U.S. Food and Drug Administration
FDA Consumer magazine
September-October 2002
Table of Contents
Topics in This Issue:
Cancers of the colon and rectum (colorectal) are the fourth most commonly diagnosed cancers and rank second among cancer deaths in the United States.
The FDA has approved Eloxatin (oxaliplatin) injection for use with infusional 5-fluorouracil (5-FU) plus leucovorin. The combination treats people with colorectal cancer whose disease has recurred or become worse following initial therapy with a combination of irinotecan with bolus 5-FU plus leucovorin.
The combination with Eloxatin was shown to shrink tumors in some people and delay resumed tumor growth. There are no data yet on the effects of the combination on survival.
The FDA reviewed the marketing application for Eloxatin in seven weeks--the fastest review to date for a cancer drug. The agency was able to review and approve the drug rapidly because of "rolling review" procedures available under new drug applications that are designated as "fast track." Drugs in development that have the potential to be an advance in treatment for serious illness may be identified as "fast track" drugs. Under this designation, rolling applications allow for the submission of some parts of the application before remaining sections are submitted.
Eloxatin is intended for use by physicians experienced in the use of cancer agents. A warning, boxed in black for emphasis, details this use and highlights reactions associated with the drug.
Eloxatin can have a toxic effect on nerve endings that may result in either an acute or cumulative pattern of side effects. This may cause the feeling of numbness or tingling, especially in the hands and feet or around the mouth and throat. For some patients, these symptoms may be worsened by exposure to cold. Another side effect, which generally improves after treatment is complete, is difficulty performing ordinary daily tasks such as buttoning clothes.
Other common side effects of Eloxatin are vomiting, diarrhea, anemia, increased risk of bleeding or infection, or allergic reaction. Women should be advised to avoid becoming pregnant while receiving this treatment because it may harm the fetus.
Eloxatin will be distributed by Sanofi-Synthelabo, Paris.
The FDA has cleared a new laboratory test to measure cholesterol levels in the skin of adults with severe coronary artery disease.
Cholesterol 1,2,3, manufactured by International Medical Innovations Inc., of Toronto, can help determine the amount of cholesterol in skin using the palm of the hand. Other tests currently used by laboratories measure cholesterol from blood samples.
To do the palm cholesterol test, an applicator pad, much like an adhesive bandage, is placed on the palm of the hand. Drops of solution are added to the pad for three minutes. A hand-held reader attached to a computer reads the amount of blue color in the pad. The results are displayed on the computer screen. The deeper the blue, the more cholesterol is present.
Specifically, the new test is for people suspected of having severe coronary artery disease, defined as 50 percent closure of two or more arteries, and those with a history of heart attack. Cholesterol 1,2,3 is not intended to be used as a substitute for the standard blood tests, nor can it substitute for an evaluation of other risk factors used to identify coronary artery disease.
Skin contains about 11 percent by weight of all body cholesterol. When severe coronary artery disease is present, the numeric values obtained with the skin cholesterol test increases. The test was not shown to be useful in identifying people with less severe coronary artery disease, and should not be used as a screening tool to determine coronary artery disease risk in the general population.
The test cannot be used on people with skin diseases on the hand or on those who recently applied skin lotions or topical medications.
Health and Human Services Secretary Tommy G. Thompson has announced new efforts to expand research on the safety of herbal ephedrine alkaloids, commonly referred to as ephedra. Marketed in the United States as weight loss, energy, and sports supplements, ephedrine alkaloids are active chemicals found naturally in a number of plants. They can also be produced synthetically.
Adverse event reports have raised questions about the safety of these products, and the FDA has advised that further scientific research is needed. HHS recently funded the RAND Corporation to conduct a review of the existing science on ephedrine alkaloids, particularly in dietary supplements. The National Institutes of Health will use this information to guide an expanded research effort on the safety of ephedrine alkaloids.
Thompson also announced plans to aggressively pursue the illegal marketing of non-herbal synthetic ephedrine alkaloid products. In June, the FDA sent six warning letters to firms unlawfully selling these products over the Internet. The FDA also warned another company for illegally promoting its ephedrine product as an alternative to street drugs.
The firms that do not correct the violations described in the warning letters face further enforcement actions. This could include seizure of the illegal product and injunction from manufacturing and distributing the product, as well as prosecution of the companies and individuals.
