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Updates

Injuries, Deaths Linked Again to GHB Abuse

After dozens of reports of injuries, including three deaths, were linked last year to GHB abuse, FDA has again warned that this chemical is unapproved and potentially dangerous.

GHB (gamma hydroxybutyric acid) has been promoted as a steroid alternative for bodybuilding and other uses for several years. (See "Steroid Substitutes: No-Win Situation for Athletes" in the December 1992 FDA Consumer.) Recently, it has gained favor as a "recreational" drug because of its intoxicating effects. Although GHB has undergone clinical testing for several indications, FDA has never approved it for sale as a medical product. It is illegal to produce or sell GHB in the United States.

In 1990, FDA began an intense investigation of GHB distribution after receiving reports of GHB-related illness, including vomiting, dizziness, tremors, and seizures. Many victims required hospitalization, and some died.

By the end of 1991, FDA and the Department of Justice had taken enforcement action against several firms and individuals involved in manufacturing, distributing and promoting GHB. The agency also instituted an automatic detention policy to prevent the import of GHB products. These actions--along with embargoes, public education campaigns, and other federal and state measures--appeared to diminish temporarily the distribution and abuse of GHB.

FDA has found that clandestine laboratories produced virtually all of the chemical accounting for the recent resurgence of GHB abuse.

FDA's Office of Criminal Investigations is working with U.S. Attorneys' offices to arrest, indict and convict individuals responsible for the illegal operations. FDA, the Centers for Disease Control and Prevention, and the Drug Enforcement Administration continue to monitor GHB abuse and to develop the most effective measures to protect the public health.

HIV Drug Approvals Increase
Options for Adults, Children

A new protease inhibitor for treating HIV infection--not only in adults but children, as well--has been approved by FDA. In addition, the agency has given "pediatric use" labeling to an already approved protease inhibitor for adults.

New protease inhibitor Viracept (nelfinavir) and the previously approved Norvir (ritonavir) are some of the most powerful medicines against HIV, the virus that causes AIDS.

FDA granted the approvals March 14. Viracept's approval came about three months after FDA received the drug application. Its labeling will include a "pediatric use" statement that gives doctors specific dosage recommendations for patients 2 to 13.

"[These] actions not only add another powerful weapon to our arsenal for treating HIV infection but provide us with critical information on using these cutting edge drugs to help HIV-positive children," HHS Secretary Donna E. Shalala said.

Viracept received "accelerated" approval, a regulatory mechanism in which FDA bases early approval for a product on laboratory markers (such as plasma HIV RNA, a measure of viral load) until clinical endpoints (such as disease progression or rates of death) are available.

The drug's "pediatric use" labeling stems from a 1994 regulatory reform measure designed to ease the process of including drug label information to help doctors treat pediatric patients with serious or life-threatening diseases. Pediatric labeling information can now be included when evidence suggests that the course of the disease and effects of a drug are similar in children and adults.

In clinical studies of up to 24 weeks, the new drug was active when used alone or with other antiretroviral drugs for HIV. But because its antiviral activity is increased when used with the other drugs, combination therapy is recommended.

The most common side effect is diarrhea, which can usually be controlled with over-the-counter medicines. Other side effects include nausea, vomiting and weakness.

The drug cannot be used concurrently with several other drugs because of possible drug interactions that cause serious, potentially life-threatening irregular heartbeats or prolonged sedation. The potential drug interactions will be clearly highlighted on the package label.

Viracept is marketed by Agouron Pharmaceuticals, of La Jolla, Calif. Norvir is marketed by Abbott Laboratories, of Abbott Park, Ill.

(See also "New Ways to Prevent and Treat AIDS," in the January-February 1997 FDA Consumer.)

Dietary Supplement Rule
Under Consideration

The question of whether FDA should establish regulations to institute current good manufacturing practices (CGMPs) for dietary supplements is being put forth to the public. The CGMPs would ensure that dietary supplements are made under conditions that will result in a safe and properly labeled product.

In an advance notice of proposed rulemaking published in the Feb. 6 Federal Register, FDA announced it would consider establishing CGMPs for dietary supplements if public comment suggested there was a need for such regulations. The agency also asked for comments on the kinds of requirements the regulations ought to include.

