challenging task, because they vary from person to person.
People may have flare-ups and remissions, and different patients respond
to different treatments. A particular type of therapy may work for a
while and then lose its effectiveness. Sometimes, stress or a change of
diet triggers symptoms. Occasionally, IC goes into remission
spontaneously.

Paradoxically, the cystoscopy used to diagnose IC also seems to make
some people feel better. To enable the doctor to look inside the bladder
with the cystoscope, the bladder is filled with water. This bladder
distention helps about 30 percent of patients, at least for the short
term, probably because the bladder is stretched and capacity is
increased. It's also possible that the procedure may interfere with the
transmission of pain signals by nerves in the bladder. The fact that IC
can only be diagnosed by cystoscopy under anesthesia explains why many
cases are overlooked even by urologists. 

In a similar procedure, Rimso-50 is instilled directly into the bladder
by a catheter. The solution is retained in the bladder for about 15
minutes before being expelled by spontaneous voiding. This treatment is
given every two weeks until maximum symptomatic relief is obtained, then
repeated as needed. 

For some patients, Rimso-50 treatments become less effective over time.
About 50 percent of patients experience significant pain relief for an
average of about 10 months. The drug works by penetrating the bladder
wall to reduce inflammation and acts as a muscle relaxant by preventing
muscle contractions that cause pain, frequency and urgency. 

Disadvantages of Rimso-50 include a garlic-like odor on the skin and
breath that may last up to 72 hours. Some patients may develop a
chemical cystitis after use of the drug that goes away within one or two
days. Patients taking Rimso-50 also require a blood test every six
months to make sure the blood count and liver and kidney function are
normal. Periodic ophthalmologic examinations are also recommended.

"You have to customize therapy for the person," says Whitmore, who
advocates a number of untraditional therapies, many of which have not
been reviewed by FDA for this purpose. They include acid-restricted
diets, alkalization of urine, bladder holding and retraining (delaying
voiding for increasingly longer intervals), biofeedback and electric
stimulation, acupuncture, muscle relaxants, antidepressants,
anti-inflammatories, antihistamines and analgesics, and an experimental
bladder "wash" consisting of an anesthetic, an antibiotic, an
anticoagulant, and hydrocortisone.

From 40 to 60 percent of IC patients may benefit from low doses of the
tricyclic antidepressant amitriptyline (Elavil and others), according to
Vicki Ratner, M.D., and colleagues in the Journal of Women's Health,
Vol. 1, No. 1, 1992. Physicians prescribe it not only to treat the
depression that is common in IC patients, but to take advantage of its
bladder-relaxing, allergy-fighting, pain-blocking, and sedating
properties.

When pain is severe, some people may benefit from transcutaneous
electrical nerve stimulation (TENS). Mild electrical impulses delivered
to the body through wires placed on the lower back or abdomen or through
devices implanted in the body may alter nerve transmissions to the
bladder and help trigger release of pain-blocking hormones. 

A bland diet helps some IC people. Doctors recommend avoiding high-acid
foods, such as citrus fruits, that may irritate the bladder, or spicy
foods that may cause the release of histamine. Restricting alcoholic
beverages, carbonated sodas, coffee and other caffeinated products, and
beverages and foods with artificial sweeteners appears to reduce
symptoms in some people.

Surgery is an option when all else fails. Some urologists may remove the
diseased portion of the bladder and attach a piece of the patient's
bowel to the remaining healthy tissue to make a larger bladder. In other
cases, the bladder is completely removed and urine is rerouted to a bag
outside the body or a pouch inside the abdomen. However, about half of
patients don't get pain relief from this procedure. 

"I don't take the bladder out unless I've used all the tricks up my
sleeve," says Whitmore. "When patients have bladders the size of a
walnut or smaller, or when they have intractable pain, then they're
candidates for cystectomy [bladder removal]. The operation has allowed
some people to get out of the house and have a life."

Whitmore tells her patients that, as with all disorders of chronic pain,
there is going to be a certain amount of anger, anxiety and depression.
"I say to them, 'I have an 85 percent chance or greater to make you
better, but I can't teach you how to cope with your illness, so you've
got to get some help.' I encourage them to go for self-hypnosis,
self-relaxation, and other coping techniques, or to seek therapy with
psychologists or psychiatrists. I tell them, 'if you can't cope, you're
not going to get better.'"

Researchers funded by the federal government, drug companies, and the
Interstitial Cystitis Association have stepped up their efforts to find
out more about the disorder. Philip Hanno, M.D., chairman, Department of
Urology, Temple University School of Medicine, Philadelphia, Pa.,
expects that in the next decade, treatment for IC will be more
beneficial than the therapy available now. He believes that ultimately
there will be a cure for most cases of this painful and disabling
condition. 

Evelyn Zamula is a freelance writer in Potomac, Md.


------------------------------------------------------------------------


IC Symptoms

The symptoms of interstitial cystitis are similar to those of a urinary
tract infection. Most people have some of the following symptoms:

 * urgent need for frequent urination both day and night

 * reduced bladder capacity

 * feelings of pressure, pain and tenderness around the bladder, pelvis
   and genital area, which may increase as the bladder fills and
   decrease as it empties.

 * painful sexual intercourse

 * in men, discomfort or pain in the prostatic area.

--E.Z.