"These products are not for everyone," says FDA Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D. "Consumers should read the labels carefully to ensure their proper use."
Consistent with industry standards and warnings that appear on many products, consumers under the age of 18 and women who are pregnant or nursing should not use these products. Consumers should consult a health-care provider before using such products if they are using a prescription drug or if they have ever had high blood pressure, heart or thyroid disease, a seizure disorder, depression, diabetes, difficulty urinating, prostate enlargement, or glaucoma.
Anyone using a monoamine oxidase (MAO) inhibitor (a drug used in the treatment of selected atypical depression) or any allergy, asthma, or cold medications containing ephedrine, pseudoephedrine, or phenylpropanolamine should consult with a physician before using dietary supplements containing ephedrine alkaloids. Phenylpropanolamine may also be found in over-the-counter (OTC) weight-loss products. Because of safety concerns, the FDA recommended in November 2000 that consumers stop using products with phenylpropanolamine and has proposed that it be removed from the market. Consumers may still have products containing the ingredient in their medicine cabinets.
Consumers should discontinue use of ephedrine alkaloids if any of the following symptoms are experienced: rapid or irregular heartbeat, chest pain, severe headache, shortness of breath, dizziness, loss of consciousness, sleeplessness, or nausea.
Thompson urged manufacturers to include the FDA's MedWatch telephone number, 1-800-FDA-1088, on product labels to encourage consumer reporting of adverse events.
The FDA is increasing its sampling of imported shrimp and crayfish (also known as crawfish) to check for the presence of the antibiotic chloramphenicol. The agency is taking this action because low levels of the drug in imported shrimp and crayfish have been detected by some states and other countries.
Chloramphenicol is a potent, broad-spectrum antibiotic used to treat serious infections in people. Federal regulations prohibit its use in food-producing animals and animal-feed products because it has not been possible to identify a safe level of human exposure to chloramphenicol.
"The FDA is concerned about any detection of chloramphenicol in shrimp and crayfish," says FDA Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D. "The agency will take whatever action is necessary to protect the public health."
FDA actions include issuing an import alert and directing inspectors to test seafood and refuse U.S. entry to any product identified and confirmed as containing more than 1 part per billion (ppb) of chloramphenicol, the lowest level currently detectable by FDA analysis methods. The agency is modifying its methods to detect 0.3 ppb, which will place U.S. methodologies in line with those used by Canada and the European Union.
The FDA is also working cooperatively with the states and other countries to share methods for determining levels of chloramphenicol in shrimp and honey, says Arnold Borsetti, Ph.D., a chemist and associate director for operations in the FDA's Center for Food Safety and Applied Nutrition. In July, the FDA held a conference call with officials in all 50 states. "We want to assure that information available to FDA, to include sampling and testing methodologies, is shared with all the states," says Borsetti. "Since there are may ports of entry for imported food products across the U.S., this information-sharing is very important to aid in the coordination and consistency of effort at both the federal and state level."
Because some states detected chloramphenicol in shrimp and crayfish imported from China and other southeast Asian countries, FDA and Chinese officials met in June to discuss these drug residues and exchange information on testing methods. Chinese officials informed the FDA that China has banned the use of chloramphenicol in animals and animal feeds. They are also testing shrimp, crayfish, and other animal-derived foods intended for export to ensure the absence of chloramphenicol and other drug residues.
The FDA will continue to work with other governments and state agencies to ensure the safety of the U.S. food supply.
The FDA has approved the first treatment for women with irritable bowel syndrome (IBS) whose primary symptom is constipation. Until this approval, medications were only available to treat women with IBS whose primary bowel symptom was diarrhea.
Zelnorm (tegaserod maleate), made by Novartis Pharmaceuticals Corp. of East Hanover, N.J., increases the movement of stools (feces) through the bowels, while drugs such as Lotronex (alosetron hydrochloride) for diarrhea-predominant IBS slow stool movement. Zelnorm also reduces pain and discomfort in the abdomen and reduces bloating and constipation, but it does not cure IBS, nor does it treat diarrhea-predominant IBS.
The drug has not been shown to be safe and effective in men.
IBS is a disorder of the intestine in which the intestine isn't functioning normally, but there is no sign of disease that can be seen or measured. Abdominal pain, cramps, gas, bloating, diarrhea and constipation are among the symptoms.