The comment period ends May 7, 1997. Written comments can be submitted to the Dockets Management Branch (HFA-305), Food and Drug Administration, 12420 Parklawn Drive, Room 1-23, Rockville, MD 20857.

FDA said in the Federal Register notice that it was considering CGMP regulations for dietary supplements because a "significant segment" of the dietary supplement industry had told the agency that such regulations would be helpful to ensure the products are safe for their intended use. Also, the Dietary Supplement Health and Education Act of 1994 states that FDA may prescribe CGMPs for dietary supplements.

The notice included draft CGMPs submitted to FDA by part of the dietary industry. FDA said the draft "provided an extremely useful starting point should FDA decide to proceed to rulemaking." The draft CGMPs cover, among other things, employee hygiene, disease control, building sanitation, proper maintenance of equipment and utensils, and production and quality control. FDA also included a series of questions on issues of interest to the agency that were not raised in the industry submission.

Dietary supplements include a broad spectrum of product forms and dietary ingredients, including vitamins, minerals, herbs, amino acids, and other substances used to supplement the diet.

Have Your Say

The public can comment on three FDA proposals featured in this issue:

Shot No Longer Only Choice for Impotence Drug

An alternative form of a previously approved drug to treat impotence is now available by prescription.

MUSE, manufactured by VIVUS Inc., Menlo Park, Calif., was approved by FDA last Nov. 19. The product is a single-use applicator pre-filled with a suppository of the drug alprostadil. FDA previously approved alprostadil in injectable form under the brand name Caverject. The drug creates an erection by relaxing the smooth muscle tissue and dilating the major artery in the penis, which enhances blood flow to the penis.

The user inserts the applicator about one inch into the urethral opening of the penis, where the drug is released, absorbed by the urethra, and transported to the surrounding erectile tissues. An erection will begin within eight to 10 minutes and may last 30 to 60 minutes. These times will vary from patient to patient.

The most common side effects of the preparation are:

Side effects seen less frequently are prolonged erection, swelling of leg veins, lightheadedness or dizziness, fainting, and rapid pulse.

Female partners of men who use MUSE may have mild vaginal itching or burning.

Men who have any of the following should not use MUSE:

Men who have been advised not to have sex should not use MUSE. Men should not use the product to have sexual intercourse with a pregnant woman unless the couple uses a condom barrier.

Impotent men and their partners can contact the Impotence Institute of America's help line at (1-800) 669-1603. (For more information on impotence, see also "Inflatable Penile Implants Under Scrutiny" in the January-February 1994 FDA Consumer and the article "First Impotence Drug" accompanying "Looking for Libido Lift? The Facts About Aphrodisiacs" in the January-February 1996 FDA Consumer.)

Virus-Free Hemophilia B Treatment Licensed

A new biological product to prevent or control potentially life-threatening bleeding in hemophilia B patients, including those who need surgery, has been licensed by FDA.

The product, BeneFix (recombinant coagulation factor IX), is produced in Chinese hamster ovary cells and, so, is free from the risk of transmitting viruses that can contaminate human blood plasma. The hamster cells have been modified to express the gene for the human blood component clotting factor IX.

Hemophilia B, also called Christmas disease, affects about 3,000 Americans who cannot form blood clots adequately because of a deficiency or defect in their clotting factor IX. Intravenous infusion of BeneFix or highly purified factor IX product from pooled human plasma temporarily corrects the defect.

Clinical trials showed that some hemophilia patients may need the hamster-derived factor IX at higher doses than are needed with plasma-derived products. During the trials, one patient developed low levels of antibodies that neutralized the product's effect, but the antibodies later disappeared. Another patient developed kidney damage, which may have been related to a blood clot.

Information about the new product's use in previously untreated hemophilia patients is limited. A clinical trial now in progress will follow 50 such patients up to five years. The sponsor also will follow previously treated patients for two years.

BeneFix is made by Genetics Institute, Cambridge, Mass.

(For more on hemophilia, see "Outlook Brighter for Youngsters with Hemophilia" in the July-August 1993 FDA Consumer.)

First Humanitarian-Use Device
Treats Fetal Urinary Blockage

An implantable fetal bladder stent to treat urinary tract obstruction in unborn babies is the first product approved under FDA's new rule for humanitarian use of medical devices.