------------------------------------------------------------------------


For More Info

More information about interstitial cystitis is available from:

Interstitial Cystitis Association
P.O. Box 1553
Madison Square Station
New York, NY 10159
(1-800) 422-1626

American Foundation for Urologic Disease, Inc.
300 West Pratt St.
Suite 401
Baltimore, MD 21201
(1-800) 242-2383

------------------------------------------------------------------------



Updates


MSG Judged Safe For Most People


The food ingredient monosodium glutamate (MSG) is safe at normally
consumed levels for the general population, according to results of a
scientific review sponsored by FDA. 

A panel of experts, convened by the Federation of American Societies for
Experimental Biology (FASEB) under contract with FDA, found no evidence
linking MSG to any serious, long-term medical problems in the general
population. 

But FASEB's report on the findings did state that evidence suggests
certain people may develop short-term reactions when they consume large
doses--approximately 3 grams or more per meal--of MSG or related "free
glutamates." These reactions, dubbed "MSG Symptom Complex" in the
report, were not linked to low levels of glutamate consumption. 

The report also expressed concern that glutamate may affect a small
group of people with severe asthma. Limited clinical studies show some
of these people experienced bronchospasm up to six to 12 hours after
being exposed to MSG. 

MSG is one of several types of glutamates--substances derived from
glutamic acid, a major building block for proteins. When glutamate that
has been bound within a protein is released during breakdown of the
protein molecule, "free glutamate" is formed. These substances can be
added to food to enhance its flavor and are the focus of much of the
concern about glutamates. Some foods, such as ripe tomatoes and parmesan
cheese, contain high levels of naturally occurring free glutamates. 

Based on a preliminary review of the FASEB report, FDA plans to propose
that foods containing significant amounts of free glutamate declare
glutamate as an ingredient on the label. This would allow consumers to
distinguish between foods with insignificant free glutamate levels and
those that might contribute to a reaction. 

Currently, foods containing added MSG must declare it as an ingredient
on their labels. Processed foods containing other ingredients with
significant levels of free glutamate (such as autolyzed yeast, soy
sauce, and some flavorings) must declare these ingredients, like any
other ingredient, on their labels. 

FDA sponsored extensive reviews of MSG and related substances in 1978
and 1980, both of which concluded MSG is safe for the general public at
common-use levels. But the 1980 review noted that additional data were
needed to judge whether a significant increase in glutamate consumption
can cause adverse effects. FASEB's report, contracted by FDA in 1992, is
the most comprehensive review of existing information on glutamate
safety. 



New Osteoporosis Therapy

Calcitonin salmon nasal spray was recently approved under the brand name
Miacalcin Nasal Spray to treat osteoporosis in postmenopausal women,
beginning five years after menopause. Previously, the only approved
treatments for treating or preventing osteoporosis had been injectable
calcitonin salmon and estrogen. 

Two clinical trials demonstrated that daily use of calcitonin salmon
nasal spray increases bone mass in the spine, although no bone-building
effects were shown on bone mass of the forearm or hip. The manufacturer,
Sandoz Pharmaceuticals Corp. of East Hanover, N.J., agreed to conduct
additional studies to evaluate the product's long-term effectiveness in
preventing fractures. 

The most common side effects during the trials included inflammation of
the membranes in the nose, nosebleeds, and sinusitis. Patients using the
nasal spray should have periodic nasal examinations for ulceration or
irritation. 

Osteoporosis, the thinning of bones in postmenopausal women and elderly
men, is a major cause of bone fractures that affect as many as 20
million Americans. Women over 45 commonly suffer fractures of the hip,
wrist or spine due to loss of bone mass from osteoporosis. 

Women on drug therapy for osteoporosis should take daily supplements of
calcium and vitamin D. This regimen--along with exercise--helps prevent
the loss of bone mass. 

(For more information about osteoporosis, see "Osteoporosis Treatment
Advances" in the April 1991 FDA Consumer.) 

Information on Norplant Available



Women who choose Norplant--a contraceptive device surgically inserted
into the upper arm--will now be given a form to sign, acknowledging that
they received information on the risks and benefits of the device before
insertion. 

Norplant, which was approved in 1990, consists of six silicone rubber
capsules containing the hormone levonorgestrel. The capsules are
surgically inserted under the skin of a woman's upper arm and provide
contraceptive protection for up to five years. The capsules are
surgically removed at the end of that time or earlier if desired. Both
procedures are done in the doctor's office. 

To help ensure that women are appropriately informed of the product's
risks and benefits before implantation, FDA and Norplant's manufacturer,
Wyeth-Ayerst Laboratories of St. David's, Pa., developed new education
materials for patients and providers. Included is the acknowledgment
form and revisions of the product package insert for doctors and
patients that include a discussion of reported adverse reactions. 

Side effects commonly associated with Norplant include vaginal bleeding,
headaches, nausea, dizziness, and nervousness. 

FDA's postmarketing surveillance of Norplant and its ongoing analysis of
adverse reaction reports have found no basis for questioning the
product's safety and effectiveness when used as directed in the
labeling. 

For more information on Norplant and the names of providers experienced
in inserting and removing the device, call Wyeth-Ayerst's toll-free
telephone line (1-800) 934-5556. 

(See also "Norplant, Birth Control at Arm's Length," in the May 1991 FDA
Consumer.) 


Treatment IND for Drug to Treat CMV

Under a treatment IND recently authorized by FDA, doctors may use the
investigational drug intravenous Vistide (cidofovir) to treat
HIV-infected patients with relapsing cytomegalovirus (CMV) retinitis
that has progressed despite treatment. 

CMV retinitis is an eye infection that can lead to blindness in people
with impaired immune systems, such as AIDS patients. 