The adverse side effect most often associated with Zelnorm was diarrhea, but the majority of people treated with the new drug reported only a single episode. In most cases, diarrhea occurred during the first week of treatment.
On June 12, President Bush signed into law the reauthorization of the Prescription Drug User Fee Act (PDUFA) that will allow the agency to collect $1.2 billion over the next five years.
Health and Human Services Secretary Tommy G. Thompson says the reauthorization will help all Americans by providing more resources for the FDA to review new drug applications in a timelier manner.
"Americans deserve timely access to potentially lifesaving new drugs as soon as possible once they are proven safe and effective," Thompson said. "This law will ensure that the FDA has the expert staff and resources to promptly review applications and get safe, effective new drugs into the hands of the people who need them."
In 1992, Congress passed PDUFA, which gave the FDA the authority to collect fees from manufacturers seeking marketing approval. Any time a company wants to submit a new drug or biologic to the agency so the product can go on the market, the company must pay a fee to support the review process. In addition, companies pay annual fees for each manufacturing establishment and for each prescription drug product marketed. Previously, taxpayers alone paid for product reviews through budgets provided by Congress. In the PDUFA program, industry provides the funding in exchange for FDA agreement to meet drug-review performance goals, which emphasize timeliness.
The 1992 PDUFA expired in 1997, and the FDA Modernization Act of 1997 amended PDUFA and extended it through Sept. 30, 2002.
Fees collected under the reauthorization will enable the FDA to increase the staff of the drug review program by 450 full-time employees and to improve working conditions and training. Equally important is the authorization to spend $70 million of the user fees to increase the agency's surveillance of the safety of drugs during the first two years (or, for potentially dangerous medications, three years) on the market. It is during this initial period, when new medicines enter into wider use, that the agency is best able to identify and counter adverse side effects that did not appear during the clinical trials.
"PDUFA will be stronger and more effective than ever. With the additional resources and an enhanced ability to monitor safety of new drugs as they enter the marketplace, we're taking a step forward in transforming FDA into an even more efficient agency, while maintaining our high standards of safety," says FDA Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D.
The FDA has determined that a product called "nicotine water" is an unapproved drug under the Federal Food, Drug, and Cosmetic Act (FD&C Act) and cannot be marketed without new drug approval by the agency.
"FDA's decision underscores our commitment that consumers be protected from drug products that have not undergone our rigorous review process," says FDA Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D.
The FDA's decision was issued in response to a citizen's petition regarding the regulation of nicotine water. The petition, which was submitted to the FDA in December 2001, requested that the agency classify and regulate nicotine water as a drug or as a food containing an unapproved food additive under the FD&C Act. The petition was submitted on behalf of several groups, including the National Center for Tobacco-Free Kids, the American Medical Association, and the American Lung.
The FDA concluded that nicotine water is an unapproved drug under the FD&C Act because it is intended to treat or mitigate nicotine addiction as a smoking cessation product. Because nicotine addiction is considered a disease, the FDA requires safety and effectiveness data to support any claims intended to treat this disease.
The FDA also determined that the product cannot be legally marketed as a dietary supplement, as it was being promoted by the manufacturer. Under the FD&C Act, a "dietary supplement" does not include a product that contains an active ingredient that the FDA has already approved for use in a drug. Because the nicotine and nicotine polacrilex in nicotine water are both active ingredients in FDA-approved smoking cessation drugs such as Nicoderm CQ, Prostep, Habitrol, and Nicorette, nicotine water cannot be marketed as a dietary supplement.
The FDA will continue to monitor the marketplace to ensure that consumers are protected from unapproved drug products.
The FDA has approved labeling changes for Celebrex (celecoxib) based on the results of the Celecoxib Long-Term Arthritis Safety Study (CLASS).
CLASS evaluated about 4,000 people with osteoarthritis (OA) and rheumatoid arthritis (RA) treated with Celebrex at doses of 400 mg twice a day (twice the highest approved dose of Celebrex to treat RA), compared to about 4,000 people treated with standard doses of ibuprofen or diclofenac. These are non-steroidal anti-inflammatory drugs (NSAIDs).
The use of low-dose aspirin for prevention of heart attack and stroke (up to 325 milligrams per day) was permitted during the study.
The results of the CLASS study did not support a change in the label related to serious gastrointestinal (GI) events, but important information about the drug was obtained. Inclusion of patients on low-dose aspirin in the study was valuable for the safety assessment of Celebrex. But the use of aspirin, a drug known to cause stomach ulcers and bleeding, may have obscured the ability to accurately compare the GI safety of Celebrex to other NSAIDs.