Using a needle guided by ultrasound, the doctor threads the stent through the mother's abdomen into the bladder of the fetus. The stent, which remains in place for the duration of pregnancy, allows urine to drain from the fetus' bladder into the amniotic cavity. After the baby is born, the doctor removes the stent and performs any necessary corrective surgery.

Previous treatment consisted mainly of inserting a needle into the fetal bladder every couple of days to drain the urine.

FDA based its Feb. 14 approval of the stent on a small clinical study by the manufacturer, Cook OBGYN, Spencer, Ind., and on the probable benefits from 15 years of limited use in emergency situations. Under the new Humanitarian Device Exemption (HDE) rule, Cook may now market its stent commercially.

The rule offers manufacturers incentives to develop devices that treat conditions or diseases affecting fewer than 4,000 people in the United States annually, as is true with fetal urinary tract obstruction.

To receive HDE approval for the device, Cook had to show that:

Ordinarily, FDA requires manufacturers of new devices to provide results of controlled clinical studies showing that their products are safe and effective. Under the HDE rule, however, the agency exempts devices for rare conditions from this requirement. There are two reasons: The devices have a limited market, and the studies are often too costly for device manufacturers, many of which are small. So, while an HDE device must be proven safe, the manufacturer and FDA--with advice from a panel of experts--make a judgment of "probable" benefit and allow the device to go on the market, rather than wait for data from clinical studies to prove effectiveness.

An HDE device may be used only in a medical facility approved by a local institutional review board and used only for the specific rare condition or disease for which it has been approved. HDE approval is valid for 18 months, after which it can be extended in 18-month increments if certain criteria are met.

(See also "FDA Eases Way for Limited-Market Devices" in the "Updates" section of the October 1996 FDA Consumer.)

New Approach Proposed
To Regulate Human Tissue

To allow promising medical uses of human cells and tissues to benefit patients as soon as possible, FDA has proposed to regulate tissue products under a new approach that bases the amount of regulation on the degree of risk.

The agency intends to use its rulemaking process to phase in the requirements over the next few years.

Human tissues have been used in such varied medical procedures as skin replacement after severe burns, tendon and ligament repair after injury, and cornea replacement for damaged eyesight. Scientists are studying other innovative uses of human cells and tissues, including treatment of Parkinson's disease, diabetes, and viral infections (including HIV). Research continues into the use of "cord blood" from the placenta and umbilical cord to treat medical conditions.

The new approach has three general goals:

Novel products and extensively processed products would need FDA's approval before marketing, while products that present a low risk would be subject to little or no FDA regulation.

Most tissues would have to be handled according to "good tissue practices" established by the agency.

Tissue-processing facilities would have to register with FDA and list their products with the agency. Product labeling and promotion would have to be clear, accurate, balanced, and not misleading.

Some tissue-related medical products are not covered by the reform because they are regulated under existing or proposed FDA standards or rules or by other agencies. These products include blood products for transfusion, tissues taken from animals, human milk, collagen, and certain types of bone marrow.

The new approach is the sixth FDA reform under the Clinton administration's "Reinventing Government" initiative. The agency published a notice of the reform in the March 4 Federal Register.

To obtain FDA's "Proposed Approach to Regulation of Cellular and Tissue-Based Products," call the agency at (1-800) 835-4709 or (301) 827-1800. Or, go to http://www.fda.gov/cber/guidelines.htm on the agency's World Wide Web site. Because the document is recent, it is near the bottom.

FDA Actions Against Violations in Fiscal Year 1996

The information provided here is also presented in graph format (156K PDF document).

Free Backgrounders

Two new backgrounders are available free from FDA.

"Alpha Hydroxy Acids in Cosmetics" (BG 97-5) gives safety precautions on using certain cosmetics [Note (June 5, 2003): This document is no longer available]. "A Handbook for Requesting Information and Records from FDA" (BG 97-6) is an updated version of "How to Make a Freedom of Information Act Request to FDA."

To order single copies, write to FDA, HFI-40, Rockville, MD 20857, or fax your order to (301) 827-5308. Include the publication number.

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FDA Consumer magazine (May-June 1997)