FDA established the Treatment IND (investigational new drug) process for
patients suffering from serious or life-threatening conditions who have
exhausted existing treatments or have no satisfactory treatments. Under
the process, patients can obtain promising experimental drugs that have
undergone sufficient clinical testing to show they may be safe and
effective. The agency based its decision to expand access to intravenous
Vistide on a controlled clinical study that showed the drug may slow CMV
retinitis progression. 

Drugs already approved to treat CMV retinitis are Foscavir (foscarnet
sodium) and Cytovene (ganciclovir sodium). Neither can cure CMV
retinitis, but both can significantly delay disease progression. 

Vistide is made by Gilead Sciences Inc., Foster City, Calif. The company
started offering the drug free under this Treatment IND program on Sept.
5. For more information, call (1-800) GILEAD-5. For more about other
AIDS clinical trials, call (1-800) TRIALS-A. 


Pertussis Vaccine Trials

Recent results of pertussis vaccine clinical trials show that three
experimental vaccines are highly effective in infants, according to the
National Institute of Allergy and Infectious Diseases, part of the
National Institutes of Health. Pertussis is also called "whooping
cough." 

The trials, sponsored by NIAID and conducted in Italy and Sweden, also
reported that the experimental vaccines caused fewer side effects than a
vaccine currently used in the United States. 

FDA's scientists in its Center for Biologics Evaluation and Research
have been instrumental in developing and evaluating acellular vaccines
and have collaborated with NIAID and the vaccine manufacturers to design
the European trials. 

The experimental vaccines are called acellular vaccines because they
contain only the parts of the pertussis bacterium thought to be
important for immunity. U.S. vaccines licensed for use in infants are
called whole-cell vaccines, because they contain the whole, inactivated
pertussis organism. 

The trials, which began in 1992, involved about 25,000 infants. Groups
of infants received either an acellular pertussis vaccine combined with
diphtheria and tetanus toxoids (DTaP), a whole-cell (DTP) vaccine, or,
in the control group, a diphtheria-tetanus vaccine. 

Three DTaP vaccines were found to be approximately 85 percent effective,
while the DTP vaccine was 36 percent effective in the Italian trial and
48 percent effective in the Swedish trial. A fourth DTaP vaccine was 58
percent effective. 

Whole-cell pertussis vaccines currently marketed in the United States
are reported to be 70 to 90 percent effective. 

Only three doses were given in the trials, compared to five doses
normally given in the United States. It is not known whether this
difference in dosage accounts for some of the disparity in the
effectiveness of the whole-cell vaccine. In addition, the epidemic
conditions in Sweden and Italy, where pertussis vaccines are not as
widely used as in the United States, differed from the United States,
where pertussis is much less common. 

Seizures were reported rarely in the trials, but occurred no more
frequently in any of the pertussis vaccine groups than in the control
group. Side effects, such as redness, pain and swelling at the site of
the injection, fever, and protracted crying, were reported to be less
common with the acellular vaccines than with the whole-cell one. 

FDA has made special efforts to encourage submission of applications for
the use of acellular pertussis vaccines in infants. The agency will
target such applications for complete review within six months of
receiving them. However, actual times to any licensing can vary,
depending on the quality and completeness of the data submitted. 

FDA recommends that parents continue to get their children vaccinated
against pertussis with available vaccines. The agency has licensed four
whole-cell pertussis vaccines and, for the fourth and fifth doses, two
acellular vaccines. 

All vaccines pose risks of side effects, but for both whole-cell and
acellular pertussis vaccines, serious, long-lasting problems are
extremely rare. The disease itself can be fatal. In 1993, 11 pertussis
deaths were reported to the national Centers for Disease Control and
Prevention. 

(For more information about pertussis vaccination, see "New Pertussis
Vaccine Offers Prevention Alternative," in the September 1992 FDA
Consumer.) 



Saraflox Approved to Control Poultry Illnesses

Saraflox (sarafloxacin), the first fluoroquinolone antibiotic to be
approved for food animals, was recently approved by FDA for use in
poultry drinking water to control illnesses caused by Escherichia coli
bacteria. 

Fluoroquinolones are the newest class of antibiotics developed for
treating infections in people and animals. Another fluoroquinolone drug,
enrofloxacin, was approved in 1989 to treat certain pet infections. 

"Sarafloxacin provides veterinarians a way of preventing disease in
poultry flocks as long as it is used appropriately," said FDA
Commissioner David A. Kessler, M.D. "It is important that antibiotics
for food animals be used correctly to minimize the potential for
development of drug-resistant microbes." 

During a public hearing in May 1994, FDA's veterinary medicine and
anti-infective drugs advisory committees recommended approval of
fluoroquinolones found to be safe and effective for animal use, but also
recommended that the agency establish conditions for approval to
minimize any potential for development of resistant bacteria. 

FDA is cooperating with the U.S. Department of Agriculture and the
national Centers for Disease Control and Prevention in a program to
detect and prevent drug-resistant microbes. In addition, the
manufacturer will test samples of animal E. coli to measure emergence of
any drug resistance. 

Saraflox, available only by prescription, is manufactured by Abbott
Laboratories, North Chicago, Ill. It was approved last Aug. 18. 



Free Info from FDA

A free brochure warning people with certain medical conditions never to
eat raw oysters is available from FDA. 

Also available are three free FDA Consumer reprints. The titles and
publication numbers are: 


 * If You Eat Raw Oysters, You Need to Know ... (FDA) 95-2293

 * Public Affairs Specialists: FDA's Walking Encyclopedias (FDA) 95-1222

 * An FDA Guide to Choosing Medical Treatments (FDA) 95-1223

 * Keeping Medical Devices Safe from Electromagnetic Interference
   (FDA) 95-4261.