The agency concluded that the drug labeling for Celebrex should continue to include the standard warning about risks associated with all NSAIDS, including risks of GI ulceration, bleeding and perforation.
The FDA also determined that safety data from CLASS should be incorporated into the labeling. The overall safety of Celebrex at twice the highest approved dose for rheumatoid arthritis was similar to commonly used doses of ibuprofen and diclofenac. Despite the high dose used, the rates of hypertension, swelling, and serious adverse events, including cardiovascular problems such as heart attacks, were no higher in people treated with Celebrex than in people treated with ibuprofen or diclofenac. People taking low-dose aspirin and Celebrex had a higher rate of upper GI events than those taking Celebrex alone.
The geriatric section of the labeling will include new information about the risk of serious GI and kidney effects in elderly people. Such findings have also been reported with other NSAIDs, and it is known that elderly people are at higher risk of GI ulcers and bleeding. Another observation reported in the labeling is that patients treated with Celebrex experienced less anemia than patients taking ibuprofen or diclofenac.
Pharmacia of Peapack, N.J., manufactures Celebrex. The drug was approved to treat rheumatoid arthritis and osteoarthritis in 1998.
In July, Wyeth Pharmaceuticals of Madison, N.J., announced that due to limitations in product component supplies, the company will no longer distribute the six-capsule Norplant System (levonorgestrel implants). The Norplant capsules are implanted under the skin of the upper arm and provide contraception for five years.
The FDA advises that women using the system contact their doctors about other contraceptive options to use after the five-year expiration date of their Norplant system. For women who prefer to have the Norplant capsules removed, Wyeth will pay for removal until December 31, 2002.
Wyeth also announced that women with Norplant capsules from certain lots may now safely stop using backup contraception. Previously, these women were advised to use backup contraception because of concerns about lower than expected release of the hormone levonorgestrel from several lots. Testing of the specified lots has not shown the effectiveness of the implants to be different from that seen in clinical trials and described in product labeling.
Norplant users who depend on condoms for protection against sexually transmitted diseases should continue to use them.
For more information, contact the Norplant System Information Line at 1-800-364-9809.
The FDA is alerting the public about Chinese weight-loss products, Chaso (Jianfei) Diet Capsules and Chaso Genpi, because they pose a potential public health risk.
The agency is alerting the public to this health risk because several people in Japan have become ill, and some have died, after consuming these diet products.
"FDA is taking this action as a precautionary measure to help assure that people are not exposed to this potentially dangerous product," says FDA Deputy Commissioner Lester M. Crawford, D.V.M., Ph.D.
Products of this type are often sold in small urban markets as alternatives to Western medicine. In 2001, the FDA issued a nationwide alert on the recall of 13 "Treasure of the East" herbal products because of a dangerous ingredient, aristolochic acid, which is toxic to the kidney.
The deaths in Japan linked to these Chinese weight-loss products may have resulted from the presence of such active drug ingredients as fenfluramine in the capsules.
Fenfluramine and another diet drug, phentermine, were used in combination for weight loss until it was determined that the combination of drugs was linked to valvulopathy, a serious and sometimes fatal heart disease. Fenfluramine and a chemically similar drug, dexfenfluramine, were removed from the market in 1997. Phentermine, when used alone, has not been associated with valvulopathy and remains on the market.
The FDA has advised its import operations personnel to be on the alert for Chaso Diet Capsules and Chaso Genpi.
The agency is urging consumers not to take these diet pills and to notify their local FDA office if the products are found in their area.
The FDA recently approved Xyrem (sodium oxybate or gamma hydroxybutyrate, also known as GHB) for treating a small population of people with narcolepsy who experience episodes of cataplexy--weak or paralyzed muscles. Because of safety concerns associated with the use of the drug, the distribution of Xyrem will be tightly controlled.
In the early 1990s, GHB was marketed purporting to be a dietary supplement for enhancing athletic performance and sexual activity and for inducing sleep. It was also abused as a recreational drug and is well-known for use in date rape. As a result of a number of serious adverse events, including death, the FDA intervened to prohibit the marketing of GHB.