To order single copies, write to FDA, HFE-88, Rockville, MD 20857. To
order 2 to 100 copies, write to FDA, HFI-40, at the same address, or fax
your order to (301) 443-9057. Include the publication number. 

------------------------------------------------------------------------


Notebook

The Notebook: a potpourri of items of interest gathered from FDA news
releases, other news sources, and the Federal Register (designated FR,
with date of publication). The Federal Register is available in many
public libraries.

Cigarette and smokeless tobacco and the reasoning behind FDA's proposed
regulation of them are the subject of a report published by FDA last
Aug. 11. "Nicotine in Cigarettes And Smokeless Tobacco Products Is A
Drug And These Products Are Nicotine Delivery Devices Under the Federal
Food, Drug, and Cosmetic Act" explains agency findings that nicotine in
cigarettes and smokeless tobacco is a drug, and that these products are
drug delivery devices and, therefore, fall under FDA jurisdiction.
Single copies are available for $21 from Superintendent of Documents,
Government Printing Office, Washington, DC 20402; telephone (202)
512-1800. Request stock number 017-012-00373-7. The document is also
available on FDA's Internet site at
http://www.fda.gov/opacom/campaigns/tobacco.html. (FR Aug. 11)

Condoms and condom-like products, including those marketed as novelty
items, are subject to all medical device regulatory requirements,
according to a new FDA policy statement. The statement supersedes the
agency's 1989 policy on condom labeling. For a free copy of the
statement, send two self-addressed labels to Division of Small Business
Manufacturers Assistance (HFZ-220), Rockville, MD 20857. Request Docket
No. 95D-0162. (FR Aug. 3)

Revised guidance for certain frozen and canned fish, with decomposition
and histamine information, is available from FDA. "Decomposition and
Histamine--Raw, Frozen Tuna and Mahi-Mahi; Canned Tuna; and Related
Species" provides lower histamine action levels. For a free copy, send
two self-addressed labels to Office of Constituent Operations, Industry
Activities Staff (HFS-565), Washington, DC 20204. Request Docket No.
95D-0157. (FR Aug. 3)

Safety and effectiveness information for 27 class III (high-risk)
medical devices must soon be submitted to FDA. The agency is requesting
the information to determine whether to revise its classification of the
devices or issue new regulations requiring premarket approval. The 27
devices include such products as lung water monitors and implanted
neuromuscular stimulators. (FR Aug. 14)

Computer submission of pharmacology and toxicology studies for new drugs
is now an option for drug sponsors under a Center for Drug Evaluation
and Research pilot program. Sponsors who want more information should
contact Patricia A. Sylvia, CDER (HFD-72), Rockville, MD 20857;
telephone (301) 443-3695. (FR Aug. 30)

Pesticide residue monitoring data for fiscal year 1994 is available from
FDA on computer diskette. This is the third annual comprehensive
compilation of monitoring data for pesticide residues in foods that FDA
has offered. To order copies of the diskettes (at $50 each), request
order number PB95-503132 from the National Technical Information
Service, Department of Commerce, 5285 Port Royal Rd., Springfield, VA
22161; telephone (703) 487-4650. In addition, shipping and handling
costs are $4 for one copy, $6 for two, and $8 for three or more copies.
(FR Aug. 24)

Lead information is available in a new pamphlet, "Protect Your Family
from Lead in Your Home," developed by the Environmental Protection
Agency and Consumer Product Safety Commission. For one free copy, call
the National Lead Information Clearinghouse at (1-800) 424-LEAD (TDD
1-800-526-5456). The document is also available through the Internet at
gopher://gopher.epa.gov:70/11/Offices/PestPreventToxic/Toxic/lead_pm.
Multiple copies are available for $26 per pack of 50 copies from the
Superintendent of Documents, P.O. Box 371954, Pittsburgh, PA 15250-7954;
telephone (202) 512-1800. Request the pamphlet by title and stock number
055-000-00507-9. (FR Aug. 1) 

------------------------------------------------------------------------


Investigators' Reports


Device Firm Closes Pending Compliance with FDA Regulations

by Dixie Farley

After FDA found manufacturing problems with sensitive eye treatment
devices, a device firm and two of its officers agreed to stop operating
until FDA requirements are met.

U.S. District Court Judge Robert E. Keeton of the District of
Massachusetts in Boston last April 25 entered a consent decree of
permanent injunction against Mira Inc., of Waltham, Mass., and Luc
Schepens and Roger O'Brien. Schepens was Mira's president, and O'Brien
its manager of quality assurance, quality control, and regulatory
affairs.

The firm specializes in devices such as cryogenic probes used to freeze
eye tissue for surgery and sterile implants used to reattach detached
retinas. The government's complaint for injunction filed with the
consent decree alleges that the devices violated FDA's good
manufacturing practice (GMP) regulations since at least 1991.

FDA inspections of Mira since 1986 had revealed numerous GMP
deficiencies. In a regulatory letter dated Feb. 20, 1991, the agency's
Boston district office advised Mira of problems with implants, such as
inadequate controls for specifications and quality assurance,
uninvestigated complaints, inadequate record keeping, unclean
conditions, and no written procedures for finished device inspection.

Further, FDA advised, Mira hadn't reported to the agency complaints
about a laser and a glaucoma device. A health-care professional
complained, for example, that filters didn't protect the operator from
possible injury from reflected laser beams. If Mira did not act promptly
to make corrections, FDA warned, the agency might invoke legal actions
such as seizure or injunction. Mira promised corrections.

Then, between November 1991 and December 1992, complainants told FDA's
Boston office that the deficiencies with the agency's GMP regulations
were continuing at the firm.

Following these complaints, FDA investigators inspected Mira and found
additional evidence of continuing violations. A 1992 inspection revealed
the firm was marketing a device without FDA clearance. Mira voluntarily
recalled the device.

During a March and April 1993 inspection, FDA engineer Richard Wright
observed practices relating to violations of GMP regulations in the
manufacture of Mira's Imex silicone implants and cryogenic freezing
instruments.

Mira buys Imex strip and sponge implants ready-made and cuts them to
size. But the firm itself molds a third Imex variety, silicone tire
implants (so-named because of their tire shape), from purchased raw
material--a medical grade elastomer.

Information included with the elastomer indicated a shelf life of only
six months, Wright found, yet Mira was using elastomer produced in 1987
to make the tire implants.

Wright found Mira had lost the elastomer's original certificate and had
the material tested only once, in September 1992. During that test,
Wright learned, the material failed the firm's own specifications for
tensile strength and elongation and wasn't tested for another
specification.

Also, Wright found Mira made a design change in its cryogenic devices
but never tested the new products to make sure they worked properly.
"The change in fact caused them to fail," he says, "so Mira had to go
back to the original design."

Wright informed Mira of his findings.

In a letter dated April 30, 1993, Mira told FDA it planned to take
corrective action "as logistical and manpower limits allow."

In July and August 1994, Wright and investigator John McCann inspected
Mira.

"Mira was not operating in a state of control," Wright says. "The GMP
problems were systemic, and the corrective actions didn't address the
root causes. Therefore, each time we'd go in, we'd invariably find
similar problems."

As a result of this inspection, FDA requested a permanent injunction.

Under the consent decree, Mira and its officers Schepens and O'Brien
agreed to:

 * stop making and shipping medical devices until the company complies
   with FDA's GMP regulations

 * undergo FDA reinspection to ensure practices comply with the law
   before resuming full operation

 * destroy devices that can't be brought into compliance with the
   Federal Food, Drug, and Cosmetic Act

 * maintain compliance with laws and regulations enforced by FDA

 * hire an expert consultant to conduct audits during the next two years
   to ensure operations continue to meet FDA's GMP regulations.

At press time, FDA was continuing to work with Mira to meet the terms of
the decree.

Dixie Farley is a staff writer for FDA Consumer.


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Bribery Attempt Lands Businessman in Jail

Bribery awareness training paid off for an FDA investigator when a San
Francisco Chinatown importer tried to pay him off during a routine
inspection.

The importer, Phillip Chew, 38, owner of Wha Shing Trading Co., was
sentenced June 13, 1995, in U.S. District Court for the Northern
District of California to four months in prison, followed by four months
of electronic home monitoring and three years' probation for bribing FDA
investigator Junes Valdemoro of FDA's San Francisco district office. He
also was fined $5,000.

Chew had hoped to sway Valdemoro into allowing possibly contaminated
food from China into the country.

Acting on what he learned in a mandatory training course, Valdemoro
enabled the Department of Health and Human Services' Inspector General's
Office of Investigations to conduct a sting operation that led to Chew's
conviction. Valdemoro assisted in the sting operation.

Chew initially offered Valdemoro money on May 4, 1994, at his Chinatown
business, after Valdemoro rejected the entry of food whose packaging was
covered with rodent droppings.

Chew told Valdemoro he would clean it up and then left the room. When he
came back, Valdemoro recalled, Chew held out a wad of money to him.

"I told him, 'No, no, that's illegal,' but he was persistent," Valdemoro
said. "He told me that it was a Chinese New Year present and that I was
his friend. Then I remembered what I learned in training: that I
shouldn't close the door on this guy. So I said, 'I'll have to think
about this.'"

Valdemoro then left the premises and called his supervisor and the
Office of the Inspector General (OIG) in San Francisco. At the OIG's
request, he participated in plans to secretly monitor his future
dealings with Chew. Officials briefed Valdemoro on what he should do and
say on subsequent visits and arranged for him to be wired for secret
audiotaping.

As directed by the OIG, Valdemoro contacted Chew later that day. Chew
offered him $300 in return for a "clean report." Valdemoro accepted the
money and turned it over to the OIG for use in its investigation.

Valdemoro returned to Chew's warehouse on May 19 for a routine
examination of a Customs entry. While Valdemoro was there, Chew put a
$100 bill into Valdemoro's lab coat and said it was a gift. Again,
Valdemoro accepted the money and turned it over to the OIG.

That same day, Chew offered to pay Valdemoro $200 to $500 to release
seven food items detained by FDA because of contamination with insects,
animal filth, feathers, rat or mouse hair, cat or dog hair, and rabbit
hair. One item had to be relabeled to include sulfites as an ingredient.
No money was exchanged.

On May 23, Chew gave Valdemoro $1,000 to have the seven food items
released, and on Aug. 17 gave him $900 to release another detained
entry. Valdemoro again gave the money to the OIG. The detained items
were never released for sale in this country. Chew also offered to give
Valdemoro a pager and cellular phone to simplify future illegal
transactions.

Chew and a business partner, Ada Lee, were arrested Oct. 13 for bribing
a government official. Chew pleaded guilty to one count of bribery. The
U.S. Department of Justice did not seek prosecution of Lee.