Xyrem has been designated as a Schedule III controlled substance for medical use, meaning it cannot be sold, distributed, or provided to anyone other than for its prescribed use. Illicit use of Xyrem will be subject to penalties under Schedule I, the most restrictive schedule of the Controlled Substances Act.
The FDA approved Xyrem based on the results of two controlled clinical trials that showed that use of the drug reduced the number of cataplectic attacks compared to a placebo. Side effects associated with Xyrem include confusion, depression, nausea, vomiting, dizziness, headache, bedwetting, and sleepwalking. Abuse of Xyrem could also lead to dependence and severe withdrawal symptoms.
Narcolepsy affects about 120,000 people in the United States. This rare condition causes an irresistible tendency to fall asleep even in unlikely circumstances, such as in the middle of a conversation. Cataplexy, a symptom of this condition, is a sudden loss of muscular control and weakness usually triggered by emotions such as amusement, anger or excitement, and is estimated to affect about 20,000 to 50,000 individuals. The effects of cataplexy range from dropping of the jaw and slumping of the head, to buckling of the legs and even collapse of the whole body. These effects can last for a few seconds or up to many minutes.
Due to serious concerns and adverse events associated with the use of Xyrem, including some events that resulted in death, the FDA worked with the drug's manufacturer, Orphan Medical Inc., to design a comprehensive risk-management program. The program includes limited distribution, physician education, patient education, the creation of a patient and physician registry, and detailed patient surveillance. Under the program, prescribers and patients will be able to obtain the product only through a single centralized pharmacy. A Medication Guide, a special patient information brochure required by the FDA, further advises patients about proper use, administration and disposal of the drug. People who have further questions are advised to talk to their doctors or to call the central pharmacy at the toll-free number 1-877-67-XYREM (1-877-679-9736).
Xyrem is approved with orphan drug status, which is available for products to treat patient populations of 200,000 or fewer.
Orphan Medical Inc. of Minnetonka, Minn., will distribute the drug. Further information on Xyrem can be found on this Web site.
The FDA has approved Neotame for use as a general-purpose sweetener in a variety of food products. Depending on its food application, Neotame is 7,000 to 13,000 times sweeter than sugar. The non-nutritive, high intensity sweetener is made by the NutraSweet Company of Mount Prospect, Ill.
Examples of uses for which Neotame has been approved include baked goods, non-alcoholic beverages, chewing gum, confections and frostings, frozen desserts, gelatins and puddings, jams and jellies, processed fruits and fruit juices, toppings, and syrups. Neotame has not been approved for use in meat or poultry. Any proposed uses of food additives in meat, poultry or eggs must also be evaluated by the U.S. Department of Agriculture.
The FDA reviewed data from more than 113 animal and human studies to determine the safety of Neotame.
The FDA has cleared two glucose test meters that will allow people with diabetes to more easily track and manage their blood sugar levels through computer technology.
The FreeStyle Tracker Diabetes Management System, made by TheraSense Inc. of Alameda, Calif., and the Accu-Check Advantage Module, made by Roche Diagnostics Corp., of Indianapolis, each have two components with associated software. Both integrate parts of each company's currently marketed glucose meters and test strips with a Handspring Visor Personal Digital Assistant (PDA).
To use the systems, a person first inserts a glucose meter module into the handheld computer, then inserts a test strip into the meter. After collecting a blood sample, the user places it onto the test strip. The handheld computer reads the glucose levels from the measurement module, displays the results, and stores the information in an electronic database. The test results also can be uploaded onto a personal computer.
In addition to measuring and tracking glucose level, the new systems allow users to track a variety of other data that may affect their health, such as insulin usage, food intake, exercise, and medicine.
Despite its name, Botox Cosmetic is a drug and not a cosmetic (see "Botox Cosmetic: A Look at Looking Good," July-August 2002 FDA Consumer). The Federal Food, Drug, and Cosmetic Act defines drugs as articles intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease, and articles (other than food) intended to affect the structure or any function of the body. Drugs, including those used for cosmetic purposes, are subject to a strict FDA approval process to assess their safety and efficacy. Cosmetics (articles intended to be rubbed, poured, sprinkled, or applied to the body such as shampoos, makeup and moisturizers) do not undergo the same rigorous review. Increasingly, the word "cosmetic" is being used as a medical term to describe a number of surgical and non-surgical treatments that are intended to enhance appearance and are performed only by a licensed health-care professional. Botox Cosmetic is one such treatment.