For his exemplary work, Valdemoro received the DHHS Inspector General's
annual Integrity Award last August.

--Paula Kurtzweil


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Seafood Maker Fined For Misbranding

When customers bought Miss Sally's stuffed crabs from Sam's Club
membership stores in southern and midwestern states through early 1994,
they got a handsome window package revealing crab shells stuffed with
what appeared to be huge chunks of crab meat. Labels listed crab meat as
a major ingredient and bore a bright orange sticker claiming "more
crabmeat than ever."

But little or no crab meat was in many of those products. Instead, the
shells were stuffed with surimi, a whitefish sometimes used as an
inexpensive crab substitute, which should have been listed on the label. 

As a result of fraudulent use of the word "crabmeat," David R.
Carrington and his company, Carrington Foods Inc., of Saraland, Ala.,
were ordered to pay $78,000 in fines last May 15 after pleading guilty
to one misdemeanor count and one felony count of food product
misbranding. 

Carrington, 50, also was sentenced to two years' probation, and his
company received five years' probation. Initially, Carrington was
indicted on a felony misbranding charge, but when he agreed to plead
guilty, the court downgraded the charge to misdemeanor, while retaining
the felony charge for his company.

FDA first became aware of Carrington's misdeeds in late 1993, when a
seafood industry consultant told FDA investigators that Carrington Foods
was not putting any crab meat in its stuffed crabs. (FDA considers
stuffed crabs without crab meat to be "imitation stuffed crabs.") In
response, FDA collected numerous samples of Carrington's products and
confirmed that little or no crab meat was present. 

In late November and early December 1993, investigators from FDA's
Mobile, Ala., resident post inspected Carrington Foods and observed its
manufacturing procedures. At the beginning of the inspection,
investigators noticed more than 1,100 pounds of frozen surimi being
thawed in the firm's production areas. Within three hours, plant
employees placed the surimi in one of the company's large coolers, where
it remained for the rest of the inspection.

Investigators observed Carrington's production of stuffed crabs for
Sam's Club. The firm used minced crab meat, an inexpensive "mushy"
product with little or no texture, unlike the chunky texture normally
seen through package windows in Miss Sally's stuffed crabs. But because
minced crab is a crab product, the plant appeared to be processing the
food legally. Analysis of a stuffed-crab sample produced during the
inspection revealed some crab meat but no surimi.

After the inspection, FDA's Nashville district office requested more
samples of Carrington Foods' stuffed crabs. Samples analyzed in FDA's
Seattle laboratory showed Carrington had been substituting surimi for
crab meat before the 1993 inspection, was using minced crab meat during
the inspection, and then switched back to surimi after the inspection. 

Because the samples clearly documented consumer fraud, in April 1994 the
agency's Office of Criminal Investigations began working with the U.S.
Attorney's Office to bring charges. In December 1994, a grand jury
indicted Carrington and his firm on misbranding charges.

Carrington Foods has since lost its contract with Sam's Club.

--John Henkel


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Defective Lenses Reconditioned

A manufacturer of implantable intraocular lenses (IOLs) was forced to
reinspect and resterilize nearly 60,000 lenses under a consent decree
the company entered into with FDA.

At press time in August, FDA expected Mentor ORC Inc., formerly Optical
Radiation Corp. (ORC) of Azusa, Calif., and Cidra, Puerto Rico, to
complete the reconditioning process in October. ORC agreed to
recondition the lenses, worth as much as $20 million, after numerous FDA
inspections found that they were not made in compliance with good
manufacturing practices (GMPs). The lenses were among 92,000 seized in
1993 because of possible defects. 

The U.S. District Court for the Central District of California entered
the consent decree on July 5, 1994, and ORC sold its IOL business to
Mentor Corp. of Santa Barbara, Calif., a few months later. Mentor
renamed the company.

Following surgery to remove cataracts, the IOLs are permanently placed
in the eyes of patients, who are typically at least 60 years old.
Defective IOLs pose an unreasonable risk to patients because damaged
IOLs can impair sight and injure tissue, leading to the need for more
surgery. Surgery may be especially risky in older people, who may have
other health problems.

FDA first uncovered GMP violations during a routine inspection of the
company's Puerto Rico facility in 1989. (The IOLs were made in San Juan
and then shipped to California for sterilizing and packaging.)
Violations continued to show up during inspections in 1991 and 1993,
despite an FDA warning and notice of adverse findings. Most of the
violations were at ORC's Puerto Rico facility, although an inspection of
the company's California plant in 1993 also uncovered deficiencies.

The inspections found that, among other things, the company failed to:

 * establish and carry out measures to ensure the devices were made
   according to design plans

 * adequately investigate physicians' complaints about the IOLs

 * validate certain manufacturing processes

 * investigate the reasons for high defect rates.

On Nov. 23, 1993, at FDA's request, U.S. marshals seized nearly 92,000
IOLs at the company's California plant. FDA allowed the IOLs to remain
at the plant until a decision was made on their fate.

Posting a $1 million bond, the company agreed to recondition the lenses,
dispose of those that failed reinspection, and pay the federal
government up to $56.50 an hour for FDA to supervise the process, which
began early this year.

The company was reconditioning the lenses at its Puerto Rico facility
and plans to move its entire IOL business to that site in the near
future.

--Paula Kurtzweil 

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Summaries of Court Actions


Summaries of Court Actions are given pursuant to Section 705 of the
Federal Food, Drug, and Cosmetic Act. Summaries of Court Actions report
cases involving seizure proceedings, criminal proceedings, and
injunction proceedings. Seizure proceedings are civil actions taken
against goods alleged to be in violation, and criminal and injunction
proceedings are against firms or individuals charged to be responsible
for violations. The cases generally involve foods, drugs, devices, or
cosmetics alleged to be adulterated or misbranded or otherwise violative
of the law when introduced into and while in interstate commerce.

Summaries of Court Actions are prepared by Food and Drug Division,
Office of the General Counsel, HHS, and are published by direction of
the Secretary of Health and Human Services.



SEIZURE ACTIONS


Food/Contamination, Spoilage, Insanitary Handling

PRODUCT: Pure Egg Noodles, imported, at Brooklyn, N.Y. (E.D.N.Y.); Civil
No. CV-95-0270.

CHARGED 1-19-95: While held for sale after shipment in interstate
commerce at Beluga Caviar International Foods, Inc., in Brooklyn, N.Y.,
the articles were adulterated in that they consisted of rodent excreta
and rodent hair, and they were held under insanitary conditions whereby
they might have been contaminated with filth--402(a)(3) and 402(a)(4).

DISPOSITION: A final order and judgment on default ordered the articles
destroyed. (F.D.C. No. 67038; S. No. 94-726-191; S.J. No. 1)


PRODUCT: Mushrooms, stems and pieces, at St. Cloud, Minn. (D.Minn.);
Civil No. 3-94-1629.

CHARGED 1-27-95: While held for sale after shipment in interstate
commerce at Cobarn's Inc., in St. Cloud, Minn., the articles were
adulterated in that they contained staphylococcal enterotoxin, and they
were prepared and packed under conditions which might have rendered them
injurious to health--402(a)(1) and 402(a)(4).

DISPOSITION: A default decree of condemnation, forfeiture and
destruction ordered the articles destroyed. (F.D.C. No. 67041; S. No.
94-742-475; S.J. No. 2)


PRODUCT: Tuna Loins, yellow fin, at Seattle, Wash. (W.D.Wash.); Civil
No. C94-1745.

CHARGED 11-23-94: While held for sale after shipment into interstate
commerce at Cityice Cold Storage Co., in Seattle, Wash., the articles
were adulterated in that they consisted of decomposed fish--402(a)(3).

DISPOSITION: A consent decree of condemnation, forfeiture and
destruction ordered the articles destroyed. (F.D.C. No. 67033; S. No.
95-737-665; S.J. No. 3)



Drugs/Human Use

PRODUCT: Aidex Antimicrobial Liquid Soap, Aidex Antimicrobial Cream,
Aidex Antimicrobial Aqueous Lotion, and Aidex Spray Cleaner, at Jessup,
Md. (D.Md.); Civil No. WN94-685.

CHARGED 3-18-94: This was a drug and device seizure. While held after
shipment in interstate commerce at Service Warehouse and Distribution
Co., Inc., in Jessup, Md., the articles were adulterated in that the
Aidex spray cleaner contained mold and an insect, and it was a class III
device without an approved application or investigational device
exemption--501(a)(1) and 501(f)(1)(B). The Aidex antimicrobial liquid
soap and aqueous lotion were non-compendial drugs whose strengths
differed from what they were represented to possess, and their labeling
falsely represented that they contained resorcinol--501(c) and 502(a).
The drugs failed to bear labeling containing adequate directions for
their intended purposes--502(f)(1). Information or notice regarding the
device was not provided at least 90 days prior to their introduction
into interstate commerce--502(o).

DISPOSITION: A stipulated order of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 66791; S. No. 93-623-9229; S.J. No.
4)


PRODUCT: Oxycodone and Aspirin, tablets, at Brooklyn, N.Y. (E.D.N.Y.);
Civil No. CV-93-2899.

CHARGED 6-30-93: While held for sale after shipment in interstate
commerce at Halsey Drug Co., Inc., in Brooklyn, N.Y., the articles were
adulterated in that the methods used in, and the facilities and controls
used for, their manufacture, processing, packing, and holding did not
conform to and were not operated and administered in conformity with
current good manufacturing practice requirements--501(a)(2)(B).

DISPOSITION: A consent decree ordered the articles destroyed. (F.D.C.
No. 66735; S. No. 93-726-092; S.J. No. 5)



CRIMINAL ACTIONS

DEFENDANTS: Quad Pharmaceuticals et al., at Indianapolis, Ind. (D.Md.);
Criminal No. 93-HAR-0147.

CHARGED 9-30-93: Count 1: The defendants, willfully and knowingly, (a)
made false statements and representations in matters within the
jurisdiction of FDA; (b) concealed material facts from FDA; (c) failed,
with intent to defraud, to establish and maintain required records; (d)
manufactured and introduced adulterated and misbranded generic drug
products into interstate commerce; and (e) corruptly influenced the
administration of law--18 U.S.C. section 371. 

Count 2: Defendant Dilip Shah, knowingly and willfully, made a material
false statement and representation to FDA in that he submitted separate
batch production records for a generic drug and stated that the batch
records reflected the manufacture by Quad of "two separate 10-liter
production batches" of the product, when only one 10-liter batch was
manufactured and was reprocessed so that it would appear that multiple
batches were manufactured--18 U.S.C. sections 2 and 1001.

Count 3: Defendants Dilip Shah and Raja Feroz, knowingly and willfully,
made a material false statement and representation to the FDA in that
they sent an annual report to FDA stating that in Quad's production of a
generic drug there were no changes to the manufacturing and control of
the drug that had not been already submitted and approved as a
supplemental application, when in fact Quad manufactured the product
using more anti-oxidant than was specified in the FDA-approved master
formula--18 U.S.C. sections 2 and 1001.

Count 4: Defendants Dilip Shah and Arun Kumar, knowingly and willfully,
concealed from FDA inspectors the existence of certain drug product
complaints, which are written records that must be maintained and made
readily available for inspection by FDA--18 U.S.C. sections 2 and 1001.

Counts 5-6: Defendants Raja Feroz, Arun Kumar, and Asad Ullah, with the
intent to defraud, introduced into interstate commerce quantities of a
generic drug which were adulterated in that the batch production records
were required to include complete information regarding the identity and
quantity of all components and materials used in the manufacturing
process and the results of all laboratory tests performed on the drugs;
however, the batch production records failed to disclose either the
addition of a residue into the batch of a previously manufactured batch
of the same product or the results of laboratory tests performed on the
residue prior to its addition--301(a), 303(a)(2), and 18 U.S.C. section
2. 

DISPOSITION: Dilip Shah pleaded guilty to one count of making a false
statement to FDA. He was sentenced to 46 months in prison and fined
$15,000. Dulal Chatterji pleaded guilty to two felony counts, one count
of obstructing a federal agency proceeding, and one count of conspiring
to defraud an agency of the United States. He was sentenced to 30 months
in prison and fined $100. Jan T. Strum pleaded guilty to concealing
material facts from FDA. He was sentenced to six months of
electronically monitored home confinement and fined $2,500. Andrew
Morris pleaded guilty to conspiring to defraud FDA and obstruction. He
was sentenced to 10 months in prison and fined $3,000. Arun Kumar
pleaded guilty to aiding and abetting the introduction into interstate
commerce of adulterated drug products with the intent to defraud. He was
sentenced to four months in prison and four months home detention.
(F.D.C. No. 65984; S.J. No. 6)


DEFENDANT: Jesus Rodriguez, d/b/a Farmacia de Watto, at Canovanas,
Puerto Rico (D.Puerto Rico); Criminal No. 94-040(RLA).

CHARGED 2-4-94: The defendant knowingly sold and offered to sell a
prescription drug that was clearly labeled "Sample--Not for
Sale"--301(t) and 303(b).

DISPOSITION: Guilty plea; sentenced to one year's probation and ordered
to pay a $50 special assessment. (F.D.C. No. 66548; S. No. 91-633-596;
S.J. No. 7)


DEFENDANT: Symbion, Inc., at Salt Lake City, Utah (C.D.Utah); Criminal
No. 94-CR-088G.

CHARGED 6-6-94: The defendant obtained investigational device exemptions
("IDEs") for its Total Artificial Heart and Acute Ventricular Assist
Device. As the sponsor of the IDEs, the defendant was required to
monitor the investigations and submit annual reports to FDA. The
defendant submitted an annual report which falsely represented that
Symbion fulfilled its own procedure and performed on-site monitoring
visits to the sites participating in the IDE studies--301(g) and
510j(g).

DISPOSITION: Guilty plea; fined $200,000 and ordered to pay a $250
special assessment. (F.D.C. No. 65990; S. No. 90-486-276; S.J. No. 8)



INJUNCTION ACTIONS

DEFENDANTS: Advance Medical Designs, Inc., Thomas E. Cottone Jr., Ronald
D. Arken, and Joseph R. Cottone Sr., at Marietta, Ga. (N.D.Ga.); Civil
No. 1-93-CV-2970.

CHARGED 12-27-93: While held for sale at Advance Medical Designs, Inc.,
in Marietta, Ga., the sterile equipment covers and transfer/decanting
devices were adulterated in that the methods used in, and the facilities
and controls used for, their manufacture, packing and storage were not
in conformity with current good manufacturing practice
regulations--501(h). The devices were also adulterated in that their
purity and quality fell below that which they purported to possess
because they were labeled "sterile" when they were not subjected to an
adequate sterilization process--501(c). The devices were misbranded in
that their labels were false and misleading because the devices were
labeled as "sterile" when they were not subjected to an adequate
sterilization process--502(a). The devices were also misbranded because
they were dangerous when used in the manner recommended or suggested in
their labeling because the devices are labeled as "sterile" when they
were not subjected to an adequate sterilization process--502(j). The
defendants introduced or caused to be introduced into interstate
commerce the adulterated and misbranded devices--301(a).

DISPOSITION: A consent decree of permanent injunction was filed, and the
defendants came into compliance with the decree. (Inj. No. 1330; S. No.
93-617-912; S.J. No. 9)



MISCELLANEOUS

ACTION: Back Technologies, Inc. v. Donna Shalala et al., at Everett,
Wash. (D.D.C); Civil No. 1:94CV02247.

CHARGED 10-19-94: Back Technologies, Inc., manufactured and marketed the
BACKTECH Back Machine, which claimed to relieve back and neck pain. The
device was not approved by FDA. FDA requested the company stop marketing
the exercise machine and submit the necessary applications for approval.
The firm failed to file a premarket approval application or a premarket
notification, yet continued to market the product--510e(a) and 510(k).

DISPOSITION: A memorandum opinion denied the plaintiff's request for
declaratory relief and granted the defendant's motion for summary
judgment. The plaintiff decided not to appeal the decision and will see
that future advertising and labeling for the product conforms with FDA's
requirements. (Misc. No. 1069, S.J. No. 10)

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